Flashcards in Cancer Genetics Deck (27):
Mechanisms of action of tumor suppressor genes
1. Regulate cell cycle
2. Regulate cell death
3. Repair DNA
What are the hallmarks of a tumor suppressor gene?
1. Loss of wildtype protein in tumor cells
2. Germline mutations increase cancer susceptibility
3. Loss of gene in animal model should confer cancer-prone phenotype (p53 null mice develop lymphomas)
Outcome of functional loss of a tumor suppressor depends upon _____ and _____
tissue / context
Ubiquitously expressed tumor suppressor
How does Rb regulate cell cycle?
Binds E2F (transcription factor) ---> represses E2F-dependent transcription of cell cycle genes
What phosphorylates Rb?
What cancers can be caused by mutation of Rb?
Small cell lung cancer
What cancers can be caused by phosphorylation of Rb?
What cancers can be caused by viral oncoprotein associated with Rb?
DNA viruses can cause tumors via inactivation of which genes?
Rb and p53
T/F: Wild-type p53 is present in tumor cells
False. Only mutant p53 has been found in tumor cells.
Loss of wildtype p53 ---> _____
What is the most frequently mutated gene in human cancers?
What regulates p53?
MDM2 binds p53 and inactivates it
Mechanisms of mutant p53 mutation
1. Bind DNA to alter gene expression
2. Bind to transcription factors to enhance their function
3. Form a complex with transcription factors to prevent their function
4. Interact with proteins to change their diversity
Which tumor suppressor functions in adhesion and signaling?
What is one of the earliest events in colorectal cancer?
Loss of APC
BRCA mutations result in what?
How do mutations cause cancer?
They result in structural rearrangements of the protein so that the protein is continuously expressed (GAIN OF FUNCTION)
Describe the Ras point mutation.
Point mutations cause Ras to become GAP-insensitive (aka Ras cannot bind GAP) --> Ras is constitutively active / GTP is constitutively bound
What is gene amplification?
Expansion of gene copy number within the cell
Where is gene amplification frequently seen?
c-myc and erbB-2 (HER2) --> amplified in breast and ovarian cancers
Two mechanisms of chromosomal rearrangement
1. Transcriptional activation of proto-oncogenes
2. Creation of a fusion gene
What is an example of transcriptional activation caused by chromosomal rearrangement?
c-myc translocations in Burkitt's lymphoma
c-myc moved to locus of Ig heavy chain
What is an example of a fusion gene caused by chromosomal rearrangement?
c-abl gene (9) fused to bcr gene (22)
causes increased kinase activity and abnormal cellular localization
Where are the majority of mutations in colorectal cancers found?
In three functional protein groups:
1. Cellular adhesion and motility (APC)
2. Signal transduction (APC)
3. Transcriptional regulation (Ras)