A mouse knock-in model exposes sequential proteolytic pathways that regulate p27Kip1 in G1 and S phase
A mouse knock-in model exposes sequential proteolytic pathways that regulate p27Kip1 in G1 and S phase
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DOI：
10.1038/35095083
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发表时间：
2001-09-20
期刊：
影响因子：
64.8
通讯作者：
Roberts, JM
中科院分区：
文献类型：
--
作者：
Malek, NP;Sundberg, H;Roberts, JM
蛋白p27(Kip1)是细胞分裂的抑制因子(1)。P27的增加导致增殖细胞退出细胞周期，而p27的减少是静止细胞恢复分裂所必需的(2，3)。P27的异常低含量与细胞过度增殖的病理状态有关，尤其是癌症(4-8)。在正常细胞和肿瘤细胞中，p27主要在翻译(9-11)和蛋白质周转的水平上被调节。细胞周期蛋白依赖性激酶2(CDK2)使p27蛋白在苏氨酸187(T187)上的磷酸化是p27蛋白降解的主要途径(12-15)。为了在体内关键地测试这一途径的重要性，我们在第187位用编码丙氨酸而不是苏氨酸的基因替换了小鼠的p27基因(p27(T187A))。在这里，我们发现表达p27(T187A)的细胞不能在细胞周期的S和G2期下调p27，但这对体外和体内的细胞增殖都有令人惊讶的温和的影响。我们为解释这一意想不到的结果所做的努力导致了控制p27的第二条蛋白分解途径的发现，这条途径由有丝分裂原激活，并在G1期专门降解p27。
The protein p27(Kip1) is an inhibitor of cell division(1). An increase in p27 causes proliferating cells to exit from the cell cycle, and a decrease in p27 is necessary for quiescent cells to resume division(2,3). Abnormally low amounts of p27 are associated with pathological states of excessive cell proliferation, especially cancers(4-8). In normal and tumour cells, p27 is regulated primarily at the level of translation(9-11) and protein turnover. Phosphorylation of p27 on threonine 187 (T187) by cyclin-dependent kinase 2 (Cdk2) is thought to initiate the major pathway for p27 proteolysis(12-15). To critically test the importance of this pathway in vivo, we replaced the murine p27 gene with one that encoded alanine instead of threonine at position 187 (p27(T187A)). Here we show that cells expressing p27(T187A) were unable to downregulate p27 during the S and G2 phases of the cell cycle, but that this had a surprisingly modest effect on cell proliferation both in vitro and in vivo. Our efforts to explain this unexpected result led to the discovery of a second proteolytic pathway for controlling p27, one that is activated by mitogens and degrades p27 exclusively during G1.