Stepanova L, Leng X, Parker S B, Harper J W
Verna and Marrs McLean Department of Biochemistry, Baylor College of Medicine, Houston, Texas 77030, USA.
Genes Dev. 1996 Jun 15;10(12):1491-502. doi: 10.1101/gad.10.12.1491.
CDC37, an essential gene in Saccharomyces cerevisiae, interacts genetically with multiple protein kinases and is required for production of Cdc28p/cyclin complexes through an unknown mechanism. We have identified mammalian p50Cdc37 as a protein kinase-targeting subunit of the molecular chaperone Hsp90. Previously, p50 was observed in complexes with pp60v-src and Raf-1, but its identity and function have remained elusive. In mouse fibroblasts, a primary target of Cdc37 is Cdk4. This kinase is activated by D-type cyclins and functions in passage through G1. In insect cells, Cdc37 is sufficient to target Hsp90 to Cdk4 and both in vitro and in vivo, Cdc37/Hsp90 associates preferentially with the fraction of Cdk4 not bound to D-type cyclins. Cdc37 is coexpressed with cyclin Dl in cells undergoing programmed proliferation in vivo, consistent with a positive role in cell cycle progression. Pharmacological inactivation of Cdc37/Hsp90 function decreases the half-life of newly synthesized Cdk4, indicating a role for Cdc37/Hsp90 in Cdk4 stabilization. This study suggests a general role for p50Cdc37 in signaling pathways dependent on intrinsically unstable protein kinases and reveals a previously unrecognized chaperone-dependent step in the production of Cdk4/cyclin D complexes.
CDC37是酿酒酵母中的一个必需基因，它与多种蛋白激酶存在遗传相互作用，通过未知机制参与Cdc28p/细胞周期蛋白复合物的产生。我们已将哺乳动物的p50Cdc37鉴定为分子伴侣Hsp90的蛋白激酶靶向亚基。此前，p50在与pp60v-src和Raf-1的复合物中被观察到，但其身份和功能一直难以捉摸。在小鼠成纤维细胞中，Cdc37的一个主要靶点是Cdk4。该激酶由D型细胞周期蛋白激活，并在G1期进程中发挥作用。在昆虫细胞中，Cdc37足以将Hsp90靶向Cdk4，并且在体外和体内，Cdc37/Hsp90优先与未结合D型细胞周期蛋白的Cdk4部分结合。在体内经历程序性增殖的细胞中，Cdc37与细胞周期蛋白D1共表达，这与它在细胞周期进程中发挥的积极作用一致。Cdc37/Hsp90功能的药理学失活降低了新合成Cdk4的半衰期，表明Cdc37/Hsp90在Cdk4稳定化中发挥作用。这项研究表明p50Cdc37在依赖内在不稳定蛋白激酶的信号通路中具有普遍作用，并揭示了Cdk4/细胞周期蛋白D复合物产生过程中一个以前未被认识的伴侣依赖性步骤。
