Patients with two defective retinoblastoma (Rb) alleles invariably develop retinoblatomas, leading to its discovery as a tumor suppressor. Why do inactivating mutations in the RB (retinoblastoma) gene contribute to the generation of cancer cells? Rb binds to E2F and represses its activation function. Rb is deactivated upon phosphorylation by mid G1 cyclin-CDKs (and, eventually, late G1 cyclin-CDKs). E2F is a transcriptional activator for a litany of genes required for DNA synthesis. If Rb is mutated, then E2F is not properly inhibited and the genome replication can get out of control. Cancer cells proceed through the cell cycle very rapidly and thus need this sort of high levels of DNA synthesis.
E2F is a key host cell transcription factor in activating cellular genes required for synthesis of dNTPs, DNA polymerases, and other proteins required for cells to begin S-phase. Also, E2F binds and activates transcription from the adenovirus E2 promoter. The E2 region encodes viral proteins required for adenovirus DNA replication. In uninfected cells, retinoblastoma (aka Rb) is bound to E2F and inactivates it; in infected cells, Rb is not bound to E2F -- the adenovirus protein E1A binds to retinoblastoma and removes it from E2F. Since E1A deactivates retinoblastoma by binding it and displacing it from E2F, it accomplishes the equivalent of mutations in both retinoblastoma alleles: there is no functional cellular retinoblastoma. SV40 and polyomavirus Large T-antigen also binds Rb; mutations of SV40 and polyomavirus Large-T that did not bind retinoblastoma did not transform cells. p110 is another tumor suppressor that was found to be absolutely identical to retinoblastoma.
|Next Steps||Study the other tumor suppressor p53|