Cross-talk between different enhancer elements during mitogenic induction of the human stromelysin-1 gene
Cross-talk between different enhancer elements during mitogenic induction of the human stromelysin-1 gene
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DOI：
10.1074/jbc.271.30.18231
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发表时间：
1996-07-26
影响因子：
4.8
通讯作者：
Saus, J
中科院分区：
文献类型：
--
作者：
Kirstein, M;Sanz, L;Saus, J
血小板衍生生长因子(PDGF)诱导人基质分解素-1的表达，这是一种参与肿瘤侵袭和转移的基质金属蛋白酶。研究表明，PDGF诱导的基质分解素-1基因依赖于RAS，涉及三个已知的启动子元件(基质分解素-1 PDGF反应元件(SPRE)位点、两个头对头多瘤病毒增强子A结合蛋白3(PEA3)位点和激活蛋白-1(AP-1)结合位点)。在有丝分裂诱导过程中，这些反应元件似乎被组织成两个独立的转录单位，SPRE-AP-1和PEA3-AP-1，这是特定元件相互作用的结果。有趣的是，Raf-1的显性负性突变体的表达显著干扰了PEA3-AP-1的诱导，但不干扰SPRE-AP-1的诱导。相反，只有通过SPRE-AP-1进行的诱导才受到非典型lambda/iota蛋白激酶C(lambda/iota PKC)显性负突变表达的显著影响。这些数据有力地表明，PDGF触发的信号流经RAS，并分成两条不同的通路，一条通过Raf，涉及PEA3-AP-1，另一条不依赖于Raf，通过lambda/IOTA PKC和SPRE-AP-1。此外，我们提出的证据表明，新的SPRE结合转录因子SPBP与c-Jun交叉偶联，反式激活SPRE位点。
Platelet-derived growth factor (PDGF) induces the expression of human stromelysin-1, a matrix metalloproteinase involved in tumor invasion and metastasis. Here it is shown that stromelysin-1 gene induction by PDGF depends on Ras and involves three previously identified promoter elements (the stromelysin-1 PDGF-responsive element (SPRE) site, the two head to-head polyomavirus enhancer A-binding protein 3 (PEA3) sites, and the activator protein-1 (AP-1) binding site). During mitogenic induction, these responsive elements appear to be organized in two independent transcriptional units, SPRE-AP-1 and PEA3-AP-1, which result from specific element cross talking. Interestingly, expression of a dominant negative mutant of Raf-1 significantly interfered with the induction through PEA3-AP-1 but not with that operating through SPRE-AP-1. Conversely, only the induction operating through SPRE-AP-1 was affected significantly by the expression of a dominant negative mutant of the atypical lambda/iota protein kinase C (lambda/iota PKC). These data strongly suggest that the signal triggered by PDGF flows through Ras and bifurcates toward two distinct pathways, one operating through Raf and involving PEA3-AP-1 and the other one Raf-independent, operating through lambda/iota PKC and SPRE-AP-1. Furthermore, we present evidence suggesting that the novel SPRE-binding transcription factor SPBP cross-couples with c-Jun to transactivate the SPRE site.