CDK inhibitors: positive and negative regulators of G1-phase progression

  1. Charles J. Sherr and
  2. James M. Roberts
  1. Howard Hughes Medical Institute, Department of Tumor Cell Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105 USA; Division of Basic Sciences, Fred Hutchinson Cancer Center, Seattle, Washington 98104 USA

This extract was created in the absence of an abstract.

Mitogen-dependent progression through the first gap phase (G1) and initiation of DNA synthesis (S phase) during the mammalian cell division cycle are cooperatively regulated by several classes of cyclin-dependent kinases (CDKs) whose activities are in turn constrained by CDK inhibitors (CKIs). CKIs that govern these events have been assigned to one of two families based on their structures and CDK targets. The first class includes the INK4 proteins (inhibitors of CDK4), so named for their ability to specifically inhibit the catalytic subunits of CDK4 and CDK6. Four such proteins [p16INK4a (Serrano et al. 1993), p15INK4b(Hannon and Beach 1994), p18INK4c (Guan et al. 1994; Hirai et al. 1995), and p19INK4d (Chan et al. 1995; Hirai et al. 1995)] are composed of multiple ankyrin repeats and bind only to CDK4 and CDK6 but not to other CDKs or to D-type cyclins. The INK4 proteins can be contrasted with more broadly acting inhibitors of the Cip/Kip family whose actions affect the activities of cyclin D-, E-, and A-dependent kinases. The latter class includes p21Cip1 (Gu et al. 1993; Harper et al. 1993; El-Deiry et al. 1993; Xiong et al. 1993a; Dulic et al. 1994; Noda et al. 1994), p27Kip1 (Polyak et al. 1994a,b; Toyoshima and Hunter 1994), and p57Kip2 (Lee et al. 1995; Matsuoka et al. 1995), all of which contain characteristic motifs within their amino-terminal moieties that enable them to bind both to cyclin and CDK subunits (Chen et al. 1995, 1996; Nakanishi et al. 1995; Warbrick et al. 1995; Lin et al. 1996; Russo et al. 1996).

Based largely on in vitro experiments and in vivo overexpression studies, CKIs of the Cip/Kip family …

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