Bandara L R, Adamczewski J P, Zamanian M, Poon R Y, Hunt T, Thangue N B
Laboratory of Eukaryotic Molecular Genetics, MRC National Institute for Medical Research, Mill Hill, London, UK.
J Cell Sci Suppl. 1992;16:77-85. doi: 10.1242/jcs.1992.supplement_16.10.
Cyclins are regulatory molecules that undergo periodic accumulation and destruction during each cell cycle. By activating p34cdc2 and related kinase subunits they control important events required for normal cell cycle progression. Cyclin A, for example, regulates at least two distinct kinase subunits, the mitotic kinase subunit p34cdc2 and related subunit p33cdk2, and is widely believed to be necessary for progression through S phase. However, cyclin A also forms a stable complex with the cellular transcription factor DRTF1 and thus may perform other functions during S phase. DRTF1, in addition, associates with the tumour suppressor retinoblastoma (Rb) gene product and the Rb-related protein p107. We now show, using biologically active fusion proteins, that cyclin A can direct the binding of the cdc2-like kinase subunit, p33cdk2, to complexed DRTF1, containing either Rb or p107, as well as activate its histone H1 kinase activity. Cyclin A cannot, however, direct p34cdc2 to the DRTF1 complex and we present evidence suggesting that the stability of the cyclin A-p33cdk2 complex is influenced by DRTF1 or an associated protein. Cyclin A, therefore, serves as an activating and targeting subunit of p33cdk2. The ability of cyclin A to activate and recruit p33cdk2 to DRTF1 may play an important role in regulating cell cycle progression and moreover defines a mechanism for coupling cell-cycle events to transcriptional initiation.
细胞周期蛋白是在每个细胞周期中经历周期性积累和破坏的调节分子。通过激活p34cdc2和相关的激酶亚基，它们控制正常细胞周期进程所需的重要事件。例如，细胞周期蛋白A调节至少两个不同的激酶亚基，即有丝分裂激酶亚基p34cdc2和相关亚基p33cdk2，并且人们普遍认为它是S期进程所必需的。然而，细胞周期蛋白A还与细胞转录因子DRTF1形成稳定的复合物，因此可能在S期执行其他功能。此外，DRTF1与肿瘤抑制因子视网膜母细胞瘤（Rb）基因产物和Rb相关蛋白p107相关联。我们现在使用具有生物活性的融合蛋白表明，细胞周期蛋白A可以指导cdc2样激酶亚基p33cdk2与包含Rb或p107的复合DRTF1结合，并激活其组蛋白H1激酶活性。然而，细胞周期蛋白A不能将p34cdc2引导至DRTF1复合物，并且我们提供的证据表明细胞周期蛋白A-p33cdk2复合物的稳定性受DRTF1或相关蛋白的影响。因此，细胞周期蛋白A作为p33cdk2的激活和靶向亚基。细胞周期蛋白A激活p33cdk2并将其募集到DRTF1的能力可能在调节细胞周期进程中起重要作用，而且定义了一种将细胞周期事件与转录起始偶联的机制。
