Oncogenes

Transfection and tumors importance

injection of morphologically transformed cells into mouse hosts causes tumors

Proto-oncogenes traits

normal genes that can be mutational targets (activation)

targets of chemical carcinogens

highly conserved and expression tightly regulated

Proto-oncogenes in charge of

cell proliferation, differentiation or apoptosis

Nobel Prize 1989

awarded for discovery of cellular origin of retroviral oncogenes

discovery of oncogenes

1900s researchers linked cancers to nonbiological agents

1980s genome found to be rich source of genes that drive cancer cell proliferation

Nonbiological agents can induce cancer through their ability to transform cells

what proto-oncogene mutations are involved with cancer?

Gain of function mutations that produce dominant transforming oncogene

what happens when proto-oncogenes are mutated?

They become oncogenes

3 ways proto-oncogenes become activated to an oncogene

Point mutations

Chromosome rearrangements

Gene amplifications

Oncogene functions

regulate cell growth and differentiation

cell surface receptors

involved in signal transduction

DNA binding nuclear proteins

execution of mitogenic signals

Ras function

off when bound to GDP but when stimulated by growth factor it exchanges GDP for GTP, when mutated it is always on

Ras proto-oncogene to oncogene mutation

Point mutation inactivates intrinsic GTPase of RAS and prevents its interactions w/ GAPs (GAPS turn it off so it’s always on)

Ras mutated in 20-30% of cancer

Which codons are mutated in ras?

12, 13th, or 61st

Chromosomal rearrangement myelogenous leukemia

translocation between 9 and 22 produces abnormal fusion protein that has part of proto-oncogene c-abl (tyrosine kinase) and bcr protein (serine/threonine kinase activity)

Chromosomal rearrangement Burkitt’s Lymphoma

overexpression of unaltered normal proto-oncogene

c-myc activated by chromosomal translocation where it is now under regulation of immunoglobulin promoter

Myc

oncogene initially discovered in genome of avian retrovirus

activated through 3 alternative mechanisms- provirus integration, gene amplification, chromosomal translocation

at high levels drives uncontrolled cell proliferation

CCND1/cyclin D1

oncogene amplification and overexpression involved in breast, lung, melanoma, oral squamos cell carcinomas

Cyclin D1 family

Cdks are catalytic subunits of heterodimeric serine threonine protein kinases involved in controlling cell cycle progression

ERBB2 gene

overexpression of it occurs in 15-30% of breast cancers

ERBB1 belongs to which family of oncogenes?

receptor tyrosine kinases

Important things

ERBB1/2

CDKs from CCND1

Myc

C-abl

bcr

DNA methylation

turns off gene

histone acetylation

acetylation activates

histone methylation

methyl group to arginines turns off

methyl group to lysines can turn off or on

histone phosphorylation

establishes other interactions w/ other histone modification

Achilles heal of cancer

•conditional expression of a Bcr-Abl fusion gene resulted in the development of leukemia that eventually killed all of the mice. Yet, when the expression of this gene was switched off, even at advanced stages of disease, the leukemic cells underwent rapid and extensive apoptosis and the mice survived