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biology of cancer > Final Exam > Flashcards

Final Exam Flashcards

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AP® Biology flashcards
1
Q

How many types of cancer have been classified

A

Over 110

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2
Q

What is cancer?

A

characterized by unregulated cell growth
Due to mutations in DNA
Normal cells lose powerful genetic circuits regulating cell death and cell division
Invasion and spread of cells from the primary site to other sites in the body
It’s a clonally evolving disease

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3
Q

Imhotep

A

An Egyptian physician in 2625 BC described breast cancer in detail and described it as a distinct disease

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4
Q

Herodus

A

Greek historian who recorded the story of Atossa, the queen of Persia, who had a bleeding lump in her breast
A Greek slave named Democedes persuaded her to allow him to excise her tumor

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5
Q

The increase in life span has resulted in

A

an accumulation of mutations in our genome, and as a result an increase in cancer incidence in older people

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6
Q

Risk of Breast cancer

A

1 in 400 for a 30 year old woman

1 in 9 for a 70 year old woman

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7
Q

How do different types of cancer manifest (characteristics)

A

cancers of different origins have distinct features
Factors that cause cancer in each tissue is different
Differences in molecular mechanisms involved in different cancers
Treatments are different

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8
Q

Carcinomas

A

85% of cancers which occur in epithelial cells

Basal cell carcinoma, Ductal carcinoma, squamous cell carcinoma

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9
Q

Sacrcomas

A

Cancers that occur in the mesoderm

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10
Q

Adenocarcinomas

A

Cancers originating in the glandular tissue

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11
Q

Normal Cell characteristics

A 
Grow in monolayers
Exhibit contact inhibition
Cannot grow in low serum media
Flat and extended morphology
Grow attached to the substrate
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12
Q

Cancer cell characteristics

A 
Grow in piles of cells called foci
Do not exhibit contact inhibition
Can grow in low serum media
Round morphology
Exhibit anchorage independence
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13
Q

Neoplasia

A

New growth, not reversible

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14
Q

Dysplasia

A

Disordered growth, which is reversible, but often results in neoplasia

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15
Q

Tumor

A

abnormal growth of cells, can be benign or maignant

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16
Q

Cancer

A

Malignant neoplasm or tumors that invade nearby tissue

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17
Q

Benign Neoplasms

A

Small in size
Slow growing
Well-defined borders
Well differentiated

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18
Q

Malignant Neoplasms

A 
Large, Rapid growth
Poorly demarcated
Poorly differentiated
Increased nuclear to cytoplasmic ratios 
Nuclear hyperchromasia and prominent nucleoli
High Mitotic activity
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19
Q

Benign tumor

A

No evidence of cancer
Do not metastasize
Some can be life-threatening

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20
Q

Malignant tumor

A

Not encapsulated

Invades and metastasizes to other tissues

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21
Q

Benign and malignant epithelial tissues

A

Benign-Adenoma, Papilloma

Malignant- Adenocarcinoma, Papillary carcinoma

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22
Q

Mesenchyme Benign and malignant tissues

A

Benign-Fibroma, Lipoma

Malignant- Sarcoma

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23
Q

Melanocyte benign and malignant tissues

A

Benign- Nevus

Malignant- Melanoma

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24
Q

Lymphocyte benign and malignant tissues

A

Benign- N/A

Malignant- Lymphoma

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25
Q

Breast cancer sites of metastasis

A

Lungs, Liver, bones

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26
Q

Colon cancer sites of metastasis

A

Liver, Peritoneum, lungs

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27
Q

Kindey cancer sites of metastasis

A

Lungs, liver, Bones

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28
Q

Lung cancer sites of metastasis

A

Adrenal gland, liver, lungs

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29
Q

Melanoma cancer sites of metastasis

A

Lungs, Skin/muscle, liver

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30
Q

Why are malignant tumors life-threatening?

A

Physical obstruction
Invading other organs and compromise their function
Compete for nutrients and oxygen and produce waste products

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31
Q

In normal tissue, overall cell number in an individual is contributed by

A 
Cell proliferation (cell growth and division)
Apoptosis (Programmed cell death)
Cell Differentiation (Inactive phase of cell growth)
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32
Q

How can marijuana affect symptoms of cancer?

A

small studies showed marijuana effectiveness in treating nausea and vomiting

neuropathic pain

less of a need for pain medicine

THC and cannabinoids can slow growth and cause death in certain types of cancer cells

slow growth and reduce spread of some forms of cancer in animal studies

marijuana has not been proven to help control or cure the disease

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33
Q

Why would marijuana be harmful?

A 
Benzo(a)pyrene
Benz(a)anthracene
Phenols
vinyl chlorides
Nitrosamides
Reactive Oxygen species
Possibly posing greater danger to the lungs
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34
Q

Overall goal of cancer therapies

A

cytostatic and cytotoxic

The best drug is the one that can be used in the lowest dose with minimal side-effects

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35
Q

Therapeutic Index

A

• Value between minimum effective dose and
maximum tolerated dose
• The larger the value the better the drug
• Many drugs are given at maximum tolerated dose
(MTD)

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36
Q

Function of Chemotherapy

A

Target DNA, RNA, and Protein to disrupt the cell cycle

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37
Q

Main goal of chemotherapy

A

Cause DNA Damage and trigger Apoptosis

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38
Q

Side effects of Chemotherapy

A

Alopecia( loss of hair)
Ulcers
Anemia

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39
Q

Types of clinical trials

A

Observational

Interventional

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40
Q

Interventional clinical trials

A

the research subjects are assigned by the investigator to a treatment or other intervention, and their outcomes are measured

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41
Q

Observational studies

A

those in which individuals are observed and their outcomes are measured by the investigators

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42
Q

Phase I Clinical Trials

A

researchers test an experimental drug or treatment in a small group of people (20-80) for the first time To evaluate safety, determine a safe dosage range, and identify side effects.

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43
Q

Phase II Clinical trials

A

larger group of people (100-300) to see if it is effective and to further evaluate its safety

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44
Q

Phase III clinical trials

A

even larger groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the experimental drug or treatment to be used safely

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45
Q

Phase IV Clinical Trials

A

post marketing studies delineate additional information including the drug’s risks, benefits, and optimal use

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46
Q

A Gene

A

a specific stretch of DNA that programs the amino acid sequence of a polypeptide.

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47
Q

Parts of a Gene

A

▪ Promoter region
▪ Terminator region
▪ Start codon
▪ Stop codon

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48
Q

Operon

A
  • An operon is a collection of genes all under the control of the same promoter.
  • Genes in an operon tend to have related functions
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49
Q

Bases of DNA and RNA

A 
▪ Adenine (A)
▪ Guanine (G)
▪ Thymine (T)
▪ Cytosine (C)
Uracil (U) * RNA ONLY
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50
Q

Nucleotide Base Pairing

A 
The functional groups 
hanging off the base 
determine which 
bases pair up:
▪ A only pairs with T.
▪ G can only pair with C

Pure As Gold
CUT Purines to get Pyrimidines
CUT The PIE

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51
Q

Purines

A

Adenine and Guanine

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52
Q

Pyrimidines

A

Cytosine
Thymine
Uracil

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53
Q

___ is the genetic material for all organisms

A

DNA

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54
Q

What is coded in DNA

A

Genetic information

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55
Q

____ Directs the production of proteins needed for the structure and function of cells

A

DNA

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56
Q

Intermediate genetic molecule

A

RNA

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57
Q

Changes to DNA sequence may have

A

severe consequences for the cell and its progeny

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58
Q

Mutations can occur in our DNA due to

A

environmental agents and endogenous

processes during metabolism

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59
Q

Cells are equipped with defense mechanisms

against mutations, such as

A

the detection and repair of DNA damage

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60
Q

Where does transcription occur in eukaryotic cells?

A

Nucleus

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61
Q

Where does Translation occur in eukaryotic cells

A

Cytoplasm

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62
Q

Does mRNA processing occur in eukaryotic cells?

A

Yes

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63
Q

True or false: Eukaryotic cells do not have introns and exons

A

FALSE

Eukaryotic cells have introns and exons

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64
Q

Features of MRNA in eukaryotic cells

A

5’ Cap and Poly A Tail

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65
Q

Can one mRNA code for multiple proteins in eukaryotic cells?

A

No

This only applies in prokaryotic cells (within operons) and this means eukaryotic cells are monocistronic

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66
Q

True or false: Eukaryotic cells have polyribosomes

A

False

Polyribosomes are only present in prokaryotic cells

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67
Q

True or False: Eukaryotic cells do not have a formyl methionine

A

True

Formyl methionine is only present in prokaryotic cells

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68
Q

Where does transcription occur in prokaryotic cells?

A

Cytoplasm

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69
Q

Where does translation occur in prokaryotic cells?

A

Cytoplasm

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70
Q

True or False: mRNA is processed (with introns and exons) in prokaryotic cells?

A

False

mRNA processing only occurs in eukaryotic cells

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71
Q

True or false: mRNA in prokaryotic cells do not have a 5’ cap and poly-A Tail

A

True

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72
Q

In Prokaryotic cells, can one mRNA code for more than one protein?

A

Yes
This means they are polycistronic
This occurs in operons

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73
Q

Are Eukaryotic cells polycistronic or monocistronic?

A

Monocistronic:

Only one mRNA can code for each protein

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74
Q

True or False:

Formyl Methionine is present in Prokaryotic cells

A

True

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75
Q

True or false: Polyribosomes are absent in prokaryotic cells

A

False

Polyribosomes are present in prokaryotic cells

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76
Q

Promoter region is involved in

A

regulating the expression of genes

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77
Q

True or False:

A promoter cannot control when and where a gene is expressed?

A

False
Promoter controls when and where a gene is
expressed

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78
Q

The promoter region interacts with

A

with proteins that affect the activity of RNA polymerase

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79
Q

Tata Box sequence

A

TATAAAA

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80
Q

Tata Box

A

An important regulatory element for most genes

is able to define the direction of transcription and also indicates the DNA strand to be read

transcription factors can bind to the TATA box and recruit RNA polymerase

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81
Q

Where is the tata box located?

A

near the start site of transcription

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82
Q

Binding of Tata Box-binding protein (TBP) is important for what proces?

A

initiation of transcription

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83
Q

Response Element (RE)

A

a short sequence of DNA within a promoter that

is recognized by a specific protein and contributes to the regulation of the gene

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84
Q

Response elements can either be _____ or ______

A

enhancer elements (EE – enhance transcription) or Inhibitor elements (IE – inhibit transcription)

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85
Q

What are the types of point mutations?

A

Silent
Missense
Nonsense

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86
Q

Silent Mutation

A

Does not affect amino acid sequence

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87
Q

Missense Mutations

A

Amino acid changed; polypeptide altered

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88
Q

Nonsense Mutation

A

Codon becomes stop codon; polypeptide is incomplete

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89
Q

Nonsense codons or STOP codons

A

UAA, UAG, UGA – do not

code for amino acids

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90
Q

Frameshift Mutations

A

Deletions or insertions that result in a shift in the

reading frame, Often result in complete loss of gene function

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91
Q

insertion Mutation

A

addition of 1 base causes a frame shift

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92
Q

Deletion Mutation

A

removal of 1 base causes a frame shift

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93
Q

Transition Mutation

A
  • substitution of one purine with another purine

▪ substitution of one pyrimidine with another pyrimidine

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94
Q

Transversion Mutation

A 
substitution of one purine to another pyrimidine
T to A/G
C to G/A
A to T/C
G to C/T
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95
Q

Translocation

A

exchange of part of one chromosome with part of another chromosome

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96
Q

Burkitt’s Lymphoma Translocation

A

8: 14

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97
Q

Acute Myeloblastic Leukemia (AML) Translocation

A

8:21

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98
Q

Gene Amplification

A

a number of natural and artificial processes by which the number of copies of a gene is increased “without a proportional increase in other genes
Elephants have amplified p53 genes and often do not get cancer

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99
Q

Chromothripsis

A

when fragments of single shattered chromosome are pieced together

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100
Q

3 possible reasons for chromothripsis

A

▪ Ionizing radiation that leads to chromosome breaks
▪ Telomere dysfunction which may lead to end-end chromosome fusions
▪ Aborted apoptosis such that cells which have initiated DNA fragmentation survive

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101
Q

Biological effects of radiation on living cells results in 3 outcomes:

A
  • Injured or damaged cells repair themselves, no residual damage
  • Cells die, being replaced through normal biological processes
  • Cells incorrectly repair themselves, resulting in a biophysical change
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102
Q

Ionizing Radiation Types

A

Includes (α) alpha particles, (β) beta particles and gamma (γ) rays

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103
Q

Function of Ionizing radiation

A

Convert electrically neutral molecules into ions
▪ Cause radiolysis generating intermediates called reactive oxygen species (ROS)
▪ ROS may react with DNA or with other biomolecules and cause damage

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104
Q

Free Radicals

A

potent carcinogens because they can

cause oxidation of DNA by oxidizing DNA bases

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105
Q

8-oxoguanine

A

an oxidized guanine nitrogen base

▪ DNA polymerase mispairs 8-oxyguanine with adenine during replication of leading to G ->T transversion

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106
Q

DNA polymerase mispairs 8-oxyguanine with

A

adenine during replication of leading to G ->T transversion

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107
Q

UVA Damage mechanism

A

via free radicle-mediated damage

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108
Q

UVA Damage Process

A

Water is fragmented generating electron-seeking ROS that cause DNA damage and G → T transversion

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109
Q

cyclobutane pyrimidine dimers causes

A

a bend in DNA helix and DNA polymerase cannot read the DNA template

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110
Q

cyclobutane pyrimidine dimers causes

A

a bend in DNA helix and DNA polymerase cannot read the DNA template

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111
Q

TT dimers are often restored but

A

TC and CC

dimers result in TC→TT and CC → TT

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112
Q

UV damaged skin is eliminated by apoptosis familiar to us as

A

peeling of the skin after sunburn

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113
Q

Mutations in P53 is important in

A

initiation of squamous cell and basal cell carcinomas it provides important growth advantage

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114
Q

Mutations in what gene are found in 66% of malignant melanoma

A

BRAF Gene

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115
Q

Major Mutations identified in skin cancers

A

(T → A) in gene

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116
Q

First demonstration that chemicals can be used for inducing cancer

A

Polycyclic aromatic hydrocarbons (PAH’s)

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117
Q

What happens in Polycyclic aromatic hydrocarbons (PAH’s)

A

Additional rings and/or methyl groups in the bay region

convert inactive phenanthrene into active carcinogen

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118
Q

DMBA (7,12-dimethyl benz(a)anthracene)

A

one of the most potent carcinogens

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119
Q

Benzo(a)pyrene (BP)

A

well known carcinogen in cigarette smoke

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120
Q

CYP1A1

A

metabolizes BP in BP diol epoxides

• Cause G → T transversions

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121
Q

Aromatic Amines in cancer

A

Heterocyclic amines (HCA’s)
• About 20 HCA’s have been identified
• Are carcinogens produced by cooking meat formed from heated amino acids and proteins

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122
Q

Asbestos

A

a group of fibrous silicate minerals that was
used extensively in building materials.
• its association with several diseases of the lung,
including lung cancer and mesothelioma

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123
Q

Erionite

A

a fibrous zeolite mineral formed from volcanic

rock

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124
Q

_______ is an important line of defense against mutations caused by
radiation and endogenous mechanisms

A

DNA Repair

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125
Q

Mutations not fixed by DNA Repair Mechanisms

A

can contribute to carcinogenesis

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126
Q

5 types of DNA Repair Systems

A
  • One-step repair
  • Nucleotide excision repair (NER)
  • Base excision repair
  • Mismatch repair
  • Recombinational repair
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127
Q

One-Step Repair

A

Direct reversal of DNA damage

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128
Q

•N-methylnitrosourea
(Nitrosamines and
Nitrosamides)

A

damages guanine by adding alkyl group

Repaired with One-Step Repair

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129
Q

DNA alkyltransferase enzyme

A

directly removes alkyl group from O6 atom of guanine and adds to itself and gets inactivated
One-Step Repair mechanism

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130
Q

Nucleotide-Excision Repair (NER)

A

Specific for helix distorting lesions such as pyrimidine dimers caused by UVB
• Cuts out 24-32 bases of one strand with the help of
exonucleases and DNA polymerase fills the gap

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131
Q

Disease associated with Nucelotide Excision Repair (NER) mutation

A

Xeroderma pigmentosum (XP)

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132
Q

Two subpathways of NER

A

Global Genome NER

Transcription-Coupled-Repair

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133
Q

Global Genome NER

A

surveys genome for helix distortion

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134
Q

Transcription Coulpled Repair

A

surveys damage that interferes
with transcription
(NER Subpathway)

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135
Q

Mismatch Repair

A

Corrects errors that have escaped editing by polymerase and also repairs insertion and deletion mutations (frameshift)

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136
Q

Recognition of mismatch is carried out by what proteins?

A

MutS homolog 2 (hMSH2/3)

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137
Q

Mutations in hMSH2/3 or hMLH1 or hPMS1/2 causes

A

HNPCC

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138
Q

Hereditary non-polyposis colorectal cancer (HNPCC)

A

most common cancer syndrome in humans

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139
Q

Steps of Mismatch Repair

A

MutL homolog 1/ homolog 1, mismatch repair system
(hMLH1/hPMS1) and hMLH1/hPMS2 are recruited
• Newly synthesized strand with mutation is identified
• Endonucleases and exonucleases remove bases around and including mismatch
• DNA polymerase synthesizes new strand

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140
Q

HNPCC Characteristics

A
  • HNPCC – Lynch syndrome
  • It is a autosomal dominant (AD) mutation disease
  • if you inherit the abnormal gene from only one parent, you can get the disease.
  • AD mutation in mismatch repair leading to microsatellite instability.
  • 80% progress to cancer.
  • Cancer of proximal colon
  • Increases your risk of other cancers
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141
Q

Recombination Repair Types

A

Homologous Recombination

Non-Homologous End Joining

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142
Q

Homologous recombination depends on

A

The presence of Sister Chromatids

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143
Q

Non-Homolgous-End-Joining

A

Does not depend of presence of sister chromatids and can lead to frame shift mutation and chromosomal translocation

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144
Q

A double-Strand break activates

A

ataxia telangiectasis mutated (ATM) kinase

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145
Q

The RAD50/MRE11/NBS1 complex uses its 5’ → 3’

exonuclease activity to

A

create single-stranded 3’ ends

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146
Q

Breast cancer type1/2 (BRCA1/2) aids in

A

the nuclear transport of RAD51

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147
Q

RAD52 facilitates

A

RAD51 binding to these exposed ends to form a nucleoprotein filament

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148
Q

RAD51 can

A

exchange a homologous sequence from a single strand within a double-strand molecule with a single-stranded sequence

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149
Q

Resolvace restores the junctions formed as a result of homologous recombination, called

A

Holliday Junctions

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150
Q

Alkylating drugs and platinum based drugs

A
  • They have similar mode of action

* They form DNA adducts by covalent bonds via an alkyl group

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151
Q

Chlorambucil

A

is a member of nitrogen mustard family of

drugs

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152
Q

Alkylating drugs and platinum based drugs Target

A

N7 position of guanine forming intra-strand and inter-strand cross-linking preventing the separation of DNA strands and interfere with replication

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153
Q

Cyclophosphamide

A

requires metabolic activation within the body
-Oxidases in liver produce an aldehyde form that
decomposes to yield an active form called phosphoramide mustard

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154
Q

Cisplatin and Carboplatin

A

are platinum-based drugs that form covalent bonds via platinum atom

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155
Q

Cisplatin and Carboplatin method

A

The molecule binds to N7 position of guanine and adenine in its DNA target
• The GG, AG and GXG adducts comprise over 90% of the total resulting in apoptosis

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156
Q

Pros and Cons of Cisplatin and Carboplatin

A

Works well with ovarian cancer but has irreversible kidney damage hence carboplatin

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157
Q

Antimetabolites

A

are structurally similar to nitrogen bases of DNA and inhibit role and nucleic acid synthesis

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158
Q

Examples of Metabolites

A

Fluorodeoxyuridylate (F-dUMP) and Methotrexate

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159
Q

F-dUMP competes with

A

dUMP for the catalytic site of thymidylate synthase , the enzyme that produces thymidylate (dTMP), inactivating the enzyme through covalent modification

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160
Q

Methotrexate is a competitive inhibitor of

A

dihydrofolate reductase (DHFR) required in thymidylate synthase reaction

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161
Q

Doxorubicin

A

a fungal anthracycline antibiotic that inhibits topoisomerase II enzyme

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162
Q

Topoisomerase II Enzyme

A

releases torsional stress during DNA replication, by trapping single-strand and double strand DNA intermediates

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163
Q

Uses and Side Effects of Doxorubicin

A
  • Cardiac damage is its most sever side effect

* Used for treating solid tumors (breast or lung)

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164
Q

Mechanisms of drug resistance

A

Increase the efflux of drugs
• A family of ATP-dependent transporters that are involved in the movement of nutrients and other molecules across membrane

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165
Q

The multiple-drug resistance gene (MDR1) codes for

A

P-glycoprotein (P-gp) which can bind to drugs such as doxorubicin, vinblastin and taxol and release the drug extracellularly

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166
Q

Transcription Factors

A

proteins that bind to gene promoters and regulate transcription

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167
Q

Transcription factors contain

A

a set of independent protein modules or domains, each having a specific role important for the function
of transcription factors.

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168
Q

Transcription Factor Domains

A

▪ DNA-binding domains
▪ Transcriptional activation domains
▪ Dimerization domains
▪ Ligand-binding domains

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169
Q

Transcriptional activation domains

A

function by binding to other components of the transcriptional apparatus in order to induce transcription by RNA polymerase

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170
Q

Dimerization domains

A

Some transcription factors work in pairs (“dimer”) and require a dimerization domain which facilitates protein-protein interactions between the two molecules

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171
Q

Ligand-binding domains

A

Some transcription factors only function upon binding of a ligand and therefore require a ligand-binding domain.

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172
Q

The activity of a transcription factor can be

regulated by several means

A

▪ Synthesis /localization in particular cell types only
▪ Covalent modification such as phosphorylation
▪ Interaction with partner proteins
▪ Ligand binding

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173
Q

AP-1 is itself activated in response to

A

specific signals such as growth factors, ROS, and radiation

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174
Q

AP-1 binds

A

either to the 12-0-tetradecanoylphorbol13-acetate (TPA) response element or the cAMP response element in the promoter region of their target genes

That interaction controls the processes of growth, differentiation, and death, and plays a role in carcinogenesis

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175
Q

The AP-1 transcription factor is actually composed of

A

two components and can be produced by dimers of proteins from the Jun (Jun, Jun B and Jun D) and Fos families (Fos, Fos B, FRAl, and FRA2)

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176
Q

Steroid hormones are lipid-soluble signaling

molecules that exert their effects by regulating

A

the transcription of sets of genes via specific receptors.

Can result in self-sufficiency growth signals

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177
Q

DNA is wrapped around proteins called

A

Histones

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178
Q

Histones are basic proteins with

A

A positive charge

which allows them to combine with negative charged DNA

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179
Q

Function of Histones

A

package and protect DNA

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180
Q

The simplest or primary level of organization of chromatin is

A

the wrapping of DNA around a protein “spool” and is referred to as the “beads on a string” array.

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181
Q

What does beads on a string mean?

A

The beads represent the nucleosome, which contains 147 base pairs (bp) of DNA wrapped 1.7 times around a core of histone proteins

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182
Q

The histone core is an octomer of histones containing

A

two copies of histones H2A, H2B, H3, and H4.

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183
Q

Each histone contains domains for

A

▪ histone-histone
▪ histone-DNA interactions
▪ NH2 -terminal lysine-rich
▪ COOH-terminal “tail” domains

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184
Q

Epigenetics refers to

A

heritable changes that is encoded by modifications of the genome and chromatin components.

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185
Q

Can Epigenetic changes cause a change in nucleotide sequence?

A

NO
They do not cause a change in the nucleotide
sequence of the DNA and therefore are not
mutations.

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186
Q

Epigenetic changes are influenced by

A

how DNA gets wraparound histones making genes readable or unreadable

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187
Q

Epigenetics instructs cells on

A

how to differentiate and develop

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188
Q

Two types of epigenetic mechanisms

A

▪ Histone modifications

▪ DNA methylation

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189
Q

Covalent posttranslational modifications (PTM) to histone proteins

A

can alter gene expression by altering chromatin structure

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190
Q

Histone proteins are subject to

A

diverse post-translational modifications
▪ Acetylation (Add Acetyl Group)
▪ Methylation (Add Methyl Group)
▪ Phosphorylation (Add Phosphorus Group)
▪ Ubiquination (Tag for degredation) via proteasome

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191
Q

Acetylation plays an important role in the following

A 
▪ Transcription 
▪ DNA replication and repair
▪ Cell cycle progression
▪ Differentiation
▪ Gene silencing
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192
Q

HAT

A

Histone Acetyltransferase

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193
Q

HDAC

A

Histone Deacetylases

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194
Q

DNA methyltransferases (DNMTs)

A

mediate the covalent addition of a methyl group

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195
Q

DNA methylation

A

the addition of a methyl group to position 5 of cytosine.

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196
Q

Methylation or demethylation can

A

turn gene on or off

Causing repression or activation of genes

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197
Q

Histone Phosphorylation

A

a transient histone modification induced by

extracellular signals such as DNA damage

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198
Q

Histone Phosphorylation is associated with various biological processes

A

▪ DNA damage response
▪ DNA repair
▪ Apoptosis
▪ Chromatin compaction

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199
Q

The 3’ end of the parental chromosomal DNA is not

replicated and thus chromosomes

A

progressively erode during each round of replication

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200
Q

When the chromosomes reach a threshold length

A

cells enter a stable and irreversible state of growth

arrest called cellular senescence

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201
Q

If cells bypass this stage because of mutation and
telomeres become critically short, chromosomal
instability results and apoptosis is induced

A

Cellular scenscence

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202
Q

Telomeres are composed of

A

several thousand repeats of the sequence TTAGGG bound by a set of associated proteins called the shelterin complex, which functions to control telomere length and protect the
chromosomal ends.

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203
Q

Telomeres shorten

A

by 100-200 bases with each round of DNA replication owing to the limits of DNA polymerases during DNA

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204
Q

Telomerase, a ribonucleoprotein containing human

telomerase reverse transcriptase activity (hTERT) and a human telomerase RNA (hTR)

A

maintain telomere length in certain cell types, such as stem cells

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205
Q

The hTERT contains

A

11 complementary base pairs to the
TTAGGG repeats and acts as a template for the reverse transcriptase to add new repeats to telomeric DNA on the 3’ ends of chromosomes.

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206
Q

Several oncogenes have been demonstrated

to regulate the expression of

A

Telomerase

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207
Q

the transcription factor c-myc ( an oncogene) increases the expression of

A

the hTERT gene via specific response elements in

the promoter region

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208
Q

miRNA (Micro RNA)

A 
• ~50-70 nucleotides long
• Endogenous RNA
• They are part of our genome 
• Coded by our own genes
• Post-transcriptional regulation of 
genes
• Conserved
• Production and processing involves 
nucleus and cytoplasm
• Full complementarity is not needed
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209
Q

siRNA

A
  • Long double stranded RNA
  • Exogenous RNA
  • Not part of our genes
  • Viral origin or from transposons
  • Post-transcriptional regulation of genes
  • Not conserved
  • Processing happens in cytoplasm
  • Requires full complementarity
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210
Q

MicroRNAs (miRNAs)

A

small, non-proteincoding RNAs (18-25 nucleotides in length) that regulate the expression of mRNAs

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211
Q

Each miRNA may be able to

A

repress hundreds of gene targets post-transcriptionally

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212
Q

miRNAs (micro RNAs) are products of

A

dsRNAs encoded in genes of our genome

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213
Q

MiRNA do not require full complementarity to

A

bind with target mRNA, e.g. one type of miRNA may
regulate many genes, as well as one gene can be
regulated by several miRNAs

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214
Q

siRNAs (short interfering RNAs)

A

products of double-stranded RNAs, which can have viral origin
Silence genes by the same mechanism as miRNA (Micro RNA)

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215
Q

MicroRNA (miRNA) Processing

A

▪ After they are transcribed by RNA polymerase II from intergenic regions or from regions that code for introns, the primary transcript is processed by ribonucleases Drosha and DGCR8 in the nucleus.
▪ This processing produces pre-miRNAs, hairpin-shaped intermediates of 70-100 nucleotides.
▪ Exportin-5 transports pre-miRNAs into the
cytosplasm where they are further processed by
ribonuclease Dicer into a double-stranded miRNA.
▪ The strands separate and a mature single-stranded molecule joins a RNA-induced silencing complex (RISC).

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216
Q

MicroRNA (miRNA) Repression

A

▪ The miRNA hybridizes perfectly to the 3’
untranslated region (UTR) of their target mRNA.
The formation of this complex in the RISC leads to mRNA cleavage and subsequent degradation.
▪ Alternatively, miRNAs may bind to imperfect
complementary sites in the 3’ UTR of their target
mRNAs. The formation of this complex in the
RISC blocks translation.

217
Q

Net Result of miRNA

A

a decrease in the amount of the protein encoded by the gene from which the mRNA has been transcribed

218
Q

Inhibitors of histone deacetylases

A

Several classes of drugs that bind to the catalytic site of HDACs and block the binding to their substrates (acetylated lysines of histone proteins) are used

▪ Short-chain fatty acids such as sodium n-butyrate;
hydroxamic acids such as SAHA; cyclic peptides such as romidepsin (formerly FK-228); and benzamide derivatives such as entinostat.

219
Q

sodium n-hydroxamic acids SAHA (vorinostat; Zolinza™)

A

have been approved by the FDA for use in the clinic for Cutaneous T cell lymphoma

220
Q

Cell growth is regulated by many external and internal signals and involves the following steps

A
  1. Extracellular growth factors must bind to specific receptors
  2. Signals must be transduced across the membrane and into cell
  3. Signal must be conducted through cytoplasm
  4. Signal must reach nucleus
  5. Genes involved cell replication are transcribed
  6. Proteins involved in cells replication are translated
  7. Translated proteins must interact with other proteins resulting in cell division
221
Q

Four types of proteins involved in transduction

of growth factor signals

A

▪ Growth factors
▪ Growth factor receptors
▪ Intracellular signal transducers
▪ Nuclear transcription factors (regulate gene expression)

222
Q

Kinases

A

are enzymes that catalyze the transfer of gamma phosphate group from ATP/GTP to hydroxyl groups on a specific amino acid in a target group

223
Q

Serine/threonine kinases

A

phosphorylate serine and threonine residues in target proteins

224
Q

Tyrosine kinases

A

phosphorylate tyrosine residues in target proteins

225
Q

Phosphatase

A

is an enzyme that removes phosphate group from a specific amino acid in a target group

226
Q

The addition / removal of the phosphate group

may

A 
▪ Serve as a recognition site for new protein-protein 
interactions 
▪ May cause conformational change 
▪ Result in the activation 
▪ Inactivation of an enzyme activity
227
Q

EGF binds to domains i and iii and then

A

Causes conformational change in receptor and results in domain iii binding to EGF
▪ This exposes domain ii and helps it to form a dimer with another EGF bound to EGFR

228
Q

Autophosphorylation

A

Dimerization enables the kinase domains of one receptor to phosphorylate the other receptor and vice versa
▪ The change in receptor conformation permits access to ATP and substrate to the catalytic kinase domain

229
Q

Autophosphorylation is crucial for

A

recruitment of cytoplasmic proteins
At this step signals from outside the cell have been
transduced to inside the cell

230
Q

Mechanisms of Termination include

A

• Additional phosphorylation and conformational change
• Dephosphorylation of tyrosine residues by tyrosine
phosphatase
• Binding of negative regulators (ERRF1 -ERBB receptor
feedback inhibitor 1 or RALT)
• Receptor endocytosis and degradation

231
Q

Autophosphorylation exposes

A

domains in intracellular fragment of EGFR which act as docking sites for recruitment of other specific intracellular proteins

232
Q

Grb2 (Growth factor receptor-bound protein 2)

A

an intracellular protein that contains one SH2 and two SH3 domains

233
Q

Grb2 binds to EGFR with its SH2 domain and two SH3 domains

A

interact with exchange protein son of sevenless (SOS)

234
Q

SOS facilitates the activation of

A

the pivotal intracellular transducer RAS

235
Q

RAS Activation

A

They are “star players” in regulating cell growth

▪ They are responsible for integrating growth factor signals from membrane to nucleus

236
Q

RAS family has 3 members

A

N-,H- and K-RAS. These are most common oncogenes

237
Q

Ras and GTP

A

RAS are are GTP-binding proteins and are activated when bound to GTP and inactivated when bound to GDP

238
Q

SOS catalyzes

A

the exchange of GDP→ GTP and GTPase activating protein (GAPs) catalyzes the hydrolysis of GTP → GDP

239
Q

Steps for RAS Activation

A

▪ RAS-GTP binds to and contributes to the activation of serine/threonine kinase RAF
▪ Activated RAF (rapidly accelerated fibrosarcoma ) phosphorylates MEK
▪ Activated MEK phosphorylates another family of serine/threonine kinase mitogen-activated protein kinase (MAPK Mitogen-Activated Protein Kinase or
ERK -extracellular signal–regulated kinases
▪ MAPK affects the activity of transcription factors via phosphorylation
▪ RAF and MEK are cytoplasmic links between RAS and MAPK

240
Q

group of proteins that bind to DNA and regulate

the expression of genes involved in growth, differentiation and death

A

Transcription Factors

241
Q

Examples of Transcription Factors

A

AP-1 family (Jun and Fos) and Myc family (Myc, Max,

Mad and Mxi) of transcription factors which control genes, involved in growth, differentiation and death

242
Q

AP-1 gene transcription factor is target of

A

MAP-Kinase

243
Q

AP-1 gene products activate

A

cyclin D genes which are critical regulators of cell cycle

244
Q

Knowledge of EGFR signaling and other pathways have led to development of

A

many therapeutics targeting individual components

245
Q

Herceptin (trastuzumab)

A

a monoclonal antibody that binds the extracellular domains of ErB2 receptor with high affinity

246
Q

Herceptin functions through

A

a combination of mechanisms including enhanced receptor degradation, inhibition of angiogenesis, cell proliferation and recruitment of immune cells, resulting in antibody-dependent cellular cytotoxicity

247
Q

Erbitux

A

another drug has 5 mechanisms of action
Cell cycle arrest of cancer cell and inhibits proliferation,
prevents metastasis, inhibits angiogenesis, antibodydependent cellular cytotoxicity, and inhibits DNA repair mechanisms

248
Q

Iressa and Tarceva (erlotinib)

A

small molecule kinase inhibitors that are directed against tyrosine kinase activity of EGFR family members

249
Q

The Reagent ISis5132 (Phase 1 clinical trials) uses

A

sense oligonucleotide against Raf mRNA resulting in
formation of RNA hybrid

The RNA hybrids are most likely targeted for degradation or block translation and result in reduction of Raf protein

250
Q

Nexavar (Sorafenib)

A

approved for renal cancer is a serine/threonine kinase inhibitor

251
Q

Normal cellular genes that can be converted to

oncogenes are referred to as

A

proto-oncogenes

252
Q

Proto-oncogenes are

A

Not “bad genes”

These are normal genes that make essential contributions to the regulation of cell proliferation and survival

253
Q

RAS proto-oncogene normal gene produces

A

normal protein that controls proliferation

254
Q

Mutations in RAS proto-oncogene can

A

transform it into RAS oncogene which can cause cancers due to uncontrolled proliferation

255
Q

Oncogenes

A

are genes whose presence can contribute to uncontrolled cell proliferation and cancer

256
Q

What type of inheritance pattern do Oncogenes display

A

Dominant mutations

257
Q

How many oncogenes have been discovered?

A

More than 100 oncogenes have been identified and

proteins they produce fall into different categories

258
Q

What function do oncogenes usually have?

A

They are usually growth factor receptors, growth
factors, enzymes that catalyze phosphorylation, and
transcription factors

259
Q

Most proteins produced by oncogenes are

components of signaling pathways that

A

promote cell proliferation survival

260
Q

Mechanism of oncogenes

A

producing abnormal amounts they interfere
with the normal signaling mechanisms and foster
excessive proliferation and survival of cancer cells

261
Q

Point mutation are mutations in

A

A single nucelotide

262
Q

Single mutation in RAS proto-oncogene results in

A

RASoncogene that produces mutated Ras protein in which single amino acid is converted from glycine to valine

263
Q

RAS oncogene point mutations have been observed in

A

many types of cancers such as bladder, lung, colon and pancreas

264
Q

What can convert proto-oncogenes to oncogenes

A

Point Mutations
Gene Amplification
Chromosomal Translocation

265
Q

Gene amplification

A

creating multiple duplicate copies of the same gene
Results in abnormal amounts of protein
chromosomes have a distinct abnormal appearance when stained

266
Q

What is the most common oncogene

A

MYC Gene

267
Q

Neuroblastoma with extensively amplified MYC gene

A

are more likely to invade and metastasize and lower survival rates

268
Q

Gene Amplification in breast cancers

A

also seen in ERBBs (HER2) gene in 25% of breast cancers

269
Q

Chromosomal translocation

A

Process in which a piece of one chromosome is broken off and moved to another chromosome

270
Q

Philadelphia chromosome

A

abnormal version of chromosome 22 in 90% of all cases of chronic myelogenous leukemia

271
Q

Translocation of ABL gene (tyrosine kinase) in chromosome 9 to BCR gene (Serine/threonine kinase) on chromosome 22 and results in

A

abnormal BCR-ABL fusion gene and fusion protein

272
Q

Autophagy

A

Self-eating
-Involves degradation of proteins and lipids in cells
through autophagosomes
-Also involves degradation of organelles (mitophagy,
reticulophagy, nucleophagy, lipophagy, xenophagy)

273
Q

a mechanism used for recycling nutrient subunits
in cells and waste clearence
▪ Helps in maintaining cellular homeostasis inside a
cell
▪ Also helps in cell death
▪ Plays a critical role in health and disease in our body

A

Autophagy

274
Q

Process of autophagy

A

▪ Starts with ER and formation of preautophagosome

▪ Matures into autophagosomes and fuses with lysosomes in cells

275
Q

Activation signals for autophagy are triggered by

A

starvation
cellular stress
infection

276
Q

Proteins involved in autophagy

A

LC3, Beclin-1, and ULK

277
Q

Autophagy is inhibited by

A

▪ Cell growth and proliferation
▪ Excess cellular energy
▪ mTOR and PI3K complex

278
Q

Necrosis

A

a passive form of cell death that happens in injured tissue or organs

279
Q

Is ATP needed for necrosis?

A

No, it is passive (requires no ATP)

280
Q

Characterisitics of Necrosis

A 
▪ It involves group of cells
▪ Involves extrinsic stimuli
▪ Increase in cell size
▪ Cell membrane damage is involved
▪ Involves local inflammatory responses
▪ No cellular markers
-Passive
281
Q

Apoptosis

A

▪ Active cell death that happens in normal cells and diseased organs

282
Q

Characterisitics of Apoptosis (#1)

A 
Active cell death in normal cells and diseased organs
▪ Need ATP for this process
▪ Involves a single cell
▪ Programmed cell death
▪ Decrease in cell size
▪ Cell membrane is intact
▪ Does not trigger local inflammatory responses or absent
▪ Involves annexin V
283
Q

True or false: Apoptosis causes the cell to explode and causes inflammation

A

FALSE:

It is organized, neat, and tidy, leaving behind little
evidence of the preexisting cell

284
Q

A special group of proteases called ________ play

main role in apoptosis.

A

Caspases

285
Q

Characteristics of Apoptosis (#2)

A 
▪ Cell shrinking
▪ Cytochrome C release
▪ Inversion of phosphatidyl serine from inside cell to 
outside
▪ Membrane blobbing and budding
▪ Chromatin condensation
▪ Precise fragmentation
286
Q

Caspases

A

They are cysteine-rich aspartate proteases
(caspases)
▪ They are proteases that recognize and cleave
at aspartate residues.

287
Q

How many mammalian caspases have been identified?

A

13

288
Q

How are caspases synthesized?

A

Synthesized as inactive enzymes (procaspase)

which when cleaved at aspartate residues results in activation of enzymes (caspase).

289
Q

caspases participate in a cascade of activation, activating

A

downstream caspases and amplifying the signals

290
Q

Cells may be induced to undergo apoptosis by

A

Extracellular signals

Internal or chemical signals

291
Q

Extracellular Signals in apoptosis

A

• Death factors can be soluble – TNF tumor necrosis
factor.
• Membrane bound – Fas ligand bound to neighbouring cells or certain immune cells.

292
Q

Internal signals in apoptosis

A

DNA damage or oxidative damage (ionizing radiation- reactive oxygen species)

293
Q

Cell stress signals/DNA damage active ATM/ ATR kinases which in turn activate

A

Chk1/Casein Kinase II

294
Q

CHk1/Casein Kinase II disrupt

A

p53-MDM2 complex, which activates P53 protein

295
Q

P53 activates BAX protein, which in turn

A

Activates and binds to BID protein

296
Q

The conformational change in BAX causes

A

BAX to insert into the outer mitochondrial membrane and oligomerize (6-8 molecules)

297
Q

In apoptosis, the mitochondria releases

A

Cytochrome C and Procaspase 9 into the cytoplasm

298
Q

In apoptosis, Cytochrome C is released, what happens

A

Procaspase 9 is released with cytochrome C and binds with APAF-1 to form the apoptosome

299
Q

Caspase aggregation leads to

A

the activation of procaspase 9 which in turn triggers caspase cascade activating caspase 3

300
Q

Caspase 3 cleaves

A

target proteins and causes apoptosis of cell

301
Q

Anti-Apoptotic Proteins

A

BCL-2
BCL-X
BCL-W
BOO

302
Q

Pro-Apoptotic Proteins

A 
BAX
BAD
BID
BAK
NOXA
PUMA
303
Q

Death signals, TNF (tumor necrosis factor) and Fas activate

A

their death receptors TNF receptor and Fas receptor

304
Q

Binding of death receptors (like TNF and Fas) cause

A

changes in shape and oligomerization of receptors

305
Q

Adaptor proteins ___________ and _________ recognize the activated receptors and lead to the aggregation of ___________.

A

TRADD (TNF receptor associated death domain)
FADD (Fas associated death domain)
Procaspase 8

306
Q

Procaspase 8 aggregation leads to

A

the activation of caspase 8

307
Q

Caspase 8 initiates

A

a caspase cascade, proteolysis and apoptosis

308
Q

Caspase cascade activates

A

caspase 3 which causes proteolysis of target proteins

309
Q

Both the intrinsic and extrinsic pathways of apoptosis activate _______ at the end

A

Caspase 3

310
Q

Caspase 3 is

A

an important mediator of apoptosis as it moves the cell into execution phase of apoptosis

311
Q

Caspase 3 causes

A

proteolysis of different target proteins

312
Q

Target proteins of Caspase 3

A

Nuclear Lamins- allowing for nuclear membrane shrinkage
Cytoskeletal proteins- such as actin filaments affecting cell structure
Activation of DNAse- resulting in cleavage of DNA

313
Q

Regulation of the Intrinsic Pathway of Apoptosis

A

Inhibitors of apoptosis proteins (IAP) regulates apoptosis by binding to and inhibiting the activity of caspase-3 and caspase-7

314
Q

Smac (Second mitochondria-derived activator) / DIABLO

A

is released from mitochondria eliminates the inhibition by IAP’s

315
Q

True or false:

The intrinsic and extrinsic pathways of apoptosis are completely separate and do not interact with each other

A

False:

There is a cross-talk between extrinsic and intrinsic pathways

316
Q

Caspase 8

A

a key regulator of extrinsic pathway also cleaves

and activates Bid in intrinsic pathway

317
Q

Where is another point in which the intrinsic and extrinsic pathways of apoptosis coincide or converge?

A

at the activation of caspase 3 which causes proteolysis

318
Q

Mutations in p53 genes

A

provide the cancer cells with a survival advantage by disrupting apoptosis is common in lymphomas

319
Q

In addition mutations in upstream regulators p53 such as

A

ATM and chk2 are also common

320
Q

Chromosomal translocation of anti-apoptotic protein Bcl2 is observed by

A

Many B-Cell Lymphomas

321
Q

What is the consequence of the chromosomal translocation of BLC-2

A

over-expression of Bcl-2 protein leads to insufficient

apoptotic turnover and accumulation of B-cell

322
Q

Mutations in BAX and BID genes that code for anti-apoptotic proteins are

A

mutated in 50% of colon tumors

323
Q

A successful chrmotherapy will be one that

A

triggers apoptosis

324
Q

Many chemotherapeutic agents

A

trigger DNA mutations or DNA damage thus activating intrinsic apoptotic pathway

325
Q

many tumors have

A

defective apoptotic pathways

and are inherently resistant to chemotherapy

326
Q

Mutations in p53 which is common in cancers inherently contributes to

A

drug resistance

327
Q

Upregulation of anti-apoptotic members of Bcl-2 family

and the downregulation of the pro-apoptotic members

A

increase the resistance to chemotherapy

328
Q

Totipotent (AKA Omnipotent) Stem Cells

A

▪ These cells are produced from the fusion of an egg and sperm cell.
▪ Cells produced by the first few divisions of the fertilized egg are also totipotent.
▪ Such cells can construct a complete, viable, organism.
▪ These cells can differentiate into embryonic (inner cell mass) and extraembryonic cell types (placenta
and other supporting tissue).

329
Q

Pluripotent stem cells

A

▪ Are the descendants of totipotent cells.
▪ Can differentiate into nearly all cells.
▪ Cells derived from any of the three germ layers.
▪ Can become any of the 200 different cell types in the
body (under right conditions)

330
Q

Multipotent stem cells

A

can differentiate into a number of cells, but only those of a closely related family of cells

331
Q

Hematopoietic stem cells

A

Hematopoietic stem cells

332
Q

Oligopotent stem cells

A

can differentiate into only a few cells, such as lymphoid or myeloid stem cells.
▪ Lymphoid stem cells and myeloid stem cells

333
Q

Unipotent stem cells

A

can produce only one cell type, their own.

▪ Epidermal stem cells in our skin give rise to epithelial skin cells

334
Q

What are stem cells?

A 
▪ Cells of variable potency that can self renew.
▪ Normally found in our body.
▪ Help in organ maintenance.
▪ Help in organ repair.
▪ Somewhat committed
335
Q

Characteristics of stem cells

A

▪ They have ability to migrate to other tissues.
▪ High level of telomerase activity.
▪ Stem cells must maintain a balance between self-renewal and differentiation

336
Q

When not dividing, stem cells are in what type of phase?

A

Quiescent/ G0 Phase

337
Q

Obligator Asymmetric Replication

A

When a stem cells divides it becomes another stem

cell and a progenitor cell

338
Q

Progenitor cell in stem cells

A

will divide rapidly, and their progeny divide and differentiate into a specific cell type

339
Q

True or False:

Differentiated cells remain in the cell cycle

A

FALSE: Differentiated cells withdraw from the cell cycle

340
Q

A block in cell differentiation results in

A

a higher net number of cells and therefore is a mechanism for tumor formation

341
Q

When do normal stem cells multiply?

A

only when you need to

342
Q

Stem cells are kept

A

Quiescent by the environment

343
Q

On stem cell activation by environmental input

A

the niche cells induce them to divide into a stem cell and progenitor cell
▪ They do this because of their signaling

344
Q

IPS Cells

A

Pluripotent stem cells that have been programmed to differentiate into a different type of cell than their original type

345
Q

What are cancer stem cells?

A

rare cells within a tumor that have the ability to self-renew

346
Q

What type of cells do cancer stem cells generate

A

Can give rise to phenotypically diverse cancer cells

347
Q

Cancer stem cells have surface proteins called markers

A

which are characteristic of the stem cell normally

present in the tissue

348
Q

Breast Cancer stem cells express what cell surface markers?

A

CD44+ and CD24 (low)

349
Q

Colon cancer stem cells over express what surface antigen?

A

CD 133

350
Q

WNT pathway

A

plays a role in stem (cancer) cell self-renewal

351
Q

Characteristics of the wnt pathway

A 
It's a stimulatory factor
19 wnt genes discovered in mammals
Involved in embryonic development
Development of the heart
involves a destruction complex
Involves Beta Catenin
352
Q

Describe the WNT signaling pathway when WNT is absent

A

WNT is not present to bind to Frizzled to create a complex with LRP
The degredation complex is present
Beta Catenin is phosphorylated and tagged with ubiquitin
Sent to proteasome
Beta Catenin Degredation
Acts as a transcriptional repressor
Groucho prevents Tcf/Lef from transcribing genes

353
Q

Describe WNT pathway when WNT is present

A

WNT is present and binds to Frizzled/LRP complex
LRP is phosphorylated and binds to axin
Degredation complex is disassembled
Beta Catenin is activated
Activated Beta Cateinin can bind to TCF/LEF and forms a complex with Pygopus and BCL9
Allows target genes to progress (ex. c-myc , cyclin-D (Cell cycle))

354
Q

FAP

A

Familial Adenomatous poly posiscoli

355
Q

FAP Characteristics

A

▪ 85% of colon cancers
▪ Caused by chromosomal instability
▪ There is a mutation in tumor suppressor gene (APC) on chromosome 5q

356
Q

What protein is important in signaling with FAP (disease)

A

Beta-Catenin

357
Q

Describe the process for which a normal colon can develop carcinoma in FAP (Disease)

A

Normal colon –→ loss of APC gene -→ colon at risk –→K-RAS mutation –→ adenoma ——-→ loss of p53 —–→ carcinoma

358
Q

True or false:

FAP develops into cancer 100% of the time and involves the entire colon (Pancolonic)

A

True

359
Q

Hedgehof signaling pathway

A

plays a role in stem (cancer) cell self-renewal

360
Q

Hedgehog proteins are involved in

A

graded signaling and organ/tissue specific gene induction

361
Q

Hedgehog proteins are involved in

A 
▪ Embryo development 
▪ Tissue self-renewal
▪ Tissue repair
▪ Carcinogenesis
▪ Role in digit formation in mammals
▪ Formation of neural tube, skin, and gut
362
Q

Hedgehog signaling

A

important roles in embryonic development, tissue self-renewal, and carcinogenesis

363
Q

Hedgehog pathway is essential for

A

pattern formation in many tissues, including the neural tube, skin, and gut

364
Q

Describe the hedgehog pathway when HH is absent

A

No HH present
Patched cannot bind to smoothened
SUFU, PKA, and Gli bind together
inhibits target genes from exiting the nucleus

365
Q

Gli

A

a Zinc-finger transcription factor

366
Q

Describe the hedgehog pathway when HH is Present

A 
HH is present
Binds to patched
Patched and smoothened associate
Sufu, PKA, and Gli Dissociate
Cyclin Ds, BCL2, VEGF, and SNAIL (effector proteins)
Promote target genes exiting the nucleus
367
Q

The process of stem cell differentiation is dependent on

A

the expression of a specific subset of genes that defines a particular type of cell

368
Q

The polycomb group (PcG) of proteins

A

represses the transcription of specific sets of genes by epigenetic modifications

369
Q

What proteins are called the guardians of stemness?

A

polycomb group (PcG) of proteins

370
Q

What are the Polycomb Group of proteins (PCG)?

A 
HOX
FOX
SOX
PAX
POU
371
Q

Metastasis

A

the spread of tumor cells from a primary tumor that is not clonal

372
Q

A primary tumor is composed of

A

subpopulations of genetically identical cells, called subclones, that differ by mutations obtained through an ongoing evolutionary process

373
Q

How many metastasized cells survive transport?

A

Only 1 in 10,000 metastasizing cells survives transport

374
Q

Steps of Metastasis

A 
Invasion
Intravasation
Transport
Extravasation
Metastatic Colonization
Angiogenesis
375
Q

Integrins (Proteins)

A

are a family of more than 24 heterodimersmade up of a range of α and β subunits that mediate cell-ECM interactions and intracellular signal transduction

376
Q

Integrin function

A

cluster in the membrane and affect the cytoskeleton through interaction with actin-binding proteins and specific kinases, such as focal adhesion kinase (FAK)

377
Q

Intracellular signals mediated at the cytoplasmic

domain of integrins induce

A

a conformational change in the extracellular domain and thus regulate the affinity of the integrins for their ECM ligands

378
Q

Integrins also have a role in anoikis

A

apoptosis triggered in response to lack of ECM ligand

binding and loss of cell adhesion

379
Q

lntegrins without suitable ECM ligands

A

recruit caspase-8 to the membrane and trigger apoptosis.

380
Q

The role of Integrins in motility

A

is obvious in melanoma cells in which their invasive front edge shows a strong pattern of expression of integrin ανβ3 that is absent in preneoplastic melanomas

381
Q

Protease

A

2 common types

  • serine proteases
  • Matrix metalloproteinases (MMPs)
382
Q

Some proteases are synthesized by tumors or they

can induce surrounding stromal cells to produce

A

MMPs (extracellular matrix metalloprotease inducer

EMMPRIN

383
Q

MMPs play an important role in

A

Metastasis, including angiogenesis

384
Q

EMT is characterized by

A

▪ Loss in cell polarity
▪ Downregulation of epithelial markers such as E cadherin,
▪ Upregulation of mesenchymal proteins such as N-cadherin
▪ Secretion of MMPs.

385
Q

Extravasation

A

Tumor cell must attach to the endothelial side of the
blood vessel

▪ Binding of tumor to E-selectin induces tyrosine phosphorylation in endothelial cells and also modifies endothelial cell shape.
▪ stress-activated protein kinase-2 (SAPK2/p38) similar to MAPK is induced in cancer cells is necessary for transendothelial migration

386
Q

Pre-Metastatic Niche

A

tumor-type specific factors released from the primary
tumor facilitate changes to the microenviromnent of a
distant and future colonization site before tumor cells
arrive

387
Q

Exosomes

A

small vesicles (30-100 nm) that carry protein and nucleic acids

388
Q

Exosomes are an important means of

A

intercellular communication between cancer cells and non cancer cells in their microenvironment and further away.

389
Q

They can carry and transfer DNA, RNA, and protein to

cells to which they can

A

fuse, and this is referred to as horizontal transfer

390
Q

Exomes are packaged in

A

multivesicular bodies that fuse with the cell membrane and are released into the circulation

391
Q

Pancreatic exosomes

A

promote the establishment of a pre-metastatic niche for liver metastasis in, a stepwise fashion

392
Q

Steps of Pancreatic exosomes to set-up the prematastatic niche

A

▪ First, pancreatic exosomes selectively fuse with Kupffercells in the liver.
▪ Kupffer cells upregulate genes involved in fibrosis,
including TGF-β, in response to macrophage migration
inhibitory factor (MMIF) enriched in the exosomes.
▪ TGF-β then induces the expression of fibronectin in
another liver cell type, stellate cells.

393
Q

Fibronectin deposits function

A

recruit bone marrow-derived cells, an important component of the pre-metastatic niche

394
Q

The altered microenvironment of pancreatic exomes

A

supports the survival and growth of pancreatic tumor cells

395
Q

Metastatic Colonization

A

the establishment of a progressively growing tumor at a distant site

396
Q

Metastasis suppressor genes

A

regulate/controls the growth of metastatic cells at secondary sites

397
Q

What happens in loss of function in normal cells?

A

increases the metastatic propensity of a cancer cell

398
Q

NM 23

A

functions as a nucleoside diphosphate kinase

and a histidine kinase that possesses metastasis inhibitory effects

399
Q

MKK4 (mitogen-activated protein kinase kinase 4)

A

a metastasis suppressor gene whose protein product

affects metastatic colonization by inducing apoptosis

400
Q

miR-335 and miR-126

A

metastasis suppressor microRNAs

401
Q

Metalloproteinase inhibitors

A

▪ These molecules appear to function in several steps of metastasis, including invasion and metastatic colonization
▪ Targeting membrane-bound MMPs by selective therapeutic antibodies

402
Q

G0 Phase

A

▪ Is outside the cell division / cell cycle
▪ The cell is in non-diving state
▪ It is dependent on the growth signals for division

403
Q

G1 Restriction point in the cell cycle

A
  • Part of G1 phase
  • Is a control point in cell division
  • If a cell crosses this point, it becomes irreversibly committed to progress through cell cycle without the need for growth factors
404
Q

Cyclins

A

proteins that have a critical role in cell cycle

Different cyclins for different stages of the cell cycle

405
Q

True or False:

There is a cyclical change in cyclin concentration during cell division

A

True

406
Q

Cyclins coordinate and regulate

A

the passage of cell through different phases of cell cycle

407
Q

Cyclins act as

A

regulatory subunits of cyclindependent kinase (cdks)

408
Q

Upon binding of cyclin to cdk partner, what happens?

A

cyclin undergoes a conformational change in the catalytic domain, exposing an active site

409
Q

Concentration of cyclins during cell division is dependent on

A

▪ Transcription of cyclin genes

▪ Regulated protein degradation

410
Q

True or false:

CDK concentration fluctuates throughout the cell cycle, depending on which phase is active at the time.

A

False:
There is no change in cdk concentration during
cell division

411
Q

CDKs along with cyclins coordinate and regulate what?

A

the passage of cell through different phases of cell cycle

412
Q

CDK proteins are regulated by

A

binding of cyclins

413
Q

Cell cycle checkpoints are important in

A

maintaining the integrity of the genome

414
Q

Cell cycle checkpoints are connected to

A

different pathways which sense and induce apoptosis in response to DNA damage

415
Q

G1 Checkpoint of the cell cycle

A

arrest of cell cycle in response to DNA damage

416
Q

G2 Checkpoint of the cell cycle

A

arrest of cell cycle in response to DNA damage and/or unreplicated DNA to ensure proper completion of S phase

417
Q

M Checkpoint of the cell cycle

A

arrest of chromosomal segregation in response to misalignment on the mitotic spindle

418
Q

Disruption of a cell cycle checkpoint leads to

A

mutation and carcinogenesis

419
Q

In cyclin-CDK complexes, p16 binds with cdk 4/6 and interferes with the binding of

A

cyclin D to cdk4/6

420
Q

In cyclin-CDK complexes, p21 inhibitor binds to

A

both cyclin E and cdk 2blocking ATP –binding site, thus disabling kinase activity.

421
Q

Inhibitors of association with CDK inhibitors are regulated by

A

ubiquitin-mediated degradation

422
Q

When CDK is bound to P16 or P21

A

CDK is inactive (P16 and P21 are inhibitors)

423
Q

A key substrate of the cyclin D-cdk 4/6 complex is

the

A

RB Protein

424
Q

Rb protein serves as

A

a molecular link for the G1-S phase transition

425
Q

Rb binds to transcription factor E2F

A

which is crucial for the expression of genes needed for S phase

426
Q

Rb protein comprises the A domain and B domain

joined by

A

a linker region

427
Q

Histone deacetylase (HDAC) binds to

A

domain B and E2F binds to domain A

428
Q

The G2 checkpoint

A

blocks entry into M phase in cells that have incurred DNA damage in previous phase or have not correctly completed S phase

429
Q

At the G2 Checkpoint, DNA damage activates

A

either of two kinases, ATM or ATR

430
Q

Activated ATM and ATR kinases, in response to DNA Damage

A

phosphorylate and activate chk1 and chk2 kinases

431
Q

One Target of ATM/ATR Kinases

A

cdc25 tyrosine phosphatase that regulate cdk activity by removing inhibitory phosphatase

432
Q

Activation of G2 checkpoint results in

A

the inhibition of cdc25 by chk1

433
Q

There is also a decatenation during G2 checkpoint

involving topoisomerase II which

A

helps in detangling daughter chromatids after DNA synthesis

434
Q

If CDC is active/not inhibited

A

CDC dephosphorylates CDK Protein
CDK Activated
Progress into M Phase of the cell cycle (Mitosis)

435
Q

If CDC is inactivated by CHK1

A

No dephosphorylation of CDK

No Progression of cells into M Phase

436
Q

Prophase (Mitosis)

A

▪ Characterized by appearance of the chromosomes
▪ Nuclear membrane starts to break down.
▪ Separation of duplicated centrosomes.
▪ Assembly of mitotic checkpoint at the centromeres.

437
Q

Metaphase (Mitosis)

A

▪ Chromosomes align on a central plate.
▪ Assembly of microtubules to form mitotic spindles.
▪ Microtubules capture of both centromere regions of a
chromatid pair results in checkpoint silencing.

438
Q

Anaphase (Mitosis)

A

▪ Characterized by spindle pulling apart.

▪ Separating sister chromatid pairs

439
Q

Telophase (Mitosis)

A

▪ Chromosomes reach their poles.
▪ Re-forming of nuclear membrane.
▪ Chromosome condensation.
▪ Cytokinesis

440
Q

Mitotic Checkpoint in cell cycle is also known as

A

The spindle assembly checkpoint

441
Q

Function of the Mitotic Checkpoint

A

▪ Ensures chromosomal segregation during mitosis and production of two genetically identical nuclei.
▪ Prevents mis-segregation of chromosomes.

442
Q

If any of the sister chromatids are not attached to

microtubules at their centromeres during mitosis

A

they recruit checkpoint proteins that act as inhibitors of anaphase-promoting complex such as securin

443
Q

When securin is attached to sister chromatids without microtubules

A

they inhibit enzyme separase

444
Q

Separase

A

cleaves the link (cohesin) between sister chromatids and helps their separation during anaphase

445
Q

Genes encoding cell cycle regulators are

A

frequently mutated in tumors

446
Q

Mutations in cell cycle regulators can result in

A

aberrant regulation of cell cycle, uncontrolled proliferation and carcinogenesis

447
Q

Some melanomas have been observed to contain

mutations in

A

CDK4 where p16 inhibitors bind

. This prevents inhibition of cyclin dependent kinases and helps in progression of cell from G1 to S phase

448
Q

Chromosomal translocations cause over-expression

of ______ in some leukemias

A

CKD6

449
Q

DNA amplification of cyclin D and E by gene

amplification occurs in

A

15% of breast cancers and 20% squamous cell carcinoma

450
Q

p16 inhibitor deletions have been observed in

A

Pancreatic Cancers

451
Q

Abnormal chromosome numbers or aneuploidy

A

caused by defects in centrosomes, mitotic spindle, or cytokinesis is often observed in many solid tumors.

452
Q

Over expression of Aurora kinase A gene has

been commonly reported in

A

94% of invasive ductal breast adenocarcinomas

453
Q

Flavopiridol acts as

A

competitive inhibitor of all cdks

454
Q

Flavopiridol Mechanisms

A

▪ Its induces cell cycle arrest at G1/S and G2/M phase.

▪ It also regulates gene expression of cyclin D1 and D3

455
Q

Paclitaxel/taxol

A

a mitotic inhibitor (Prevents Mitosis)

456
Q

The Yew tree

A

contains a mixture of poisons, paclitaxel and taxine B. Taxine B is what causes death in those that eat the leaves/seeds of the plant due to cardiac arrest. Taxol contains the purified paclitaxel

457
Q

Paclitaxel’s mechanism of action

A

(at the doses seen with poisoning) is to prevent microtubules from depolymerizing. If the microtubules attached to chromosomes cannot shrink, chromosomes cannot be separated. The cell is ”frozen“ in mitosis. This event causes the failure of the affected cell to pass certain cell cycle check points, and the cell undergoes programmed cell death (Apoptosis)

458
Q

Tumor suppressor genes

A

are genes whose loss or inactivation can lead to cancer

459
Q

Tumor suppressor genes are also involved in

A

DNA repair mechanisms

460
Q

Tumor Suppressor Genes are also called

A

“anti-oncogenes”

461
Q

The function of tumor suppressor genes is

A

to inhibit cell proliferation and/or promote cell death

462
Q

Tumor Suppressor Genes mutation type

A

loss-of-functionmutations

463
Q

RB1 Chromosome Location

A

13q14

464
Q

RB1 Gene Function

A

Transcriptional regular of the cell cycle

465
Q

RB1 Human tumors associated with sporadic mutation

A

Retinoblastomas , Osteosarcoma

466
Q

RB1 Associated cancer syndrome

A

Familial Retinoblastoma

467
Q

P53 Chromosome Location

A

17q11

468
Q

P53 Gene Function

A

Transcriptional Regulator/ Growth arrest/ apoptosis

469
Q

P53 Human tumors associated with sporadic mutation

A

Sarcomas, breast, brain tumors

470
Q

P53 Associated cancer Syndrome

A

Li-Fraumeni

471
Q

BRCA 1 and 2 Human Tumors

A

Breast/Ovarian Tumors

472
Q

VHL Gene Function

A

Regulates proteolysis

473
Q

VHL HUman Tumors

A

Hemangiomas, Renal, Pheochromocytoma

474
Q

VHL Associated Cancer syndrome

A

Von Hippel Lindau

475
Q

APC Chromosome Location

A

5q21

476
Q

APC Gene Function

A

Binds and Regulates Beta Catenin Activity

477
Q

APC Human tumors

A

Colon Cancer

478
Q

PTEN Associated Cancer Syndrome

A

Cowden Syndrome
BZS
Ldd

479
Q

Describe P13K Activation by RAS

A 
EGF Binds to EGFR
Binds to PI3K
PTEN binds to PIP 2 and PIP 3
Activates AKT
MTOR
Leads to Proliferation or Apoptosis
This pathway inhibits Apoptosis
480
Q

Tumor suppressor genes are often recessive in nature because

A

one intact allele is sufficient to inhibit growth

481
Q

In tumor suppressor genes, One of the alleles can be mutated due to

A

any known mechanisms of mutagenesis

482
Q

The mutated allele in tumor suppressor gene can be transmitted to daughter cells during cell division through any of the following mechanisms of

A

“Loss of Heterozygosity”

483
Q

Knudson’s 2-Hit Hypothesis

A
  • Explains the mechanism of tumor suppressor genes
  • States that both alleles must be mutated to trigger carcinogenesis
  • Explains certain individuals have increased risk of cancer
  • They inherit mutated tumor suppressor allele
484
Q

Tumor suppressor genes arise through a

phenomenon known as

A

“Loss of Heterozygosity”

485
Q

Methods for losing heterozygosity

A

▪ Mitotic nondisjunction
▪ Mitotic recombination
▪ Gene conversion

486
Q

Methods for losing heterozygosity

A

▪ Mitotic nondisjunction
▪ Mitotic recombination
▪ Gene conversion

487
Q

Retinolastoma

A 
Rare type of childhood cancer occurs 1 in 
20,000
▪ There are two forms of disease
▪ Familial form
Sporadic Form
488
Q

Retinolastoma

A 
Rare type of childhood cancer occurs 1 in 
20,000
▪ There are two forms of disease
▪ Familial form
Sporadic Form
489
Q

Familial Retinoblastoma

A

Rare type of childhood cancer occurs 1 in
20,000
▪ There are two forms of disease
▪ Familial form

490
Q

Sporadic Retinoblastoma

A

▪ 60% of cases
▪ The individual acquires two somatic mutations in two
alleles
▪ They usually affect one eye

491
Q

Sporadic Retinoblastoma

A

▪ 60% of cases
▪ The individual acquires two somatic mutations in two
alleles
▪ They usually affect one eye

492
Q

Retinoblastoma (RB) Tumor suppressor gene

A

▪ First tumor suppressor gene to be isolated and characterized
▪ RB gene produces a protein called Rb protein

493
Q

Rb protein controls

A

cell proliferation in the absence of growth factors

494
Q

In normal nondividing cells, Rb protein controls cell proliferation

A

binding to E2F transcription factor

495
Q

E2F transcription factor when bound to Rb protein

A

cannot activate transcription genes coding for
enzymes and other proteins required for initiating DNA replication
Hence, No Cell division

496
Q

E2F transcription factor when bound to Rb protein

A

cannot activate transcription genes coding for
enzymes and other proteins required for initiating DNA replication
Hence, No Cell division

497
Q

RB Protein in dividing cells that receives growth factor
signals through growth signaling pathways leads
to

A

production of cyclin-cdk complexes

498
Q

Cyclin-cdk complexes catalyze

A

the phosphorylation of Rb protein which results in

release of E2F transcription factor

499
Q

E2F transcription factor when unbound to Rb protein

A

can activate transcription genes coding for enzymes and other proteins required for initiating DNA replication
This results in cell division

500
Q

What happens to Rb when interacting with The viral proteins adenovirus ElA, papilloma virus E7, and SV40 Large T antigen

A

Inactivates Rb

501
Q

The ability of both E1A and E7 to degrade RB, uses

A

the ubiquitin-proteasome system

502
Q

The biochemical events involved in RB degradation by E7 involves

A

E7 binds to a ubiquitin-protein ligase (E7-AP) and forms a dimer that subsequently binds to RB.

503
Q

After E7 binds to a ubiquitin-Protein ligase and forms a dimer that binds to RB,

A

RB is then ubiquitinated and tagged for recognition by the proteosome for degradation

504
Q

After E7 binds to a ubiquitin-Protein ligase and forms a dimer that binds to RB,

A

RB is then ubiquitinated and tagged for recognition by the proteosome for degradation

505
Q

What is the most important tumor suppressor gene?

A

P53

506
Q

2 homolgs of P53

A

P63 and P73

507
Q

What is the msot commonly mutated genes in human cancers?

A

P53

508
Q

True or False:

P53 is known as the Guardian of Stemness?

A

False:

It is known as the guardian of the genome because products of P53 are at the heart of tumor suppressive mechanisms

509
Q

p53 protein plays a very important role in

A

Protecting cells from the effets of DNA Damage

510
Q

P53 Regulates How many genes

A

over 300 different genes promoter regions

511
Q

P53 Regulates How many genes

A

over 300 different genes promoter regions

512
Q

P53 Chromosome Location

A

Located on chromosome 17 and contains 11 exons that code of 53kDa protein

513
Q

P53 is a transcription factor containing 4 distinct domains

A

▪ Amino-terminal transactivation domain
▪ DNA binding domain which binds to DNA
▪ Oligomerization domain (helps in the formation of tetramer by binding to other monomers)
▪ Carboxy-terminal regulatory domain

514
Q

As p53 can induce inhibition of cell proliferation or apoptosis in a cell, the factors that determine biological outcome depends on

A

Absence of Myc

Presence of Myc

515
Q

In the absence of oncogene transcription factor Myc

A

p53 interacts with transcription factor MIZ-1 which in turn causes the expression of cyclin-cdk inhibitor p21 protein resulting in cell cycle inhibition

516
Q

In the presence of oncogene transcription factor Myc

A

Myccompetes with p53 and binds to MIZ-1 thus preventing the expression of p21 genes

517
Q

p53 interacts with apoptosis stimulating protein of p53 (ASPP) and

A

triggers apoptosis in the cell

518
Q

Li-Franmeni syndrome is predominantly characterized by

A

a germline mutation of the p53 gene and leads to a

predisposition to a wide range of cancers.

519
Q

Li Fraumeni Characteristics

A

• It is an autosomal dominant disease, so an affected
individual has a 50% chance of passing the mutation to
each offspring.
• Patients have a 25-fold increased risk of developing
cancer before they are 50 years old compared with the
general population.
• The young age at which individuals develop cancer and the frequent occurrence of multiple primary tumors in individuals are characteristic features of the syndrome.
• The types of cancer seen within families that carry the
mutation include sarcomas, breast cancer, leukemia, and brain tumors.

520
Q

P53 interaction with Adenovirus ElB, and papilloma virus E6 and SV40 Large T antigen

A

inactivate p53

521
Q

The ability of E6 to degrade p53

A

uses the ubiquitin-proteasome system

522
Q

The biochemical events involved in p53

degradation by E6 are as follows

A

6 binds to a ubiquitin-protein ligase (E6-AP) and forms a dimer that subsequently binds to p53

523
Q

p53 is then ubiquitinated and tagged for

A

recognition by the proteasome for degradation

524
Q

Angiogenesis

A

the process of forming new blood vessels from pre-existing ones by the growth and migration of endothelial cells in a process called “sprouting.”

525
Q

In adults angiogenesis is reserved for

A

Wound Healing

Female Reproductive Cycle

526
Q

The Neovasculature in cancer is different from normal vessels

A

▪ Leaky
▪ Tortuous and chaotic flow pattern
▪ Allow cells easy access to the circulation
▪ Loose association with pericytes and extracellular matric (ECM)
▪ Lack normal hierarchy artery-arteriole-capillary-venule-vein
▪ Endothelial cells express more of integrins αvβ3 and αvβ5
▪ Pericytes and ECM show specific angiogenic markers (e.g. NG2 and oncofetal fibronectin, respectively

527
Q

Anti-Angiogenic Factors

A 
Angiostatin
Endostatin
Prolactin (16kD)
P53
Thrombospondin 1,2
528
Q

Pro-Angiogenic Factors

A

Vascular Endothelial Growth Factor (VEGF)
Fibroblast Growth Factor (FGF )
Hepatocyte-Derived Growth Factor (HGF)
Epidermal Growth Factor (EGF)

529
Q

Pro-Angiogenic Factors

A

Vascular Endothelial Growth Factor (VEGF)
Fibroblast Growth Factor (FGF )
Hepatocyte-Derived Growth Factor (HGF)
Epidermal Growth Factor (EGF)

530
Q

The VEGF family currently consists of five family

members

A

VEGF A, B, C, D, E

531
Q

VEGF A-E transmit their signal via

A

3 receptor tyrosine kinases

VEGFR 1, 2, 3

532
Q

The interaction of VEGF-A with its receptor VEGFR-2 is responsible for

A

the majority of angiogenic effects.

533
Q

VEGFR-1 acts as a decoy by regulating or inhibiting the amount of

A

VEGF-A available to VEGFR-2

534
Q

VEGFR-3 and its ligand VEGF-C play a role in

A

development of the lymphatic vascular system

535
Q

Plasminogen can be cleaved by proteinases, such as

A

matrix metalloproteinases(MMPs), to release the angiogenic inhibitor, angiostatin

536
Q

Angiostatin binds to

A

its endothelial cell surface receptors and stops the VEGF-VEGFR

537
Q

Endostatin is a fragment of collagen XVIII and can be

A

proteolytically released by elastase and cathepsin

538
Q

Endostatin blocks

A

MAPK activation in endothelial cells and also MMPs

539
Q

Name the Ten Hallmarks of cancer

A 
Susatained Proliferation Signals
Tumor-Supporting Inflammation
Evading Apoptosis
Deregulating cellular energetics/metabolism
Genome instability and Mutation
Invasion and Metastasis
Inducing Angiogenesis
Enabling replicative immortality
Avoiding immune destruction
Evading growth suppressors

biology of cancer (4 decks)

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