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BC4009 > Lecture 16 & 17 (TSGs) > Flashcards

Lecture 16 & 17 (TSGs) Flashcards

1
Q

2 best studied tumour suppressor proteins

A

Rb and p53

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2
Q

What happens when tumour suppressor proteins are implicated in cancer?

A

They have lost their function - no longer able to negatively control cellular growth

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3
Q

Many tumourigenic DNA viral oncoproteins sequester…

A

Rb and p53

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4
Q

Tumorigenic DNA viral oncoproteins that interact with Rb (under-phosphorylated)

A
  • SV40 large T
  • Adenovirus E1A
  • HPV E7 antigen
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5
Q

Tumorigenic DNA viral oncoproteins that interact with p53

A
  • SV40 large T
  • Adenovirus E1B55K
  • HPV E6 antigen
  • EBNA-1
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6
Q

How does Rb negatively control cellular growth?

A
  • by repressing expression of genes that stimulate cell proliferation through its ability to bind E2F transcription factors & inhibit their activity
  • by activating expression of genes that inhibit proliferation
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7
Q

Two Rb-related proteins

A

p107 and p130 (pocket proteins)

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8
Q

Where do most mutations which inactive Rb occur?

A

in its pocket region

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9
Q

Rb pocket domains shown strong homology to which 2 general transcription factors?

A

TBP and TFIIB

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10
Q

How can transcriptional regulation by Rb be mediated?

A
  1. E2F (transcriptional activator)
  2. ATF (nuclear oncoprotein)
  3. RCE (retinoblastoma control element) sites
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11
Q

What transcription factor is implicated in Rb control of transcription from RCE sites?

A

SP-1

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12
Q

How does Rb function in terminal differentiation of muscle cells?

A

by preventing binding of MyoD dimers to DNA

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13
Q

The overall structure of the Rb protein depends on its __ state

A

phosphorylation

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14
Q

Most frequently implicated gene in human cancers

A

p53 (found inactivated - deleted/mutated)

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15
Q

p53 is a nuclear transcription factor that’s particularly active in response to…

A

cellular stress

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16
Q

Normal function of p53

A

To sense if problems are occurring within the cell (e.g. if there’s extensive nucleic acid damage, p53 will induce expression of genes involved in DNA repair and if this is unsuccessful, p53 will induce expression of genes involved in apoptosis)

17
Q

p53 functions as a __ and is subject to __

A

tetramer
phosphorylation

18
Q

~50% of ovarian cancer tumours have a __ mutation

A

p53

19
Q

Motif for p53 binding

A

5’ Pu-Pu-Pu-C-(A/T)-(A/T)-G-Py-Py-Py 3’

20
Q

4 domains of p53

A
  • N-terminal transactivation domain
  • DNA-binding domain (contains a zinc ion)
  • Oligomerisation domain
  • C-terminus regulatory domain
21
Q

How many different promoter regions can p53 bind?

A

~300

22
Q

p53 is normally present in __ levels in cells

A

low

23
Q

p53 is typically bound to __ , which regulates its turnover

A

MDM2

24
Q

Examples of events that will lead to the activation of p53

A
  • lack of nucleotides
  • UV radiation
  • ionising radiation
  • oncogene signalling
  • hypoxia
  • metabolic stress
  • blockage of transcription
25
Q

How does MDM2 regulate p53 turnover?

A

MDM2 expression is controlled by p53 (auto-regulatory loop). When MDM2 is expressed, it will associate with p53 and flag it for degradation. If problems arise within the cell, MDM2 will separate from p53 to liberate p53 activity.

26
Q

What is MDM2?

A

a ubiquitin ligase

27
Q

Activation of which kinases (due to DNA damage) leads to p53 phosphorylation, preventing it from binding to MDM2?

A

ATM and DNA-PK

28
Q

Examples of stress-activated kinases that perturb p53/MDM2 association

A
  • ATR
  • Casein kinase II
29
Q

Activated oncogenes such as Ras can induce the activity of another tumour suppressor protein called __ , which can bind MDM2

A

p14 ARF

30
Q

3 ways to prevent p53 degradation by MDM2

A
  • activated kinases
  • activated oncogenes
  • auto-regulatory loop
31
Q

p53 elicits cell cycle arrest in response to DNA damage through transcriptional induction of a gene called __

A

p21

32
Q

What does p21 inhibit?

A

several cyclin-CDK complexes

33
Q

p53, p21 and __ act together to sense DNA damage, halt cell cycle and repair DNA

A

PCNA

34
Q

What is NF-1?

A

a GTPase activating protein (GAP) for Ras

35
Q

NF-1 is __ when it’s implicated in cancer (neurofibromatosis)

A

inactivated (unable to stimulate Ras to hydrolyse GTP)

36
Q

How can overexpression of Rev-1 reverse Ras-induced transformation?

A

believed to do so by abortively sequestering Ras effector proteins like Raf and PI3K

37
Q

Genes implicated in hereditary breast and ovarian cancer (HBOC) syndrome

A

BRCA1 and BRCA2

38
Q

Tumour suppressor protein implicated in many colorectal cancer cases

A

APC

39
Q

What is PTEN?

A

a phosphatase that dephosphorylates PIP3 back into PIP2

BC4009 (11 decks)

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