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Cell biology > Week 13: Cell-cycle Checkpoints and Cancer Intro > Flashcards

Week 13: Cell-cycle Checkpoints and Cancer Intro Flashcards

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1
Q

Cell cycle control system

A

complex network of regulatory proteins that act as a series of binary (on/off), irreversible, biochemical switches
- Ensures that the cell cycle events occur in a proper sequence and each event is completed before the next begins

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2
Q

checkpoints

A

major regulatory transitions which arrest the cell cycle if previous events have not been completed or environment is unfavorable ⇒ series of mechanisms to make sure you don’t go to the next cell cycle step unless you confirm the current or previous events are completely done

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3
Q

what are the cell cycle checkpoints?

A
  1. G1
  2. S
  3. G2
  4. M
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4
Q

G1 checkpoint general info

A

growth phase at the start which is a gap phase right after mitosis (M phase)
- You have 2 daughter cells each starting G1
- Cells will probably be small ⇒ want to make sure the cell is big enough to enter the next cycle
- Also makes sure the cell has enough nutrition and is in a good environment to divide

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5
Q

S general info

A

begin replication

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6
Q

G2 checkpoint general info

A

waiting phase before you start dividing
- Make sure that you have doubled the genetic information completely

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7
Q

M checkpoint general info

A

undergo division and cytokinesis

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8
Q

G1 checkpoint

A

sense the cell size, physiological state of the cell, and environmental conditions
- Nutrition, growth factors, mitogens, etc.

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9
Q

how is G1-S transition regulated?

A

mitogens stimulates G1-S transition
- Activation of MAP kinase results in an increased production of gene regulatory proteins such as Myc (downstream)

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10
Q

Myc

A

transcription factor that triggers increased G1-Cdk activity via gene activation
- helps promote cell cycle entry and stimulates gene transcription that increases cell growth

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11
Q

Delayed genes

A

downstream of Myc there are many target genes

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12
Q

what is S-phase initiation controlled by?

A

E2F and Retinoblastoma protein (rb)

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13
Q

what is the activation pathway of Myc? (5)

A
  1. mitogen binds a ligand to a transmembrane protein mitogen receptor
  2. the protein stimulates Ras
  3. activation of transcription regulatory proteins occurs in the cytosol
  4. transcription regulatory proteins enter the nucleus and bind to a gene sequence
  5. Myc is transcribed and translated
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14
Q

what are the 2 molecules for G1/S transition?

A
  1. E2F
  2. Rb
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15
Q

E2F protein

A

transcriptional factor required for the transcription of S-phase genes (G1/S and S-cyclins, DNa polymerase, E2F
- Once you activate E2F you get more E2F

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16
Q

Rb protein

A

regulatory protein that binds and inhibits E2F

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17
Q

what is the process of the G1-cdk to the G1/S transition? (5)

A
  1. Mac delayed response of gene expression activates G1-cdk
  2. G1-Cdk phosphorylates Rb (phosphorylated Rb is inactive) and E2F is released and activated
  3. active E2F activates positive feedback and S-phase gene transcription for G1/S-cyclin and S-cyclin
  4. G1/S transition is activated and cyclins activate G1/S-cdk as well as S-Cdk
  5. S-Cdk activates DNA synthesis for replication of chromosomes
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18
Q

what does E2F promote?

A

more E2F production through positive feedback

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19
Q

G1/S-Cdk phosphorylates what?

A

Rb to inactivate it and stop binding with E2F

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20
Q

S-cdk phosphorylates what?

A

Rb to inactivate it and stop binding with E2F

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21
Q

what are the key molecules for S phase?

A

DNA polymerase for replication
- All other molecules used are downstream of E2F

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22
Q

T/F we know a lot about the G2/M checkpoint? What do we know?

A

we do not know much
- Unreplicated DNA inhibits Cdc25 is all that we know but not how this is done

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23
Q

G2/M checkpoint

A

ensures that DNA is replicated properly ⇒ initiation of mitosis cannot occur until DNA replication is completed
- entry into mitosis is blocked by incomplete DNA replication

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24
Q

Hydroxyurea

A

inhibits DNA synthesis by halting it in S phase

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25
Q

caffeine

A

blocks G2/M checkpoint mechanism

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26
Q

what was the experiment done with the G2/M checkpoint?

A

hydroxyurea or caffeine (chemicals) cause inhibition of G2/M because no active Cdc25
- When you add the additional toxin caffeine at a high dose, it also inhibits the checkpoint which means it wrongly will undergo mitosis and result in broken sets of chromosomes in daughter cells
- They will die if lucky but may become cancerous

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27
Q

what does the combination of hydroxyurea and caffeine do?

A

induces incomplete DNA replication and broken/incomplete sets of chromosomes which causes suicidal mitosis

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28
Q

metaphase checkpoint (kinetochore attachment)

A

ensures that all chromosomes have attached to the spindle
- Sister chromatid separation cannot occur until all chromosomes are properly attached to the spindle and unattached chromosomes block sister chromatid separation

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29
Q

what do unattached kinetochores block?

A

APC/C-cdc20 complex

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30
Q

spindle assembly checkpoint

A

ensures that cells do not enter anaphase until all chromosomes are properly attached to the spindles
- Improperly attached kinetochores send out a diffusible signal that blocks Cdc-20-APC/C activation

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31
Q

what do unattached kinetochores catalyze conformational changes in?

A

Mad2
- Mad2 (with other proteins) binds and inhibits Cdc20-APC/C

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32
Q

DNA damage checkpoint

A

arrests the cell cycle when DNA is damaged to give time for DNA repair mechanisms ⇒ cells sense the damage

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33
Q

what are the 2 ways DNA damage checkpoint works?

A
  1. G1 checkpoint prevents entry into S phase
  2. G2 checkpoint prevents entry into mitosis
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34
Q

DNA Damage checkpoint (G1)

A

DNA damage triggers the activation of a set of protein kinases ⇒ ATM, ATR, Chk1, Chk2

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35
Q

ATM and ATR

A

activate the actual players against DNA damage called Chk1 and 2

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36
Q

Chk1/2

A

when active these phosphorylate p53 as their major target
- you don’t find p53 in normal cells because it is always synthesized and degraded

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37
Q

p53

A

is usually bound and ubiquitylated by Mdm2 (Ubi ligase) and degraded in proteasomes
- Phosphorylation of p53 blocks Mdm2 binding, resulting in p53 accumulation because it is unubiquitylated ⇒ done by Chk1 and Chk2
- Active p53 enters the nucleus and binds the regulatory region of the p21 gene (CKI protein) and stimulates expression

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38
Q

p21 protein (CDK inhibitor protein)

A

binds to and inactivates G1/S-Cdk and S-Cdk arresting cells in G1

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39
Q

DNA damage checkpoint (G2)

A

when DNA is damaged, Chk1 and Chk2 phosphorylate and inhibit Cdc25 blocking progression into mitosis
- cdc25 activates M-cdk

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40
Q

what do growth factor signals activate? (growth factors include mitogen)

A

mTORC1 kinase

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41
Q

aside from growth factors what also stimulates activation of mTORC1?

A

cytosolic amino acids

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42
Q

mitogen

A

promotes division

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43
Q

growth factors

A

increase cell size

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44
Q

mTORC (mechanistic target of rapamycin)

A

when active it stimulates protein synthesis, lipid synthesis, and reduces protein turnover ⇒ controls cell size
- kinase that integrates information coming from growth factors such as insulin like growth factors conveying information of nutrition
- nutrition like amino acids, etc. get integrated

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45
Q

what does mTORC1 do downstream?

A

promotes synthesis of macromolecules

46
Q

growth in cells; what phase?

A

increased size of cell ⇒ G1 phase

47
Q

proliferation

A

division

48
Q

endoreplication cycle checkpoints (unconventional)

A

S and G results in polytenization
- no M and no cytokinesis

49
Q

Polytenization

A

giant chromosomes with many stacks of replication on one another
- Ex: drosophila salivary gland, fat body, etc.

50
Q

what is the degree of politely in drosophila?

A

1024-2048 DNA (2^10-11)
- 10-11 cycles of replication

51
Q

glue proteins

A

multiple copies of genes allows a high level of gene expression ⇒ this can happen in a very short time frame
- Larva stage is a feeding time for drosophila but at the end they want to find a place to stick to a substrate with the glue protein
- Cells typically want to make a lot of proteins via transcriptional activation

52
Q

Syncytium formation

A

occurs when there are replications of chromosomes and mitosis but no cytokinesis in 1 cell (Synchronous) ⇒ occurs in drosophila
Mitosis without cytokinesis
- S and M phase only (skips G)

53
Q

what does syncytium result in?

A

thousands of nuclei in 1 cell ⇒ first 13 rounds mitosis (extremely rapid in 10 min intervals)

54
Q

what cells in the human body become syncytial and how/

A

muscle cells become syncytial by fusing after being multiple cells

55
Q

what kind of experiment would help you figure out how cells divide without killing the cell?

A

label chromosomal histones (H2A) with RFP as well as microtubule tubulin protein (spindles) with GFP

56
Q

2 properties of cancer

A
  1. Reproduce in defiance of the normal restraints on growth and division
  2. Invade and colonize territories normally reserved for other cells
57
Q

key properties of cancer (6)

A
  1. Disregard signals that regulate cell proliferation
  2. Avoid apoptosis
  3. Escape replicative senescence and avoid differentiation
  4. Genetically unstable
  5. Invade surrounding tissues
  6. Survive and proliferate in foreign sites (metastasis)
58
Q

senescence

A

a phase of time when cells proliferate a lot before they stop and start differentiation

59
Q

carcinomas

A

arise from epithelial cells

60
Q

adenocarcinomas

A

arise from glandular tissue

61
Q

sarcomas

A

arise from connective tissue or muscle cells

62
Q

leukemias

A

from white blood cells and their precursors

63
Q

lymphomas

A

derived from lymphocytes and found mainly within lymphoid organs

64
Q

what are the majority of cancers?

A

epithelial cell cancers which lead to carcinomas
- There are also other types such as myelomas, leukemias, and lymphomas

65
Q

neoplasm

A

tumor arising from the growth and proliferation of a cell in defiance of normal controls

66
Q

benign

A

tumor is self limiting in growth and noninvasive ⇒ difference in invasion ability
- Usually these are easily removable

67
Q

malignant

A

tumors have the ability to break away and travel via blood and lymph to other sites to form a metastasis

68
Q

carcinogens

A

cause of mutations ⇒ chemicals, ionizing radiations (X-ray), viruses
- Types consist of chemical, physical, and biological

69
Q

what initiates cancer?

A

mutations in the genes

70
Q

most cancers can be traced to what?

A

a single abnormal cell
- A single mutation is not enough to cause a cancer

71
Q

Chronic myelogenous leukemia (CML)

A

leukemia from white blood cells have the philadelphia chromosome created by a translocation between chromosome 9 and 22
- The site of breakage in all the leukemic cells is identical in any given patient indicating the cancer arises from a unique accident in a single cell

72
Q

spontaneous mutation rate

A

10-6 mutations/gene*cell division => The number of divisions that occur over a lifespan is 1016
- Development of a cancer typically requires a substantial number of independent genetic mutations to occur in the lineage of one cell

73
Q

T/F cancers increase with age

A

(T) The incidence of cancer increase with age as mutations accumulate
- cancer as a disease is age dependent
- peaks around 85 and then starts to decline again

74
Q

when did global smoking peak? What was the lag time?

A

in 1990 and global lung cancer deaths caused by smoking followed after decades
- Phenomenon of tumor progression during this lag time where prospective cancer cells accumulated genetic and epigenetic changes
- The time needed to accumulate mutations explains the lag

75
Q

what color are proliferating cells on a purple stain?

A

Proliferating cells are the dark stains

76
Q

where are dividing cells in normal epithelium?

A

only in the basal layer

77
Q

what are the progressive stages of an epithelial cancer?

A
  1. normal epithelium
  2. low grade intraepithelial neoplasia
  3. high grade intraepithelial neoplasia
  4. invasive carcinoma
    - at first it is limited to the basal side of the epithelial tissue ⇒ eventually all epithelial layers are filled with actively dividing cells which invade and break the lamina into the connective tissue
78
Q

what happens when cells have more mutations?

A

they predominantly grow due to natural selection
- Abnormal cells can become more and more abnormal and they grow more predominantly

79
Q

heterogeneity

A

over time a variety of competing subclones arise in a tumor
- when they divide faster they have a further chance of speeding up division allowing them to become the dominant cell type => This also allows for them to become more mutated (mutagenesis selection)

80
Q

what is cancer formation considered?

A

microevolution

81
Q

genetic instability

A

mutations interfere with replication and genome maintenance leading to increases of mutation rates
- Defects in DNA repair ⇒ changes in DNA sequence, translocations and duplications, defects in chromosome segregation during mitosis ⇒ changes in karyotype

82
Q

what happens when you hit a fundamental mechanism of genetic maintenance?

A

mutation becomes significant enough so you can’t maintain normal karyotypes

83
Q

what cells are responsible for tissue maintenance in normal organ homeostasis?

A

stem cells
- Stem cells divide relatively slowly and undergoes asymmetric division to self renew and differentiate into multiple cell types (transit amplifying cells) ⇒ become different cells
- This creates heterogeneous cell populations

84
Q

what cells do some cancers contain?

A

cancer stem cells

85
Q

Cancer stem cells (CSCs)

A

maintain the tumor and large number of dividing cancer transit amplifying cells ⇒ derived from CSCs but have a limited capacity for self renewal

86
Q

what happens when CSCs are purified and injected into an imunnodeficient animal?

A

they have a greatly enhanced ability to create new tumors in vivo

87
Q

how do CSCs contribute to cancer returning?

A

many current cancer therapies preferentially kill the most rapidly proliferating cells, slow dividing cancer stem cells are less sensitive to these treatments

88
Q

what kinds of mutations do cancer cells incur?

A

mutations that disable apoptotic mechanisms

89
Q

what 2 things increase tumor growth?

A
  1. an increase in cell division
  2. a decrease in apoptosis
90
Q

what do normal cells need to be attached to to survive? What about cancer cells?

A

normal cells do not divide unless they are attached to the substratum but cancer cells often divide in suspension

91
Q

contact inhibition

A

normal cells stop moving and dividing when culture reaches confluence

92
Q

transformed cancer phenotype

A

cancer cells continue dividing and pile up in layer upon layer in culture ⇒ when these cells change from normal they are transformed cells

93
Q

foci

A

piles of uninhibited transformed (cancer) cells

94
Q

where are cells extruded from in normal conditions?

A

cells are extruded into the lumen to generally undergo apoptosis

95
Q

what happens when tumor cells are extruded apically

A

they might survive but are likely to be eliminated

96
Q

what happens when tumor cells are extruded basally?

A

can more readily initiate invasion ⇒ this is different from extrusion on the apical side

97
Q

what do normal adult cells do with glucose?

A

generally fully oxidize almost all glucose to produce ATP via oxidative phosphorylation
- Only when O2 is deprived, the normal cells convert pyruvate to lactate

98
Q

what do cancer cells do with glucose?

A

they have abnormally increased glucose uptake and reduced oxidative phosphorylation (100-1000x more glucose uptake)
- This occurs regardless of oxygen presence
- This may be related to the condition of cancer where cells have a difficult time accessing oxygen via vessels

99
Q

androgenesis

A

new blood cell formation created by cancers

100
Q

Warburg effect (by-products?)

A

abnormally high glucose uptake where tumor cells form lactate and small molecule building blocks required for cell growth
- Byproducts like lactate which is building blocks may be helpful for cancer cells which facilitates rapid proliferation

101
Q

what do tumor cells and supporting connective tissue/stroma rely on?

A

communication
- Cancer cells want oxygen and to clear waste through blood vessels
- It’s not just vessels, but they also want to change their surrounding environments like the ECM

102
Q

what do cancer cells create around them?

A

a microenvironment

103
Q

tumor stroma

A

includes cancer cells, pericytes (vascular smooth muscle cells), fibroblasts, inflammatory white blood cells, blood and lymphatic vessels
- The tumor and its stroma evolve together

104
Q

metastasis steps

A
  1. break through the basal lamina
  2. invade capillary
  3. travel through bloodstream
  4. adhere to the vessel wall
  5. exit from the blood vessel
  6. form metastasis at a different site
105
Q

Epithelial mesenchymal transition (EMT)

A

cells are now floating (migrating) in connective tissues after breaking through the basal lamina to make them more mobile ⇒ epithelial like genes are no longer expressed and become more like mesenchymal genes

106
Q

what are the 2 components of Epithelial mesenchymal transition

A
  1. loosen cell-cell/cell-ECM adhesion ⇒ reduce both cadherins and integrins
  2. Degrade ECM ⇒ secrete proteases and heparanases breaking into ECM
107
Q

when can EMT happen aside from cancer?

A

EMT happens during normal development and regeneration ⇒ such as in drosophila

108
Q

Circulating tumor cells (CTCs)

A

when tumor cells are traveling through the bloodstream after breaking the basal lamina

109
Q

what happens when tumor cells exit from the blood vessel in their new location? what are the odds?

A

start proliferation at the new side inside of the new organ area
- This step is very difficult because cells know who they usually interact with and the new cells are very foreign
- The chance of the cells surviving at the foreign site is not that high

110
Q
A

Cell biology (15 decks)

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