Cell cycle-controlled interaction of nucleolin with the retinoblastoma protein and cancerous cell transformation
Cell cycle-controlled interaction of nucleolin with the retinoblastoma protein and cancerous cell transformation
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DOI：
10.1074/jbc.m513335200
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发表时间：
2006-08-04
影响因子：
4.8
通讯作者：
Wernet, Peter
中科院分区：
文献类型：
--
作者：
Grinstein, Edgar;Shan, Ying;Wernet, Peter
视网膜母细胞瘤蛋白(Rb)是一种多功能的肿瘤抑制因子，在某些类型的人类癌症中经常失活。核仁蛋白是增殖和癌细胞中一种丰富的多功能磷蛋白，近年来被发现是细胞周期调节的转录激活因子，控制宫颈癌中人乳头瘤病毒18型(HPV18)癌基因的表达。在这里，我们发现在细胞周期的G(1)期，在完整的细胞中，核仁素与Rb结合在一起，这种复合体的形成是由Rb的生长抑制结构域介导的。与Rb结合可抑制核仁的DNA结合功能，从而抑制核仁与HPV18增强子的相互作用，导致Rb介导的对HPV18癌基因的抑制。核仁在上皮细胞内的分布是依赖于Rb的，而人类癌症组织中核仁定位的改变是由于Rb的丢失造成的。我们的研究结果表明，由于RB缺失而导致的核仁活性失控有助于恶性肿瘤的发生，从而为RB介导的肿瘤抑制的分子网络提供了进一步的见解。
Retinoblastoma protein (Rb) is a multifunctional tumor suppressor, frequently inactivated in certain types of human cancer. Nucleolin is an abundant multifunctional phosphoprotein of proliferating and cancerous cells, recently identified as cell cycle-regulated transcription activator, controlling expression of human papillomavirus type 18 (HPV18) oncogenes in cervical cancer. Here we find that nucleolin is associated with Rb in intact cells in the G(1) phase of the cell cycle, and the complex formation is mediated by the growth-inhibitory domain of Rb. Association with Rb inhibits the DNA binding function of nucleolin and in consequence the interaction of nucleolin with the HPV18 enhancer, resulting in Rb-mediated repression of the HPV18 oncogenes. The intracellular distribution of nucleolin in epithelial cells is Rb-dependent, and an altered nucleolin localization in human cancerous tissues results from a loss of Rb. Our findings suggest that deregulated nucleolin activity due to a loss of Rb contributes to tumor development in malignant diseases, thus providing further insights into the molecular network for the Rb-mediated tumor suppression.