p27Kip1 and cyclin dependent kinase 2 regulate passage through the restriction point
p27Kip1 and cyclin dependent kinase 2 regulate passage through the restriction point
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DOI：
10.4161/cc.5.19.3318
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发表时间：
2006-10-01
期刊：
影响因子：
4.3
通讯作者：
Stacey, Dennis W.
中科院分区：
文献类型：
--
作者：
Hitomi, Masahiro;Yang, Ke;Stacey, Dennis W.
当静止细胞被刺激重新进入细胞周期时，仅在G（1）期的限制点之前需要生长因子。在这一点之后，细胞不再需要生长因子，增殖信号分子，甚至蛋白质合成来启动DNA合成，这在几个小时后开始。因此，了解限制点的分子性质构成了生长调节研究的主要目标之一。我们最近证明，p27 Kip 1（p27）调节通过G（1）期在活跃的增殖培养，并启动这些研究，以确定它是否也参与通过限制点后刺激静止细胞。在支持这一建议，我们发现，通过限制点需要有丝分裂原依赖性抑制高水平的p27通常存在于静止细胞。此外，随着培养进展到中期-G（1）期，通过限制点的细胞比例通过p27水平的人工抑制而增加，而该比例通过p27水平的升高而降低。p27通过调节细胞周期蛋白依赖性激酶（CDK）2的后续活化磷酸化来执行这一关键功能，我们也表明这是DNA合成起始所必需的并与之密切相关。我们的结论是，p27在中期G（1）期的表达水平决定了细胞何时通过限制点，并通过调节随后的CDK 2激活。
When quiescent cells are stimulated to reenter the cell cycle, growth factors are required only until the restriction point in G(1) phase. After this point the cell no longer requires growth factors, proliferative signaling molecules, or even protein synthesis in order to initiate DNA synthesis, which starts several hours later. Consequently, understanding the molecular nature of the restriction point constitutes one of the major goals in studies of growth regulation. We recently demonstrated that p27Kip1 (p27) regulates passage through G(1) phase in actively proliferating cultures, and initiated these studies to determine if it is also involved in passage through the restriction point following stimulation of quiescent cells. In support of this suggestion, we found that passage through the restriction point requires mitogen-dependent suppression of the high p27 levels normally present in quiescent cells. Moreover, as the culture progresses to mid-G(1) phase, the proportion of cells that pass the restriction point is increased by artificial suppression of p27 levels, while this proportion is reduced by elevation of p27 levels. p27 performs this critical function by regulating the subsequent activating phosphorylation of cyclin dependent kinase (CDK) 2, which we also show is necessary for and closely associated with the initiation of DNA synthesis. We conclude that the p27 expression level at mid-G(1) phase determines when a cell passes through the restriction point, and does so by regulating subsequent CDK2 activation.