IGF-I and vasoactive intestinal peptide (VIP) regulate cAMP-response element-binding protein (CREB)-dependent transcription via the mitogen-activated protein kinase (MAPK) pathway in pituitary cells:: requirement of Rap1
IGF-I and vasoactive intestinal peptide (VIP) regulate cAMP-response element-binding protein (CREB)-dependent transcription via the mitogen-activated protein kinase (MAPK) pathway in pituitary cells:: requirement of Rap1
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DOI：
10.1677/jme.1.01703
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发表时间：
2005-06-01
影响因子：
3.5
通讯作者：
Cacicedo, L
中科院分区：
文献类型：
--
作者：
Fernández, M;Sánchez-Franco, F;Cacicedo, L
在以往的研究中，我们发现血管活性肠肽(VIP)的介导以及丝裂原活化蛋白激酶(MAPK)和cAMP/蛋白激酶A(PKA)信号通路之间的相互作用参与了胰岛素样生长因子I(IGF-I)和VIP诱导的乳酸菌的增殖。这些事实促使我们研究了IGF-1和VIP诱导的乳酸菌增殖的细胞内机制。培养的雄性大鼠垂体细胞暴露于IGF-I(10(-7)M)或VIP(10-7M)刺激MAPK级联反应。在带有Rap1 GTPase激活蛋白(Rapt Gap1)表达载体的GH4C1细胞中的研究表明，VIP诱导的MAPK激活减少，表明VIP依赖的细胞外信号调节激酶(ERK)通路的激活需要PKA-Rap1信号。IGF-I通过Ras-MAPK途径诱导cAMP反应元件(CRE)结合蛋白(CREB)磷酸化，而VIP通过PKA直接磷酸化CREB。利用瞬时转染Cre报告基因的GH4C1细胞，研究了调节IGF-1和VIP-CREB依赖的基因转录的机制。IGF-I和VIP刺激Cre介导的转录需要同时激活Ras-MAPK和cAMP/PKA信号。这种激活在APPT Gap1存在的情况下被阻断。综上所述，我们发现IGF-I和VIP能刺激垂体细胞MAPK活性和CREB的磷酸化。此外，VIP依赖的PKA-Rap1-ERK通路的激活介导了VIP和IGF-I对GH4C1细胞CREB依赖的转录的影响。因此，VIP和IGF-I诱导的乳酸菌增殖可能与Rap1有关。
In previous studies we demonstrated that vasoactive intestinal peptide (VIP) mediation, and interactions between mitogen-activated protein kinase (MAPK) and cAMP/protein kinase A (PKA) signaling pathways are implicated in insulin-like growth factor I (IGF-I)- and VIP-induced lactotroph proliferation. These facts led us to investigate the intracellular mechanisms involved in IGF-1- and VIP-induced lactotroph proliferation. Exposure of cultured male rat pituitary cells to IGF-I (10(-7) M) or VIP (10-7 M) stimulated the MAPK cascade. Studies in GH4C1 cells, with an expression vector for Rap1 GTPase-activating protein (Rapt GAP1), demonstrated reduced VIP-induced MAPK activation, indicating that VIP-dependent activation of the extracellular signal-regulated kinase (ERK) pathway requires PKA-Rap1 signaling. IGF-I induced cAMP-response element (CRE)-binding protein (CREB) phosphorylation through the Ras-MAPK pathway, whereas VIP phosphorylated CREB directly via PKA. The mechanisms that regulate IGF-1- and VIP-CREB-dependent gene transcription were examined using GH4C1 cells transiently transfected with a CRE reporter gene. IGF-I and VIP stimulation of CRE-mediated transcription required activation of both Ras-MAPK and cAMP/PKA signaling. This activation was blocked in the presence of Rapt GAP1. In summary, we showed that IGF-I and VIP stimulated MAPK activity and the phosphorylation of CREB in pituitary cells. Furthermore, VIP-dependent activation of PKA-Rap1-ERK pathways mediated VIP and IGF-I effects on CREB-dependent transcription in GH4C1 cells. Thus, it is possible that VIP- and IGF-I-induced lactotroph proliferation may involve Rap1.