Hypoxic repression of STAT1 and its downstream genes by a pVHL/HIF-1 target DEC1/STRA13
Hypoxic repression of STAT1 and its downstream genes by a pVHL/HIF-1 target DEC1/STRA13
复制标题
DOI：
10.1038/sj.onc.1209842
复制
发表时间：
2007-02-08
期刊：
影响因子：
8
通讯作者：
Lerman, M. I.
中科院分区：
文献类型：
--
作者：
Ivanov, S. V.;Salnikow, K.;Lerman, M. I.
DEC 1/STRA 13是一种bHLH型转录调节因子，参与免疫调节、缺氧反应和肿瘤发生。我们最近证明，STRA 13与STAT 3相互作用的转录激活STAT依赖的启动子。在这里，我们通过研究其在STAT 1表达中的作用来追踪STRA 13在JAK/STAT通路中的参与。首先，我们发现VHL缺陷或HIF-1激活导致由STRA 13介导的内源性STAT 1的抑制。然后，我们的特点STAT 1近端启动子，以评估其响应STRA 13的瞬时共表达在荧光素酶报告分析。使用序列截短和定点突变的STAT 1启动子与STRA 13缺失构建体，我们表明，STRA 13 C-末端反式激活结构域，这是已知的结合HDAC 1，主要决定了抑制活性。通过TSA抑制和染色质免疫沉淀（ChIP）测定验证HDAC活性参与STAT 1调节。因此，我们证明了STRA 13介导的STAT 1转录抑制利用HDAC 1依赖性机制。此外，我们还发现，未磷酸化STAT 1的靶点，如抗原呈递基因和CASP 1，也可能通过相同的STRA 13介导的机制受到缺氧的抑制。因此，新发现的HIF-1和STAT 1之间的联系揭示了STRA 13在缺氧和致癌作用中以前未知的作用。
DEC1/STRA13 is a bHLH type transcriptional regulator involved with immune regulation, hypoxia response and carcinogenesis. We recently demonstrated that STRA13 interacts with STAT3 in the transcriptional activation of STAT-dependent promoters. Here, we pursue STRA13 involvement in the JAK/STAT pathway by studying its role in STAT1 expression. First, we showed that VHL deficiency or HIF-1 activation resulted in the repression of endogenous STAT1 mediated by STRA13. We then characterized the STAT1 proximal promoter to assess its response to STRA13 by transient coexpression in a luciferase reporter assay. Using sequential truncation and site-directed mutagenesis of the STAT1 promoter with STRA13 deletion constructs, we showed that the STRA13 C-terminal trans-activation domain, which is known to bind HDAC1, mostly determines the repressive activity. Involvement of HDAC activity in STAT1 regulation was validated by TSA inhibition and chromatin immuno-precipitation (ChIP) assay. Thus, we demonstrate that STRA13-mediated repression of STAT1 transcription utilizes an HDAC1-dependent mechanism. Furthermore, we show that targets of unphosphorylated STAT1, such as antigen presenting genes and CASP1, are also repressed by hypoxia possibly through the same STRA13-mediated mechanism. Thus, the newly discovered link between HIF-1 and STAT1 reveals a previously unknown role of STRA13 in hypoxia and carcinogenesis.