Question

If the GTPase function of Ras is destroyed, Ras will always be on/activated. This causes increased Cyclin D and S phase genes expression by transcription factor E2F. Describe how this activation of Ras causes this increased expression of both Cyclin D and S phase genes by explaining the role/function of the following:

• Raf, MEK, ERK
• Myc
• Cyclin D/Cdk4 or Cdk 6
• Rb
• E2F

also indicate if any of the above are a kinase or transcription factor

Answer 1

Solution: The retinoblastoma (Rb) is a tumor suppressor protein that inhibits the specialized transcription factor E2F during the progression of cell cycle. When E2F is free, they can activate G1-S transition cyclins and S-phase cyclins. So the cell can progress further into the synthesis phase. So by preventing E2F by Rb, uncontrolled proliferation can be inhibited. Activated G1 cyclin cdk complexes(Cyclin D/ cdk 4 or 6) phosphorylates and removes Rb, thereby allowing cells to progress further into the cell cycle.

So we have to activate early response genes like c-fos, c-jun, c-myc. These gene products activate G1 phase cyclin CDKs. Activation of these early response genes occur through the MAP kinase pathway. Mutation to RAS protein(proto-oncogene), the signaling intermediate in the MAP kinase pathway induces the signal even in the absence of proper ligand binding to the receptor. Thus mutated RAS switch on this signaling cascade chronically. This produces early response genes and they inturn activate uncontrolled cellular proliferation and ultimately leads to cancer.