Gastrin induces c-fos gene transcription via multiple signaling pathways.
Gastrin induces c-fos gene transcription via multiple signaling pathways.
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胃泌素通过多种信号通路诱导 c-fos 基因转录。
DOI：
10.1152/ajpgi.1999.276.2.g415
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发表时间：
1999
期刊：
影响因子：
--
通讯作者：
Todisco,A
中科院分区：
文献类型：
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作者：
Stepan,VM;Tatewaki,M;Matsushima,M;Dickinson,CJ;delValle,J;Todisco,A
我们先前观察到胃泌素(G17)对AR42J大鼠腺泡细胞株的营养作用是由丝裂原活化蛋白激酶(MAPK)通过蛋白激酶C(PKC)依赖和非依赖途径诱导c-fos转录介导的。在这项研究中，我们进一步研究了针对c-fosin对G17反应的信号通路。G17诱导含有小鼠c-fos启动子−356+109序列的细胞中的荧光素酶活性增加6倍，该序列包括SIS诱导元件、血清反应元件和钙/cAMP反应元件调节元件。加入选择性蛋白激酶C抑制剂GF-109203X或丝裂原活化蛋白激酶/细胞外信号调节激酶抑制剂PD-98059，荧光素酶活性下降80%。G17诱导ELK-1和SAP-1a的转录活性，这两种转录因子与SRE的E26转换特异性(Ets)DNA序列结合，这一作用可被GF-109203X和PD-98059抑制。Ets序列的点突变导致G17刺激的c-fostranscription诱导4倍，对表皮生长因子(EGF)的诱导诱导1.3倍。相反，SRE富含CA的G(Carg)序列的突变阻止了G17和EGF的转录激活。GF-109203X或PD-98059均不影响G17对Ets突变体的诱导作用。由于SRE的激活涉及到小的GTP结合蛋白Rho A，我们研究了Rho A在G17诱导c-fostranscription中的作用。通过特异性抑制剂C3或表达显性负的Rho A基因使Rho A失活，可将G17对野生型和ETS突变结构的诱导抑制60%。C3还能抑制G17刺激的AR42J细胞的增殖。因此，G17通过Rho A依赖的途径靶向c-fos启动子Carg序列，而Rho A似乎在G17的营养作用调节中发挥重要作用。
We previously observed that the trophic actions of gastrin (G17) on the AR42J rat acinar cell line are mediated by mitogen-activated protein kinase (MAPK)-induced c-fosgene transcription via protein kinase C (PKC)-dependent and -independent pathways. In this study, we further investigated the signaling pathways that target c-fosin response to G17. G17 led to a sixfold induction in luciferase activity in cells transfected with plasmids containing the −356+109 sequence of the murine c-fospromoter, which includes the Sis-inducible element (SIE), serum response element (SRE), and the Ca2+/cAMP response element (CRE) regulatory elements. Addition of either the selective PKC inhibitor GF-109203X or the MAPK/extracellular signal-regulated kinase inhibitor PD-98059 resulted in an 80% reduction in luciferase activity. G17 induced the transcriptional activity of both Elk-1 and Sap-1a, transcription factors that bind to the E26 transformation specific (Ets) DNA sequence of the SRE, and this effect was inhibited by both GF-109203X and PD-98059. Point mutations in the Ets sequence led to a 4-fold induction of c-fostranscription stimulated by G17 and to a 1.3-fold induction in response to epidermal growth factor (EGF). In contrast, mutations in the CA rich G (CArG) sequence of the SRE prevented transcriptional activation by both G17 and EGF. G17 induction of the Ets mutant construct was unaffected by either GF-109203X or PD-98059. Because activation of the SRE involves the small GTP-binding protein Rho A, we examined the role of Rho A in G17 induction of c-fostranscription. Inactivation of Rho A by either the specific inhibitor C3 or by expression of a dominant negative Rho A gene inhibited G17 induction of both the wild-type and the Ets mutant constructs by 60%. C3 also inhibited G17-stimulated AR42J cell proliferation. Thus G17 targets the c-fospromoter CArG sequence via Rho A-dependent pathways, and Rho A appears to play an important role in the regulation of the trophic action of G17.