OAZ regulates bone morphogenetic protein signaling through Smad6 activation
OAZ regulates bone morphogenetic protein signaling through Smad6 activation
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DOI：
10.1074/jbc.m510004200
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发表时间：
2006-02-24
影响因子：
4.8
通讯作者：
Hata, A
中科院分区：
文献类型：
--
作者：
Ku, MC;Howard, S;Hata, A
信号转导系统激活的强度和持续时间是细胞对刺激反应特异性的重要决定因素。目前还不清楚不同的细胞如何响应相同的细胞因子产生不同强度和持续时间的信号。我们研究了转录激活因子和Smad 1/4辅因子OAZ在调节骨形态发生蛋白（BMP）信号传导中的作用。我们证明，BMP 4刺激后，OAZ-Smad 1/4复合物结合并激活编码Smad 6的基因，Smad 6是BMP通路的特异性抑制剂。从多能胚胎癌细胞中去除内源性OAZ可以防止BMP 4诱导Smad 6，并延长BMP刺激后磷酸化Smad 1的检测期。相反，在通常不表达OAZ的细胞中，例如成肌细胞和平滑肌细胞，强制OAZ表达导致响应于BMP 4的更快和更高的Smad 6诱导，Smad 1磷酸化减少，以及BMP介导的反应减弱。我们的研究结果表明，OAZ可以通过Smad 6改变BMP刺激的强度和持续时间，并表明OAZ的组织特异性表达是BMP信号的细胞反应的关键决定因素。
The intensity and duration of activation of a signal transduction system are important determinants of the specificity of the cellular response to the stimulus. It is unclear how different cells can generate a signal of varying intensity and duration in response to the same cytokine. We investigated the role of the transcriptional activator and Smad1/4 cofactor OAZ in regulating bone morphogenetic protein (BMP) signaling. We demonstrate that upon BMP4 stimulation, an OAZ-Smad1/4 complex binds to and activates the gene encoding Smad6, a specific inhibitor of the BMP pathway. Removal of endogenous OAZ from pluripotent embryonal carcinoma cells prevents the induction of Smad6 by BMP4 and extends the period of detection of phosphorylated Smad1 after BMP stimulation. Conversely, in cells that do not normally express OAZ, such as myoblasts and smooth muscle cells, forced OAZ expression leads to faster and higher Smad6 induction in response to BMP4, decrease of Smad1 phosphorylation, and attenuation of BMP-mediated responses. Our results demonstrate that OAZ can alter the intensity and duration of the BMP stimulus through Smad6 and indicate that the tissue-specific expression of OAZ is a critical determinant of the cellular response to the BMP signal.