Tashiro Etsu, Tsuchiya Ayako, Imoto Masaya
Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama 223-8522, Japan.
Cancer Sci. 2007 May;98(5):629-35. doi: 10.1111/j.1349-7006.2007.00449.x. Epub 2007 Mar 14.
Cyclin D1 binds to the Cdk4 and Cdk6 to form a pRB kinase. Upon phosphorylation, pRB loses its repressive activity for the E2F transcription factor, which then activates transcription of several genes required for the transition from the G1- to S-phase and for DNA replication. The cyclin D1 gene is rearranged and overexpressed in centrocytic lymphomas and parathyroid tumors and it is amplified and/or overexpressed in a major fraction of human tumors of various types of cancer. Ectopic overexpression of cyclin D1 in fibroblast cultures shortens the G1 phase of the cell cycle. Furthermore, it has been demonstrated that introduction of an antisense cyclin D1 into a human carcinoma cell line, in which the cyclin D1 gene is amplified and overexpressed, causes reversion of the malignant phenotype. Thus, increased expression of cyclin D1 can play a critical role in tumor development and in maintenance of the malignant phenotype. However, it is insufficient to confer transformed properties on primary or established fibroblasts. In this review, we summarize the role of cyclin D1 on tumor development and malignant transformation. In addition, our chemical biology study to understand the regulatory mechanism of cyclin D1 transcription is also reviewed.
细胞周期蛋白D1与细胞周期蛋白依赖性激酶4（Cdk4）和细胞周期蛋白依赖性激酶6（Cdk6）结合形成pRB激酶。磷酸化后，pRB失去对E2F转录因子的抑制活性，E2F转录因子随后激活从G1期过渡到S期以及DNA复制所需的几个基因的转录。细胞周期蛋白D1基因在中心细胞淋巴瘤和甲状旁腺肿瘤中发生重排并过表达，并且在各种类型癌症的大部分人类肿瘤中扩增和/或过表达。在成纤维细胞培养物中异位过表达细胞周期蛋白D1会缩短细胞周期的G1期。此外，已经证明将反义细胞周期蛋白D1导入细胞周期蛋白D1基因扩增并过表达的人癌细胞系中会导致恶性表型的逆转。因此，细胞周期蛋白D1表达增加在肿瘤发生和维持恶性表型中可能起关键作用。然而，它不足以赋予原代或已建立的成纤维细胞转化特性。在本综述中，我们总结了细胞周期蛋白D1在肿瘤发生和恶性转化中的作用。此外，我们也综述了旨在了解细胞周期蛋白D1转录调控机制的化学生物学研究。
