JM Lecture 54: Oncogenes

Question 1

Describe the ways RNA tumor viruses have been shown to act through oncogenic mechanisms.

Answer 1

1. viral genome contains the oncogene that is in the activated form (e.g. RSV)
2. the virus integrates in a genomic locus that results in aberrant expression of a cellular genome (e.g. ALV)

Question 2

What are the mechanisms for activation of oncogenes in human cancers?

Answer 2

when a proto-oncogene is…

1. deletion or point mutation in coding sequence
2. regulatory mutation
3. gene amplification
4. chromosome rearrangement

Question 3

How do deletion or point mutations in coding sequence result in human cancers?

Answer 3

they result in hyperactive protein made in normal amounts

constitutive activation

Question 4

How do regulatory mutations result in human cancers?

Answer 4

they result in normal protein that is greatly overproduced

Question 5

How do gene amplifications in proto-oncogenes result in human cancers?

Answer 5

normal protein is greatly overproduced (normally due to increases in copy number)

Question 6

How can chromosome rearrangement at the site of a proto-oncogene result in human cancers?

Answer 6

1. nearby regulatory DNA sequence causes normal protein to be overproduced (affects expression level)
2. fusion to actively transcribed gene produces hyperactive fusion protein (production of a novel, fusion protein)

Question 7

What are the most common missense mutations that contribute to human cancers and what do they result in?

Answer 7

Ras- loss of GTPase activity

Raf- constitutive activation as a kinase (commonly found in melanoma)

Question 8

What kinds of genes undergo amplification to lead to human cancers?

Answer 8

1. gene products that are normally limited in the cell (e.g. Myc, Cyclin D1, and Ckd4)
2. growth factor receptors (e.g. EGFR, Her2)- typically require a ligand to bind for dimerization and activation, but it is hypothesized if there are enough clumped together they can activate themselves
3. creation of an autocrine loop (e.g. overexpression of PDGF –> same cell expressing both growth factor and receptor)

Question 9

What are the possible configurations of chromosomal translocations?

Answer 9

1. reciprocal translocation (between two different chromosomes)
2. inversion within the same chromosome
   * both can involve regulatory regions (alter expression of a normal protein) or coding regions (resulting in expression of a novel, fusion protein)

Question 10

Provide examples of transcriptional regulation of relevant genes altered by gene rearrangements.

Answer 10

Burkitt’s Lymphoma (t(8;14))- involves myc gene and immunoglobulin enhancer
Folicular B-cell lymphoma (t(14;18))- bcl-2 gene and immunoglobulin enhancer
Parathyroid adenoma (inversion of chromosome 11)- parathyroid hormone promoter and cyclin D1 gene

Question 11

Provide examples of how gene rearrangement involving coding regions results in transcriptional over-expression/

Answer 11

Chronic Muelogenous Leukemia (CML)- Philidelphia chromosome translocation of 9q+ (c-abl gene) 22q+ (bcr gene)
Acute Promyelocytic leukemia (APL)- reciprocal translocation of chr 15 (PML gene) and chr 17 (RAR gene)

Question 12

What can you use to treat CML?

Answer 12

Gleevec- inhibits BcrAb1 (which is not found in normal cells)

Question 13

What is required to transform cells in culture?

Answer 13

activated Ras and a cooperating oncogene (e.g. myc or E1A)