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BIOLOGY AND TREATMENT CANCER > week 18 p1 > Flashcards

week 18 p1 Flashcards

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AP® Biology flashcards Biology 101 flashcards
1
Q
  1. What is oncogene
A

Oncogenes arise from gain-of-function mutations which over-activate genes involved in cell proliferation

Mutated gene whose protein is produced in either higher quanity or altered manner to increase activity

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2
Q

What is protooncogene

A

• A proto-oncogene is the normal unmutated gene which regulates cell proliferation

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3
Q
  1. Who discovered SRC
A

In 1911 Peyton Rous identified the Rous Sarcoma Virus which could be transmitted between chickens causing cancer

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4
Q
  1. What is The discovery of src (retroviral transfer)
A

• In 1911 Peyton Rous identified the
Rous Sarcoma Virus which could be
transmitted between chickens
causing cancer.

• In 1941 he transformed normal
cells into tumour cells in culture by
infecting them with the virus

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5
Q

What happen in the 1960s

A
  • In the 1960s everyone was working on RSV (Harry Rubin, Howard Temin, Peter Vogt and Hidesaburo and Teruko Hanafusa)
    * They isolated RSV strains that did not transform cells
    • Other strains could transform but could not replicate themselves
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6
Q
  1. what did Tentin and the other disover about the gene
A
  • one gene was responsible for the transforming capacity
    • and that this was separate from the genes necessary for viral replication
    • At the same time another group of scientists found out that the RSV genome was made of RNA not DNA (Crawford, Robinson, Duesberg)
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7
Q

What happened in 1970s

A

Molecular biology was invented
Temin continued his work using this technology and isolated reverse- transcriptase from RSV

Baltimore and his group simultaneouslyisolated it from another virus    This explained how a virus (made of RNA) could integrate into a mammalian     genome (made of DNA) becoming a provirus
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8
Q

what else occurred in 1970

A

This enabled some more ground-breaking scientists (Stehelin and Bishop)

to reverse transcribe the RSV genome and generate labelled probes to the src gene.

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9
Q

How did the SRC originality

A

avian cellular gene and was “stolen” by the RSV virus and turned into an oncogene by a viral promoter.

Un-mutated chicken src was called a proto-oncogene

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10
Q

How is SRC oncogene is derived from the host genome

A
  • Virus is uncoated on the entry in the host cell
    • Reverse transcriptase make DNA copy of the vital genome in the host cell
    • Second strand of DNA is made by copying the first
    • Viral DNA is integrated into the host chromosomes
    • Viral mRNA is transcribed
    • Viral proteins are are produced if the retrovirus has been picked up by the mamelian gene, this mean that oncoproteins will be also be produced
    • Viral particles are assembled
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11
Q

How does Oncogenes and human cancer

A
  • Retroviral activation of proto-oncogenes is associated with many animal tumours
    • However, very few retroviruses are involved in human cancers
    • Human tumours contain activated oncogenes without the viral intermediary
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12
Q

what was the discovery of RAS (mammalian cell transfection)

A
  • • Begins with viruses in the 60s again:

* •Lather it became possible to transfect DNA into mammalian cells without viral vectors.

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13
Q

what is DNA transfection assay

A

• DNA from tumour cell lines collected
• Transfected into mouse cultured cells
• Transformed cells identified by increased growth and loss of contact inhibition
• Transformed cells produce tumours in athymic (nude)
mice

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14
Q

how was Multiple RAS genes exist

A

Between 1981 and 1984 the human homologues

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15
Q

What are the different Ras

A

• HRAS was discovered in DNA from the EJ/T24
bladder carcinoma line
• KRAS was discovered in DNA from lung and colon cancers
• NRAS was discovered in DNA from Neuroblastomas

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16
Q

what is Reciprocal translocation in ph chromoskmes

A 
A reciprocal translocation between
       Chromosomes 9 and 22
       t(9;22)(q34;q11)
    • The translocation affects an gene called
      ABL on Chr9 
	• fusing it to the BCR gene on
      Chr22.
    • The BCR-ABL fusion functions as an
      oncogene
17
Q

what is MYC (oncogenic amplification)

A

Double minute chromosomes are “small
chromatin bodies whose origin and
function are uncertain”

• In neuroblastoma (up to 80%) they exist
in multiple copies and contain the gene
N-MYC

18
Q

What is IDH1 (Next Generation DNA Sequencing)

A 
• Discovered by sequencing 20,661 protein coding
  genes 22 human glioblastoma (GBS)
  tumour samples.
• In 5 of the tumours they identified a
  mutated gene not previously known to
  be mutated in (GBS) – IDH1
• All 5 tumours had the same point
  mutation
• IDH1 has subsequently been found to
  be mutated in many types of glioma,
  colon cancer, and AML
19
Q
  1. What are Other oncogenes identified by Next Generation DNA Sequencing
A

The study involving IDH1 took around 3 years – compare that
with >60 for SRC
• Almost all future Oncogenes are likely to be discovered this
way
• Systematic sequencing of cancer genomes is now underway in
may laboratories eg
The Cancer Genome Project
Genomics England, 100,000 genomes project
Other oncogenes found this way include: IDH2, EZH2, and there
will be many more

20
Q

what is the function of proto-oncogenes

A

Self sufficient in growth signals

21
Q
  1. How does protooncogenes play an role in signal transduction
A
  • Extracellular: growth factors and receptors
    • Cytoplasmic: signal transduction
    • Nuclear: signal transcription back to cytoplasm
    • Signal translation
22
Q

What are the Growth factor proto-oncogen

A

• Molecules that stimulate cells to enter the cell cycle
e.g a hormone or vitamin
Oncogenic activation of receptor tyrosine kinases occurs through spefic mutations that leads to tyrosine activation
• Platelet-derived growth factor - (PDGF) - Sarcoma
• Fibroblast growth factor 1-7 - (FGF1-7) Breast Cancer
• Insulin-like growth factor 1-2 - (IGF1-2) - Wilms tumour
• Transforming growth factor - (TGF) a and b -Breast
Cancer

23
Q

What does growth factor interact with

A

receptors -receptor tyrosine kinases

24
Q

what is an example that could occur in Signal transducers

A 
• Eg SRC
	• non-receptor tyrosine kinase
	• Associates with activated receptors
	•  These include EGFR and PDGFR\
	• It becomes phosphorylated which
	•   activates its own kinase domain
 It phosphorylates downstream pathways involved in cell proliferation, survival, motility, cell-cell adhesion
25
Q

demonstrate how KRAS is also e.g. of signal transduction

A
  • Has Small GTPase
    • Activated by EGFR receptor
    • This leads to GDP molecules on KRAS being replaced by GTP
    • KRAS is now active.
    • It recruits RAF proteins and activates them so they
    • phosphorylate MEK
    • Yellow( red circfles in the diagram) highlighted is oncogenes
    • Pink (green circle in the diagram )highlight is tumour suppressor gene
26
Q

How does BRAF I in signal transduction occurs

A

• Serine threonine kinase
• Activated by GTP-KRAS
• Phosphorylates downstream
kinases MEK and ERK

27
Q

Give e.g. of transcription factors

A

• c-MYC
• bind directly to DNA usually at promoters
• Each transcription factor as a specific recognition sequence
• MYC binds at an E Box
• They have multiple target genes
• They often have binding partners (eg MYC and MAX)
• They can activate or repress transcription depending on binding partners, tissue type, context
c-MYC is amplified in Burkitts lymphoma, B-CLL

28
Q

how is c-JUN an e.g. of transcription factor

A

• Encodes part of the AP-1 transcription factor
• One binding partner is FOS (another oncogene)
• JUN is overexpressed in multiple cancer types including breast,
skin and liver.
• Overexpression is often caused by gene amplification

29
Q

how is Activation in human tumours happen

A
  • Activated cellular oncogenes have a DOMINANT gain-of-
    • function effect
    • Only one allele needs to be mutated.
    • (as opposed to the recessive tumour suppressor genes, here both alleles must be mutated
30
Q

How is oncogene activated

A

• Genetic mutation resulting in increased expression or stability: Point mutation, Chromosomal translocation
• Amplification: Many copies of the oncogene
Deregulated expression: Normal number of copies of the oncogene, but with abnormal increased expression

31
Q

how does KRAS cause Genetic mutation (point mutation)

A

KRAS (lung, colon, pancreas, skin etc)
• KRAS (and NRAS and HRAS) is typically activated by a point
mutation at one of three codons: 12, 13 or 61.
• The position and sequence of the mutation varies between
tissue types and can have therapeutic implications • Mutation at these sites causes a structural alteration which
favours GTP binding causing constitutive activation.

32
Q

ow can EGFR cause Genetic mutation (point mutation)

A

• EGFR (multiple cancer types)
• Missense mutations in the ATP binding domain cause over-
activation of the kinase.

33
Q

how can FGFR3 ECD cause genetic mutation (point mutation) ( uterine cancer)

A
  • specific amino acid substitutions that promote receptor dimerization
    • g FGFR3 S249C results in unpaired cysteine residues,
    • Allowing abnormal receptor dimerization through intermolecular disulphide bonding .
34
Q

how does BCR-ABL cause Genetic mutation (translocation)

A

• c-ABL is a non-receptor tyrosine kinase, a signal transduction protein
• It is normally tightly regulated
• BRC has serine/threonine kinase activity. It’s function
is still not clear.
• The fusion protein has greatly increased kinase activity which
activates multiple known cancer pathways (RAS, AKT, JUN)
• It is also trapped in the cytoplasm preventing it from inducing
apoptosis, a normal function of ABL

35
Q

how does MYCN (Neuroblastoma) promote Amplification

A

• Double minute chromosomes are small chromatin bodies
• They exist in multiple copies,sometimes >100 per cell
• Genes on DMs are expressed meaning that MYC expression
is increased in proportion with the number of DMs

36
Q

how does HER2/ERBB2 (Breast cancer) promote amplification

A
  • Also amplified on DMs
    • Or amplified in tandem arrays
    • These are detected as homogeneously staining regions (HSR)
37
Q

how does cMYC (Burkitts lymphoma) cause Deregulation of expression (translocation)

A

A translocation between chromosome 8 and usually 14
• MYC expression is normal tightly regulated by sequences in the surrounding DNA
• The immunoglobulin (IgH) transcriptional enhancers and
promoters are highly and constitutively active
• On the translocated chromosome the IgH transcriptional
machinery drives high levels of MYC
• Continuous MYC drives continuous proliferation\

BIOLOGY AND TREATMENT CANCER (4 decks)

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