Differential regulation of hepatocyte DNA synthesis by cAMP in vitro in vivo.
Differential regulation of hepatocyte DNA synthesis by cAMP in vitro in vivo.
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cAMP 体外体内肝细胞 DNA 合成的差异调节。
DOI：
10.1152/ajpgi.1996.271.5.g780
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发表时间：
1996
期刊：
影响因子：
--
通讯作者：
Diehl,AM
中科院分区：
文献类型：
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作者：
Westwick,JK;Fleckenstein,J;Yin,M;Yang,SQ;Bradham,CA;Brenner,DA;Diehl,AM
腺苷3′，5′-环单磷酸腺苷（cAMP）可在包括肝细胞在内的多种培养细胞中阻止表皮生长因子（EGF）诱导的DNA合成，但其在体内对细胞增殖的影响尚不清楚。本研究比较了补充cAMP对体内70%肝部分切除（PH）和体外EGF诱导的肝细胞增殖的影响，并确定了cAMP对生长调节转录因子家族AP-1和正常激活AP-1的激酶级联反应的影响。虽然在PH时注射二丁基腺苷3′，5′-环单磷酸（30 mg/kgip）使肝脏cAMP浓度增加至少100倍，持续数小时；在PH后24小时，cAMP不抑制[3H]胸苷在肝脏的掺入或增殖细胞核抗原的表达。cAMP处理导致PH后细胞外信号相关激酶（ERK）活性完全抑制，并短暂降低nh2末端Jun核激酶（JNK）活性，但不降低c-jun mRNA或蛋白的表达。与已知的cAMP对培养细胞jun-B的刺激一致，cAMP处理增加了ph后jun-B mRNA、蛋白质和DNA的结合活性。令人惊讶的是，cAMP治疗增强了大鼠PH后的Raf激酶活性。在原代肝细胞培养中，添加cAMP可抑制JNK和ERK活性、AP-1和c-Jun总转录活性以及DNA合成。因此，升高的cAMP在培养物和体内均抑制ERK和JNK活性，在培养物中抑制肝细胞增殖，而在体内无抑制作用。这表明体内机制补偿了cAMP对某些生长相关信号级联的抑制，并强调了从简单细胞培养系统推断完整动物生理的潜在风险。
Adenosine 3',5'-cyclic monophosphate (cAMP) prevents epidermal growth factor (EGF)-induced DNA synthesis in many types of cultured cells, including hepatocytes, but its effects on cellular proliferation in vivo are unknown. This study compares the effects of supplemental cAMP on hepatocyte proliferation induced in vivo by 70% partial hepatectomy (PH) and in vitro by EGF and determines the effects of cAMP on AP-1, a family of growth-regulatory transcription factors, and the kinase cascades that normally activate AP-1. Although injection of dibutyryladenosine 3',5'-cyclic monophosphate (30 mg/kgip) at the time of PH increased liver cAMP concentrations at least 100-fold for several hours, it did not inhibit hepatic incorporation of [3H]thymidine or proliferating cell nuclear antigen expression 24 h after PH. cAMP treatment led to a complete inhibition of extracellular signal-related kinase (ERK) activity and transiently reduced NH2-terminal Jun nuclear kinase (JNK) activity after PH but did not decrease the expression of c-jun mRNA or protein. Consistent with the known cAMP stimulation of jun-B in cultured cells, cAMP treatment increased jun-B mRNA, protein, and DNA binding activity post-PH. Surprisingly, cAMP treatment enhanced Raf kinase activity after PH in rats. In primary hepatocyte cultures, supplemental cAMP inhibited JNK and ERK activity, total AP-1 and c-Jun transcriptional activities, and DNA synthesis. Thus elevated cAMP inhibited ERK and JNK activity in culture and in vivo and inhibited hepatocyte proliferation in culture but not in vivo. This suggests that in vivo mechanisms compensate for cAMP inhibition of certain growth-related signaling cascades and emphasizes potential risks of extrapolating from simple cell culture systems to explain physiology in intact animals.