p27Kip1 alters the response of cells to mitogen and is part of a cell-intrinsic timer that arrests the cell cycle and initiates differentiation
p27Kip1 alters the response of cells to mitogen and is part of a cell-intrinsic timer that arrests the cell cycle and initiates differentiation
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DOI：
10.1016/s0960-9822(98)70177-0
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发表时间：
1998-04-09
期刊：
影响因子：
9.2
通讯作者：
Raff, MC
中科院分区：
文献类型：
--
作者：
Durand, B;Fero, ML;Raff, MC
背景资料：在许多脊椎动物细胞谱系中，前体细胞在停止和终末分化成有丝分裂后细胞之前分裂有限次数。目前还不知道是什么原因导致它们停止分裂。我们一直在研究增殖前体细胞的“停止”机制，这些细胞产生少突胶质细胞，这些细胞在中枢神经系统中制造髓鞘。我们先前表明，细胞周期蛋白依赖性激酶抑制剂p27（Kip 1）（p27）在培养的前体细胞增殖过程中逐渐积累，并且增加的时间过程与p27积累是细胞内在计时器的一部分的可能性一致，该计时器在适当的时间阻止细胞周期并启动分化。我们现在提供了直接的证据，证明p27是内在计时器的一部分。我们发现，虽然p27（-/-）前体细胞停止分裂和分化几乎一样快的野生型细胞时，剥夺了有丝分裂原，当刺激饱和量的有丝分裂原，他们有一个正常的细胞周期时间，但往往通过一个或两个以上的分裂比野生型细胞之前，他们停止和分化。p27（+/-）细胞的行为处于中间状态，最多经历一次额外的分裂，这表明p27的水平对计时器的工作方式很重要。我们还表明，p27（-/-）前体细胞比野生型细胞更敏感的促有丝分裂作用的血小板衍生growthfactor.Conclusions：这些研究结果表明，p27是正常的定时器，确定少突胶质细胞前体细胞停止分裂和分化，至少在体外的一部分。似乎p27在许多其他细胞谱系中起着类似的作用，这可以解释p27（-/-）和p27（+/-）小鼠的表型。(C)Current Biology Ltd ISSN 0960-9822。
Background: in many vertebrate cell lineages, precursor cells divide a limited number of times before they arrest and terminally differentiate into postmitotic cells. It is not known what causes them to stop dividing. We have been studying the 'stopping' mechanism in the proliferating precursor cells that give rise to oligodendrocytes, the cells that make myelin in the central nervous system. We showed previously that the cyclin-dependent kinase inhibitor p27(Kip1) (p27) progressively accumulates in cultured precursor cells as they proliferate and that the time course of the increase is consistent with the possibility that p27 accumulation is part of a cell-intrinsic timer that arrests the cell cycle and initiates differentiation at the appropriate time.Results: We now provide direct evidence that p27 is part of the intrinsic timer. We show that although p27(-/-) precursor cells stop dividing and differentiate almost as fast as wild-type cells when deprived of mitogen, when stimulated by saturating amounts of mitogen they have a normal cell-cycle time but tend to go through one or two more divisions than wild-type cells before they stop and differentiate. Cells that are p27(+/-) behave in an intermediate way, going through at most one extra division, indicating that the levels of p27 matter in the way the timer works. We also show that p27(-/-) precursor cells are more sensitive than wild-type cells to the mitogenic effect of platelet-derived growth factor.Conclusions: These findings demonstrate that p27 is part of the normal timer that determines when oligodendrocyte precursor cells stop dividing and differentiate, at least in vitro. It seems likely that p27 plays a similar role in many other cell lineages, which could explain the phenotypes of the p27(-/-) and p27(+/-) mice. (C) Current Biology Ltd ISSN 0960-9822.