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I have always been interested in processes that regulate cell proliferation and cancer. An early fascination with RNA tumor viruses prompted me to clone two retroviral oncogenes (FES and FMS). Although the functions of the encoded oncoproteins were initially mysterious, we deduced that the FMS proto-oncogene encoded the cell surface receptor for macrophage colony-stimulating factor-1 and identified mutations in the receptor that were responsible for triggering growth-promoting signals in the absence of ligand. In searching for growth factor-responsive genes that might govern a cell's decision to replicate its chromosomal DNA, we discovered a novel class of regulators, the three D-type cyclins, and identified cyclin-dependent kinase-4 (CDK4) as a target of allosteric regulation. Cyclin D/CDK complexes act as growth factor sensors, integrating extracellular, mitogen-induced signals with the cell cycle engine to promote cell proliferation by phosphorylating the retinoblastoma protein (RB). Conversely, molecules that specifically inhibit these cyclin-dependent kinases, such as the so-called INK4 proteins, can efficiently arrest cell proliferation in an RB-dependent manner. Drugs that inhibit CDK4 are now finding their way into the clinic as agents that potently inhibit tumor growth. Surprisingly, an alternative reading frame protein (ARF), embedded within the p16INK4A locus, induces cell cycle arrest by activating p53. Thus, the INK4A-ARF locus and a second genetically linked INK4B gene regulate a tumor suppressor network that governs the functions of both RB and p53. Deletion of the INK4-ARF locus leads to combined interruption of RB and p53 signaling and is one of the most frequent events in cancer.
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