The ability of a cancerous cell to break through senescence is governed by mutations affecting the pRb pathway, the p53 pathway, and the activation of Ras. As already discussed, pRb acts as the ultimate inhibitor of the G1 to S transition by binding and converting the E2F transcription factor into a repressor. Hyperphosphorylation of pRb, initially by cyclin D/Cdk4/6 and then cyclin E/Cdk2, dissociates pRb from E2F, allowing E2F-mediated transcription to occur. The importance of pRb in cancer is documented in hereditary retinoblastoma, which originally defined pRb as a tumor suppressor protein. In hereditary retinoblastoma, patients inherit one wild type and one mutant allele of RB1. The normal allele of RB1 is lost in a somatic cell, leading to the development of an RB1-/- tumor. This loss of heterozygosity (LOH) defines the classic tumor suppressors.3 Although mutation of RB1 itself leads mainly to retinoblastoma and some osteosarco-mas, the importance of the pRb pathway to all cancers has been confirmed by mutation of pRb or pRb pathway modifiers in other tumors. Nearly all known tumors contain a mutation that activates Cdk4, amplifies cyclin D, or eliminates the Cdk4/6 inhibitor p16INK4A. In particular, a high percentage of breast cancers exhibit overexpression of cyclin D1, whereas p16INK4A is often inactivated in melanomas and pancreatic cancer.4 Even more strikingly, known human tumor viruses, such as human papilloma virus, the causative agent of most cervical cancers, and Kaposi's sarcoma-associated herpesvirus, the causative agent of Kaposi's sarcoma, target the pRb pathway specifically through direct pRb inactivation or by expression of a constitutively active D-type viral cyclin, respectively. Finally, mutations in the pRb pathway appear to be mutually exclusive, with tumors containing mutations in only one gene in the pathway. Of special note, mutations within p16INK4A are especially potent because it shares its second exon, read in a different frame, with the p14ARF (alternate reading frame) tumor suppressor, which functions in the regulation of p53.2,13 The two proteins are both considered products of one gene, CDKN2A.
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