cAMP response element-binding protein (CREB) is required for epidermal growth factor (EGF)-induced cell proliferation and serum response element activation in neural stem cells isolated from the forebrain subventricular zone of adult mice
cAMP response element-binding protein (CREB) is required for epidermal growth factor (EGF)-induced cell proliferation and serum response element activation in neural stem cells isolated from the forebrain subventricular zone of adult mice
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DOI：
10.1507/endocrj.k11e-104
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发表时间：
2011-09-01
影响因子：
2
通讯作者：
Arita, Jun
中科院分区：
文献类型：
--
作者：
Iguchi, Hironobu;Mitsui, Tetsuo;Arita, Jun
神经发生受到多种环境因素、细胞外信号和细胞内信号转导途径的调控，不仅发生在发育中的大脑，也发生在成人大脑中的局限性区域，包括前脑室下区(SVZ)。我们研究了转录因子cAMP反应元件(CRE)结合蛋白(CREB)是否参与了成年小鼠SVZ分离的神经干细胞(NSCs)增殖的调控。蛋白激酶A(PKA)抑制剂H89和KT5720处理神经干细胞可抑制表皮生长因子(EGF)刺激的NSC增殖。当CREB的显性-负性突变体(MCREB)表达时，也观察到类似的抑制作用。EGF处理增加了Cre介导的转录活性，但这一增加远低于腺苷环化酶激活剂Forsklin的处理，后者既不改变NSCs的基础增殖，也不改变EGF刺激的NSCs增殖。无论是PICA抑制剂还是MCREB的表达都不能阻断EGF诱导的细胞外信号调节激酶(ERK)的磷酸化，ERK是一种介导EGF有丝分裂作用的蛋白激酶。然而，MCREB抑制了EGF诱导的几个即刻早期基因的表达，包括c-fos、c-jun、jun-B和fra-1，以及随后的AP-1转录激活。MCREB的表达也抑制了EGF刺激由血清反应元件(SRE)介导的转录激活的能力，SRE是调节c-fos基因表达的启动子序列。这些结果表明，在ERK激活和SRE介导的转录激活之间的水平上，CREB的基础活性是NSCs中EGF有丝分裂信号所必需的。
Neurogenesis, which occurs not only in the developing brain but also in restricted regions in the adult brain including the forebrain subventricular zone (SVZ), is regulated by a variety of environmental factors, extracellular signals, and intracellular signal transduction pathways. We investigated whether the transcription factor cAMP response element (CRE)-binding protein (CREB) is involved in the regulation of cell proliferation of neural stem cells (NSCs) isolated from the SVZ of adult mice. Treatment of NSCs with the protein kinase A (PKA) inhibitors H89 and KT5720 inhibited epidermal growth factor (EGF)-stimulated NSC proliferation. Similar inhibition was observed when a dominant-negative mutant of CREB (MCREB) was expressed. EGF treatment increased CRE-mediated transcriptional activity, but this increase was much less than that caused by treatment with the adenylate cyclase activator forskolin, which changed neither basal nor EGF-stimulated proliferation of NSCs. Neither PICA inhibitors nor MCREB expression blocked EGF-induced phosphorylation of extracellular signal-regulated kinase (ERK), a protein kinase mediating EGF's mitogenic action. However, MCREB suppressed EGF-induced expression of several immediately early genes including c-fos, c-jun, jun-B, and fra-1 and subsequent AP-1 transcriptional activation. MCREB expression also inhibited the ability of EGF to stimulate transcriptional activation mediated by the serum response element (SRE), a promoter sequence regulating c-fos gene expression. These results suggest that basal activity of CREB is required for the mitogenic signaling of EGF in NSCs at a level between ERK activation and SRE-mediated transcriptional activation.