Pro-proliferative Factor KLF5 Becomes Anti-proliferative in Epithelial Homeostasis upon Signaling-mediated Modification
Pro-proliferative Factor KLF5 Becomes Anti-proliferative in Epithelial Homeostasis upon Signaling-mediated Modification
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DOI：
10.1074/jbc.m806270200
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发表时间：
2009-03-06
影响因子：
4.8
通讯作者：
Dong, Jin-Tang
中科院分区：
文献类型：
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作者：
Guo, Peng;Dong, Xue-Yuan;Dong, Jin-Tang
在上皮稳态期间，干细胞分裂以产生祖细胞，祖细胞不仅增殖以产生细胞团，而且响应于细胞信号传导以从增殖状态转变为分化状态。这种转变涉及转录因子的功能改变，但其潜在的分子机制知之甚少。最近的研究表明，Kruppel样因子（KLF），包括KLF 5在干/祖细胞的更新和维持。在这里，我们证明了促增殖因子KLF 5在上皮稳态的体外模型中，在TGF β介导的乙酰化作用下具有抗增殖作用。在用或不用TGF β处理的HaCaT表皮细胞系中，我们发现KLF 5不仅是细胞增殖所必需的，而且在这些细胞中TGF β诱导的抗增殖中也是必不可少的。KLF 5抑制p15（CDKN 2B）的表达，细胞周期抑制剂，没有TGF β，但成为TGF β诱导的p15表达在相同的细胞中的共激活剂。从机制上讲，TGF β募集乙酰化酶p300使KLF 5乙酰化，乙酰化反过来改变了KLF 5与p15启动子的结合，导致KLF 5功能逆转。这些研究不仅表明，一个基本的转录因子可以既促增殖和抗增殖的上皮细胞的稳态，他们也提出了一个独特的机制，如何转录调控的变化，从增殖到增殖抑制的过渡。此外，他们将KLF 5确定为TGF β信号传导的重要辅因子。
During epithelial homeostasis, stem cells divide to produce progenitor cells, which not only proliferate to generate the cell mass but also respond to cellular signaling to transition from a proliferative state to a differentiation state. Such a transition involves functional alterations of transcriptional factors, yet the underlying molecular mechanisms are poorly understood. Recent studies have implicated Kruppel-like factors (KLFs) including KLF5 in the renewal and maintenance of stem/progenitor cells. Here we demonstrate that the pro-proliferative factor KLF5 becomes anti-proliferative upon TGF beta-mediated acetylation in an in vitro model of epithelial homeostasis. In the HaCaT epidermal cell line treated with or without TGF beta, we found that KLF5 was not only essential for cell proliferation, it was also indispensable for TGF beta-induced anti-proliferation in these cells. KLF5 inhibited the expression of p15 (CDKN2B), a cell cycle inhibitor, without TGF beta, but became a coactivator in TGF beta-induced p15 expression in the same cells. Mechanistically, TGF beta recruited acetylase p300 to acetylate KLF5, and acetylation in turn altered the binding of KLF5 to p15 promoter, resulting in the reversal of KLF5 function. These studies not only demonstrate that a basic transcription factor can be both pro-proliferation and anti-proliferation in epithelial homeostasis, they also present a unique mechanism for how transcriptional regulation changes during the transition from proliferation to inhibition of proliferation. Furthermore, they establish KLF5 as an essential cofactor for TGF beta signaling.