近日，美国加州大学圣克鲁斯分校Seth M. Rubin及其研究团队发现p27能够变构激活周期蛋白依赖性激酶4，并拮抗palbociclib抑制。相关论文发表在2019年12月13日出版的《科学》上。

研究人员发现，当p27被酪氨酸激酶磷酸化时，变构激活CDK4与细胞周期蛋白D1（CDK4-CycD1）形成复合物。结构和生化数据表明，磷酸化的p27（phosp27）与CDK4的结合改变了三磷酸腺苷激酶位点，从而促进了视网膜母细胞瘤抑癌蛋白（Rb）和其他底物的磷酸化。令人惊讶的是，纯化的内源性phosp27-CDK4-CycD1复合物对靶向CDK4的药物palbociclib不敏感。相反，palbociclib主要靶向乳腺肿瘤细胞中的单体CDK4和CDK6（CDK4/6）。这些数据将phosp27-CDK4-CycD1定义为一种活性Rb激酶，其对临床相关的CDK4/6抑制剂具有耐药性。

研究人员表示，p27蛋白是细胞增殖的典型负调节因子，主要通过抑制细胞周期蛋白依赖性激酶（CDK）发挥作用。在某些情况下，p27与活性CDK4相关，但尚未发现激活机制。

附：英文原文

Title: p27 allosterically activates cyclin-dependent kinase 4 and antagonizes palbociclib inhibition

Author: Keelan Z. Guiley, Jack W. Stevenson, Kevin Lou, Krister J. Barkovich, Vishnu Kumarasamy, Tilini U. Wijeratne, Katharine L. Bunch, Sarvind Tripathi, Erik S. Knudsen, Agnieszka K. Witkiewicz, Kevan M. Shokat, Seth M. Rubin

Issue&Volume: 2019/12/13

Abstract: The p27 protein is a canonical negative regulator of cell proliferation and acts primarily by inhibiting cyclin-dependent kinases (CDKs). Under some circumstances, p27 is associated with active CDK4, but no mechanism for activation has been described. We found that p27, when phosphorylated by tyrosine kinases, allosterically activated CDK4 in complex with cyclin D1 (CDK4-CycD1). Structural and biochemical data revealed that binding of phosphorylated p27 (phosp27) to CDK4 altered the kinase adenosine triphosphate site to promote phosphorylation of the retinoblastoma tumor suppressor protein (Rb) and other substrates. Surprisingly, purified and endogenous phosp27-CDK4-CycD1 complexes were insensitive to the CDK4-targeting drug palbociclib. Palbociclib instead primarily targeted monomeric CDK4 and CDK6 (CDK4/6) in breast tumor cells. Our data characterize phosp27-CDK4-CycD1 as an active Rb kinase that is refractory to clinically relevant CDK4/6 inhibitors.

DOI: 10.1126/science.aaw2106

Source: https://science.sciencemag.org/content/366/6471/eaaw2106