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颠覆癌症新教条:细胞周期蛋白D激活抑癌因子RB

来源:生物谷 2014-07-09 08:56

2014年7月9日讯 /生物谷BIOON/--近日,加州大学医学院圣地亚哥分校医学院研究人员研究发现,一种对调节细胞周期进程必不可少的蛋白质实际上激活一个关键的肿瘤抑制因子,而不是如以前认为的那样灭活肿瘤抑制因子。

该研究结果发表在杂志eLife上。 细胞周期蛋白D在细胞复制(细胞周期)过程中第一阶段合成,被认为帮助驱动复杂的多阶段过程,其中包括与视网膜母细胞瘤(Rb)蛋白相互作用,Rb的功能是通过抑制细胞周期进程,防止细胞过度生长,直到细胞准备分裂,RB是一种肿瘤抑制蛋白。

但Rb突变或功能失调与几个主要的癌症相关,其与细胞周期蛋白D一直被认为促进癌症,因为细胞周期蛋白D被认为是通过磷酸化过程灭活Rb的肿瘤抑制功能。

研究人员Steven F. Dowdy博士和他的同事精心计算在细胞周期进展中,添加到RB的磷酸盐数量。有多达14个,但科学家发现,细胞周期蛋白D只是添加了其中一个单一的磷酸盐,单磷酸盐的作用是激活RB,而不是灭活它。

研究人员说,这一发现从根本上改变了对G1期细胞周期调控的理解和许多相关癌症的分子起源。(生物谷Bioon.com)

Cyclin D activates the Rb tumor suppressor by mono-phosphorylation

A. M. Narasimha, M. Kaulich, G. S. Shapiro, Y. J. Choi, P. Sicinski, S. F. Dowdy.

The widely accepted model of G1 cell cycle progression proposes that cyclin D:Cdk4/6 inactivates the Rb tumor suppressor during early G1 phase by progressive multi-phosphorylation, termed hypo-phosphorylation, to release E2F transcription factors. However, this model remains unproven biochemically and the biologically active form(s) of Rb remains unknown. In this study, we find that Rb is exclusively mono-phosphorylated in early G1 phase by cyclin D:Cdk4/6. Mono-phosphorylated Rb is composed of 14 independent isoforms that are all targeted by the E1a oncoprotein, but show preferential E2F binding patterns. At the late G1 Restriction Point, cyclin E:Cdk2 inactivates Rb by quantum hyper-phosphorylation. Cells undergoing a DNA damage response activate cyclin D:Cdk4/6 to generate mono-phosphorylated Rb that regulates global transcription, whereas cells undergoing differentiation utilize un-phosphorylated Rb. These observations fundamentally change our understanding of G1 cell cycle progression and show that mono-phosphorylated Rb, generated by cyclin D:Cdk4/6, is the only Rb isoform in early G1 phase.

 

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