V-Src and other viral oncogenes

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First Hallmark

Sustaining proliferative signaling

Second Hallmark

Evading growth suppressors

Third Hallmark

Activating invasion and metastasis

Fourth Hallmark

Enabling replicative immortality

Fifth Hallmark

Inducing angiogenesis

Sixth Hallmark

Resisting cell death

Sustaining Proliferative Signaling

signal to proliferative and divide, gas pedal, normal cells require mitogenic growth signals to move from a not dividing to a proliferative state; oncogenes

Oncogenes act

by mimicking growth stimulating pathways

Oncogenes

genes whose prodOucts are capable of transforming a normal cell into a cancer cell

Oncogenes result from

the mutation of normal genes (proto-oncogenes)

Mutations

changes in the bases of DNA, which may include transitions, transversions, deletions, amplification, insertions or translocations

Oncogene addiction

the dependence of a cancer cell on a specific oncogene for its maintenance

Peyton Rous

1911, chicken virologist, chicken cancer-sarcoma, could inject the tumor from one chicken to another and give cancer to the other chicken

Peyton Rous also

strained and filtered the tumor and injected and still observed tumor growth, called it Rous Sarcoma Virus (RSV)

4 main components of RSV Genome

• gag

• pol

• env

  • src

Gag

shell (protectivec)

Pol

provide enzymes (reverse transcriptase, etc.)

Env

surface proteins (attach and enter cells)

Src

oncogenes

Viral gene from RSV that kept the cells growing

Src

Src is

the first oncogene discovered

Who are the first people to discover src

Steven Martin, Peter Vogt, and Peter Duesberg

Oncogene

gene capable of causing cancer

Howard Temin and David Baltimore

Discovery of enzyme Reverse Transcriptase, added RSV to plate of normal cells, cells grow - did not die as a result of viral infection, RSV incorporated into cell’s DNA

Viral carcinogenesis

Normal cells + viral infection → affected cell that has viral DNA+ normal DNA → can lead to cell apoptosis or pre -cancer →→→ cancer

Retrovirus

virus with reverse transcriptase (RT)

RSV is an

RNA virus that when enters the cell, uses RT activity to transcribe viral RNA into double stranded complementary DNA, new viral cDNA then gets integrated in the host DNA

Harold Varmus and J. Michael Bishop

studied evolution of viral Src, found nearly identical version of viral Src inside normal cells (c-Src : cellular), normal Src was turned off and tightly regulated, but viral Src was always on

The Src protein

• viral v-Src

• Cellular c- Src

Viral v-Src

found in RSV; ALWAYS “ON” CAUSING PROLIFERATIVE SIGNALS; has no inhibitory domain

Cellular c-Src

found in normal cells; regulated and “obedient”; has inhibitory domain

Proto-oncogenes

normal cell genes can cause cancer; cancer proteins/genes do not have to come from virus

Varmus and Bishop Nobel Prize in 1989

the cellular origin of retroviral oncogenes

Is Src commonly mutated?

no

Does Src play a role in oncogenic signaling

yes; it is a central member to major cell signaling hubs within the cell

Simian viarus 40 (SV40)

Polyomavirus (DNA virus), found in monkeys and humans, possible link to cancer, often found in many samples, but still controversial

Large T antigen (TAg)

a protein encoded on viral genome