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...ng et al., 1994). C23. Cyclin A:Cdk2, in normal human fibroblasts, exists in complex with p21Cip1 bound to PCNA (Zhang et al., 1993). C24. Raf1 can bind and activate Cdc25A (Galaktionov et al., 1995; =-=Weinberg, 1995-=-), perhaps by phosphorylation. C24a. Raf1 is activated by Ras in a complex manner involving phosphorylations, as well as positive and negative effects of 14-3-3 interactions (Roy et al., 1998; Thorson...

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...., 1995, 1997; Klinghoffer et al., 1996; Dudek et al., 1997; Vanhaesebroeck et al., 1997). In the continued presence of mitogenic signals, cyclin D1– CDK4 complexes assemble and accumulate throughout G1 phase, enter the nucleus and undergo phosphorylation by CDK-activating kinase (CAK) to yield active holoenzymes. One key function of the cyclin D-dependent kinases is to initiate phosphorylation of the retinoblastoma protein (Rb), thereby helping to cancel its activity as a transcriptional repressor of a bank of genes, including cyclins E and A, whose activities are required for S phase entry (Weinberg, 1995; Sherr, 1996). A separate, non-catalytic action of cyclin D-dependent kinases is the sequestration of CKIs, including p27Kip1 and p21Cip1 (Sherr and Roberts, 1995). The Cip/Kip proteins interact with a variety of cyclin–CDK complexes through a conserved N-terminal domain that contains both cyclin and CDK binding sites (Toyoshima and Hunter, 1994; Chen et al., 1995, 1996; Luo et al., 1995; Nakanishi et al., 1995; Lin et al., 1996; Russo et al., 1996). Cyclin D-dependent CDKs isolated from mammalian cells appear to be less susceptible to Cip/Kip-mediated inhibition than are other classes of cyc...

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...le gate in late G1 marks the end of a requirement for external growth factor stimulation and correlates with the phosphorylation of the retinoblastoma protein (pRb) by cyclindependent kinases (cdks) (=-=Weinberg, 1995-=-, Sherr, 1996). The G1/S cell cycle arrest observed in suspended fibroblasts has been attributed to increased levels of the cdk inhibitors p27 Kip1 and p21 Cip1 , which inhibit the kinase activity of ...

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...operationally separates the cell cycle into an initial mitogen-dependent period and a largely cellautonomous, growth factor-independent period from the commitment to enter S phase until cell division =-=(4, 51, 62, 63, 66, 73)-=-. The commitment process at the G 1 checkpoint reflects complex integration of a plethora of positive and negative extracellular and intracellular signals transduced by multiple cascades into the cell...

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... of RB can arrest some, but not all, tumor cell lines in G 1 (10, 39, 44, 47). This growth-inhibitory activity of RB depends on its ability to bind cellular proteins and to assemble protein complexes =-=(47, 48, 51)-=-. Biochemical analysis has revealed the presence of at least three distinct protein binding functions in RB. The first protein binding function identified in RB was the A/B pocket, which is comprised ...

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...y in vivo, and genetic analyses have confirmed that these proteins have different biological consequences. While pRB is mutated in 30% of all human tumors, neither p107 nor p130 is a tumor suppressor =-=(68)-=-. Similarly, the mutation of pRB, p107, or p130 within otherwise isogenic mouse strains gives rise to very different phenotypes (14, 15, 41, 45, 46). Clearly, the different biological consequences of ...

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...ing cell growth in G 1, is now well established (27, 46, 59). Rb activity is regulated by phosphorylation in G 1 (7, 9, 19, 47, 49, 55, 56, 62), through the action of the G 1 cyclin-dependent kinases =-=(18, 26, 31, 33, 41, 81)-=-. The growth-regulatory activity of Rb directly coincides with its ability to physically interact with and regulate E2F (1, 3, 11, 28, 29, 39, 63). Indeed, overexpression of the E2F1 product, or produ...