Lecture 2: Tumor Suppressors Flashcards
What types of cells have been mutated to cause a loss of function in the development of cancer?
tumor suppressors
What are 5 characteristics of tumor suppressors?
1) Loss of function mutations on both alleles.
2) Targeted allelic loss; this can be by methylation (silencing) or deletion of the gene.
3) Inherited mutations that predispose one to cancer.
4) Somatic mutations in spontaneous tumors.
5) Ability to inhibit transformed cells in vitro.
Who argued that one bad copy of a tumor suppressor that is inherited predisposes one to cancer?
Bob Weinberg
Inherited mutations of which tumor suppressor gene predisposes one to breast cancer?
BRCA-1
How many mutations are needed to inactivate a tumor suppressor?
2
Is there a greater probability that a tumor suppressor will be inactivated or that an oncogene will be created?
The probability is the same.
What was the 1st tumor suppressor identified? By whom?
Rb (retinoblastoma suppressor gene); identified by Bob Weinberg.
What are 5 ways to deactivate the Rb tumor suppressor gene if you already have one bad copy of the gene?
1) Deletion of the Rb gene.
2) Point mutation.
3) Gene conversion.
4) Nondisjunction (loss of the normal chromosome)
5) Nondisjunction and duplication (loss of the normal chromosome and duplication of the abnormal chromosome)
What was the 2nd tumor suppressor identified?
p53
What does p53 do?
Causes cell-cycle arrest in cells with damaged DNA.
What happens if p53 is inactivated?
Cell division will continue with damaged chromosomes.
Which tumor suppressor is the only one to require only one mutation to be inactivated?
p53
What happens to tumor suppressors and oncogenes when p53 is inactive?
Oncogenes won’t turn off, tumor suppressors won’t come on.
Which tumor suppressor is a transcription factor and regulates both other tumor suppressors and oncogenes?
p53
True or false: There is not a single instance of an inherited tumor suppressor?
False (there is not a single instance of an inherited oncogene)
What is the p53 pathway?
ARF (TS) —>MDM2 (oncogene)—>p53 (TS)
ARF suppresses the MDM2 oncogene; MDM2 can inactivate p53.
What are three ways that the function of p53 can be affected?
1) Mutate p53.
2) Amplify MDM2 (oncogene that can de-activeate p53).
3) Inactive ARF (TS that controls MDM2).
Which scientist recognized that p53 is a tumor suppressor, not an oncogene? What was the key factor that led her to conclude this?
Suzy Baker; p53 is inherited.
Most viruses are ________ and must reverse transcribe _______ to make cancer.
RNA; DNA
Which viruses are made of DNA and make proteins that get rid of p53 and Rb tumor suppessors?
1) Simian Virus 40
2) Human Adenovirus
3) Human Papillomavirus
What 2 types of cancer are caused by the Human Papillomavirus?
Cervical and throat cancer
How does the Human Papillomavirus cause cancer?
It makes E6 and E7 genes that bind and get rid of p53 and Rb tumor suppressors.
What oncogene does NF1 tumor suppressor inhibit?
Ras
What condition is caused by an inactivated NF1 tumor suppressor? What are its characteristics?
Neurofibromatosis-1; tumors in the nervous system (usually relatively benign).
Which tumor suppressor regulates AKT activity?
PTEN; it regulates the P13K oncogene.
True or false; P13K, when active, converts PIP2 to PIP3.
True
How does PTEN regulate AKT activity?
It deactivates P13K, driving the PIP2–>PIP3 reaction in reverse (PIP3—->PIP2), preventing the activation of downstream AKT targets.
What do the tumor suppressors BRCA1 and BRCA2 do? With what type of cancer is mutations in these tumor suppressors associated?
They repair damaged DNA; breast cancer.
What does ARF stand for?
Alternate reading frame protein
What does ARF respond to?
Oncogenes
Which two tumor suppressors are 70% identical at the DNA level? How much alike are they at the protein level?
INK4 and ARF; 0% at the protein level
A mutation on which exon inactivates both Ink4 and ARF?
exon 2
Which tumor suppressor controls tumor suppessor p53? How?
ARF; by inactivating the oncogene MDM2
True or false: Cancer is a selective event in the human genome.
False
Which tumor suppressor controls the tumor suppressor Rb?
Ink4
What is the most silenced locus in the entire genome? When does it become more active?
The Ink4/ARF locus; later in life (as mammals age).
What is the trade-off of the Ink4 and ARF tumor suppressors?
They suppress cancer, but promote aging.
Why have Ink4 and ARF remained linked in mammals despite the risk of their simultaneous de-activation by a mutation on exon 2?
To keep them off until later in life, and this is best done if they are right next to each other.
_______ make the cell cycle go; ______make the cell cycle stop.
Oncogenes; tumor suppressors
Which genes inhibit CDK4s, but are still tumor suppressors?
Ink4s; because they can be mutated in familial cancers and, though they perform a redundant function, each does so in different tissues.
Why are the CDK inhibitors p21, p27, and p57 not tumor suppressors even thought they stop the cell cycle?
They aren’t familially predisposed and they perform a redundant function for all cells in the body (you would need 6 mutations to inactivate all of these genes to kill their function).
What is nondisjunction?
Chromosome loss
How does Simian Virus 40 deactivate of Rb and p53?
With Large T antigen
How does Human adenovirus deactivate Rb and p53?
Makes E1A and E1B proteins that bind p53 and Rb.
How does the Human Papillomavirus deactivate Rb and p53?
Makes E6 and E7 proteins that bind p53 and Rb.
What are the 4 major tumor suppressor?
1) Rb
2) p53
3) ARF
4) INK4a
What type of gene is the BRCA1?
Tumor suppressor gene (helps repair DNA)
What oncogene is targeted by NF1?
Ras
What is PTEN and what does it do?
It is a tumor suppressor (a phosphatase) that converts PIP3 back into PIP2 and inhibiting AKT activity (it functions just the opposite of PI3K, a kinase).
What is the configuration of p53?
It is a tetramer
Why is only one hit needed to deactivate p53?
A single mutant copy makes a protein that performs in a dominant negative fashion. One mutant copy in the tetramer makes the whole tetramer a mutant.
Which intracellular kinase that functions to inhibit apoptosis is inhibited by PTEN?
AKT (Protein kinase B)
Which oncogene can deactivate p53? Which tumor suppressor prevents this?
MDM2; ARF
Which CDK inhibitors stop the cell cycle, but are not tumor suppressors?
p21, p27, and p57; they all perform the same functions and you could therefore lose one and still maintain function.
At DNA level, INK4a and ARF are ______% identical. At the protein level, they are _______% identical.
70%; 0%
Which exons are part of INK4a?
1a, 2, and 3
Which exons are part of ARF?
1b, 2, and 3
True or false: A mutation on exon 1b will only affect INK4a?
False; it will only affect ARF
True or false: A mutation on exon 2 will only affect INK4a?
False. It will affect both ARF and INK4a.
What is the only thing that turns ARF on?
oncogenes