p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest.

By K. Polyak, J. Kato, M. Solomon, C. Sherr, J. Massagué, J. M. Roberts, A. Koff. 1994

Cell-cell contact and TGF-beta can arrest the cell cycle in G1. Mv1Lu mink epithelial cells arrested by either mechanism are incapable of assembling active complexes containing the G1 cyclin, cyclin E, and its catalytic subunit, Cdk2. These growth inhibitory signals block Cdk2 activation by raising the threshold level of cyclin E necessary to activate Cdk2. In arrested cells the threshold is set higher than physiological cyclin E levels and is determined by an inhibitor that binds to cyclin E-Cdk2 complexes. A 27-kD protein that binds to and prevents the activation of cyclin E-Cdk2 complexes can be purified from arrested cells but not from proliferating cells, using cyclin E-Cdk2 affinity chromatography. p27 is present in proliferating cells, but it is sequestered and unavailable to interact with cyclin E-Cdk2 complexes. Cyclin D2-Cdk4 complexes bind competitively to and down-regulate the activity of p27 and may thereby act in a pathway that reverses Cdk2 inhibition and enables G1 progression.

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1. Carlos L. Arteaga
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5. Yang Lim
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7. J. Slingerland
8. J. Massagué

Citations in the corpus

• In silico protein interaction screening uncovers DONSON’s role in replication initiation (2023, background): “The defects seen upon DONSON depletion mirrored the effect of adding the CDK2 inhibitor p27 Kip ( 33 , 34 ) (Fig.1D,lane4,CDKi),suggestingthatDONSON functionsatthefinalstageofCMGassembly.”
• Living with or without cyclins and cyclin-dependent kinases. (2004, unknown): “, two potent inhibitors of Cdk2 (Polyak et al. 1994; Reynisdottir et al. 1995; Sherr and Roberts 1995).”
• CDK inhibitors: cell cycle regulators and beyond. (2008, unknown): “…p21Cip1/Waf1/Sdi1 (p21, encoded by cdkn1a) (el-Deiry et al., 1993; Gu et al., 1993; Harper et al., 1993; Xiong et al., 1993), p27Kip1 (p27, cdkn1b) (Polyak et al., 1994a; Polyak et al., 1994b; Toyoshima and Hunter, 1994), and p57Kip2 (p57, cdkn1c) (Lee et al., 1995; Matsuoka et al., 1995) share a…”
• Regulation of the Cdk inhibitor p27 and its deregulation in cancer (2000, unknown): “…in cells arrested by transforming growth factor-␤ (TGF-␤), by contact inhibition, and by lovostatin (Koff et al., 1993; Hengst et al., 1994; Polyak et al., 1994; Slingerland et al., 1994). p27 acts in G0 and early G1 to inhibit G1 cyclin cdks, with the primary target being E-type cy-…”
• PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest (2002, background): “p27 Kip1 was first identified as a mediator of TGF-β1-induced G1 arres”
• Molecular mechanisms underlying ErbB2/HER2 action in breast cancer (2000, background): “Under physiological conditions, it seems that p21Waf1 and p27Kip1, which can act as inhibitors of cyclin E- and A-dependent kinases, also act to positively regulate cyclin D-dependent kinases (Cheng et al., 1999; Polyak et al., 1994; Toyoshima and Hunter, 1994).”
• The logic of TGFβ signaling (2006, background): “In fact, p27Kip1 was the first identified mediator of the CDK inhibitory effect of TGFb [71,72].”
• Bcl11b is required for differentiation and survival of αβ T lymphocytes (2003, background): “To examine which apoptosis regulators are affected by the loss of Bcl11b, we analyzed the expression and phosphorylation of apoptosis-related protein”