JM Lecture 55: Tumor Suppressors

Question 1

List examples of syndromes associated with increased incidence of cancers caused by mutations of specific genes.

Answer 1

Familial Retinoblastoma (pRb)
Wilms' Tumor (WT1)
Hereditary Breast Cancer (BRCA1, BRCA2)
Hereditary Melanoma (p16, p15)
Li-Fraumeni (p53)

Question 2

What distinguishes DNA tumor viruses from RNA tumor viruses?

Answer 2

DNA tumor viruses contain novel oncogenes within their genome that do not have a cellular counterpart

Question 3

Provide examples of DNA tumor viruses.

Answer 3

Simian virus 40 (express large T antigen that binds to both cellular p53 and Rb, inactivating their function)
Adenovirus (similar mechanism using E1A binding to pRb and E1 binding to p53)
Human Papilloma Virus (expresses E7 inactivating pRb and E6 which target p53 for degradation)

Question 4

What are the two forms of human retinoblastoma?

Answer 4

sporadic- typically occurs in a single eye, not associated with secondary tumors
hereditary- generally involves both eyes, involves secondary, non-ocular tumors

Question 5

Describe the key characteristic of active oncogenes.

Answer 5

gain of function arising from mutating a single allele

Question 6

Describe the key characteristic of mutated tumor suppressor genes.

Answer 6

loss of function requiring an effect on both genes

Question 7

What is the most commonly altered gene in human cancer?

Answer 7

p53

Question 8

Describe the pathway of mutated p53 and its role in tumor suppression inhibition.

Answer 8

mutations in p53 are most common in its “hotspots” (DNA binding regions or structural components for DNA articulation)
causes reduced protein degradation and increased stability because it can no longer interact with Mdm2 (its inhibitor) which is inhibited by ARF (which is upregulated by teh activation of Myc, Ras, and E1A by oncogenes)

Question 9

What is the job of p53 as a transcription factor?

Answer 9

upregulates genes such as p21 (cdk inhibitor) and PUMA and NOX (promoters of apoptosis)

Question 10

Describe the pathway of mutated APC tumor suppressor on human cancer.

Answer 10

frameshift mutations in APC genes result in expression of truncated proteins that no longer bind to beta-catenin (transcriptional regulation promoting cell proliferation) so it never gets phosphorylated and degraded –> continually active

Question 11

Name the ways haplo-insufficiency can result in loss of tumor suppressor function.

Answer 11

reduced expression
dominant negative effect
transcriptional silencing

Question 12

What is haplo-insufficiency?

Answer 12

where only one allele needs to be altered for tumor suppressor inactivation

Question 13

Describe reduced expression.

Answer 13

mutation of only one allele can result in reduced expression of the tumor suppressor protein (brings expression below the threshold for full tumor suppressor activity needed)

Question 14

Describe dominant negative effects.

Answer 14

one allele is mutated while the other remains wild type

presence of the mutated form of protein can complex with the wild type so that it is no longer able to function

Question 15

Describe transcriptional silencing of wild-type allele.

Answer 15

when one allele is inactivated by mutation and the remaining allele is silenced through some epigenetic means