A FoxO-Smad synexpression group in human keratinocytes
A FoxO-Smad synexpression group in human keratinocytes
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DOI：
10.1073/pnas.0605333103
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发表时间：
2006-08-22
影响因子：
11.1
通讯作者：
Massague, Joan
中科院分区：
文献类型：
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作者：
Gomis, Roger R.;Alarcon, Claudio;Massague, Joan
转化生长因子β（TGF -β）通过激活Smad转录因子发出信号。活化的Smad蛋白与不同的DNA结合辅因子结合，用于识别和调控特定的靶基因。叉头框O家族成员（FoxO1、FoxO3和FoxO4）在细胞周期蛋白依赖性激酶抑制剂p15Ink4b和p21Cipl的诱导中发挥这样的作用。为了描绘人角质形成细胞中TGF -β反应的组织形式，我们确定了一组基因，其被TGF -β激活需要FoxO和Smad两种功能。结果表明，在这些细胞中对TGF -β的115种即时基因激活反应中，有11种需要FoxO因子。FoxO1、FoxO3和FoxO4作为这些作用的介导因子具有冗余性。Smad4作为受体磷酸化的Smad2/3的伙伴，对所有这些反应都是必需的。这些结果确定了一个FoxO - Smad共表达组，即一组由共同机制响应TGF -β共同诱导的基因。除了p15INK4b和p21CIP1，这些基因还包括应激反应的介导因子（GADD45A、GADD45B和IER1）以及适应性细胞信号反应的基因（CTGF、JAG1、LEMD3、SGK、CDC42EP3和OVOL1）。对这些基因启动子区域的生物信息学分析揭示了Smad和FoxO结合元件的多种构型，这意味着这组基因在调控特性上存在差异。实际上，一部分依赖于FoxO/Smad的TGF -β基因反应还需要转录因子CCAAT/增强子结合蛋白β。FoxO - Smad共表达组的组成表明，应激反应和适应功能伴随着角质形成细胞对TGF -β的细胞生长抑制反应。
Transforming growth factor 13 (TGF-beta) signals through activation of Smad transcription factors. Activated Smad proteins associate with different DNA-binding cofactors for the recognition and regulation of specific target genes. Members of the forkhead box 0 family (Fox01, Fox03, and Fox04) play such a role in the induction of the cyclin-dependent kinase inhibitors p15Ink4b and p21Cipl. To delineate the organization of the TGF-beta response in human keratinocytes, we defined the set of genes whose activation by TGF-beta requires both FoxO and Smad functions. FoxO factors are shown to be essential for 11 of the 115 immediate gene activation responses to TGF-beta in these cells. Fox01, Fox03, and Fox04 act redundantly as mediators of these effects. Smad4, which functions as a partner of receptor-phosphorylated Smad2/3, is required for all of these responses. These results define a FoxO-Smad synexpression group or group of genes that are jointly induced by a common mechanism in response to TGF-beta. In addition to p15INK4b and p21CIP1, these genes include mediators of stress responses (GADD45A, GADD45B, and IER1) and adaptive cell signaling responses (CTGF, JAG1, LEMD3, SGK, CDC42EP3, and OVOL1). Bioinformatic analysis of the promoter region of these genes reveals diverse configurations of Smad and FoxO binding elements, implying differences in the regulatory properties of this group of genes. indeed, a subset of FoxO/Smad-dependent TGF-beta gene responses additionally require the transcription factor CCAAT/enhancer-binding protein P. The composition of the FoxO-Smad synexpression group suggests that stress reactions and adaptive functions accompany the cytostatic response of keratinocytes to TGF-beta.