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首页> 外文期刊>American Journal of Physiology >Activation of cAMP-guanine exchange factor confers PKA-independent protection from hepatocyte apoptosis.
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Activation of cAMP-guanine exchange factor confers PKA-independent protection from hepatocyte apoptosis.

机译：cAMP-鸟嘌呤交换因子的激活赋予PKA独立保护免受肝细胞凋亡的作用。

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摘要

cAMP has previously been shown to promote cell survival in a variety of cell types, but the downstream signaling pathway(s) of this antiapoptotic effect is unclear. Thus the role of cAMP signaling through PKA and cAMP-regulated guanine nucleotide exchange factors (cAMP-GEFs) in cAMP's antiapoptotic action was investigated in the present study. cAMP's protective effect against bile acid-, Fas ligand-, and TNF-alpha-induced apoptosis in rat hepatocytes was largely unaffected by the selective PKA inhibitor, Rp-8-(4-chlorophenylthio)-cAMP (Rp-cAMP). In contrast, a novel cAMP analog, 8-(4-chlorophenylthio)-2'-O-methyl (CPT-2-Me)-cAMP, which activated cAMP-GEFs in hepatocytes without activating PKA, protected hepatocytes against apoptosis induced by bile acids, Fas ligand, and TNF-alpha. The role of cAMP-GEF and PKA on activation of Akt, a kinase implicated in cAMP survival signaling, was investigated. Inhibition of PKA with RP-cAMP had no effect on cAMP-mediated Akt phosphorylation, whereas CPT-2-Me-cAMP, which did not activate PKA, induced phosphatidylinositol 3-kinase (PI3-kinase)-dependent activation of Akt. Pretreatment of hepatocytes with the PI3-kinase inhibitor, Ly-294002, prevented CPT-2-Me-cAMP's protective effect against bile acid and Fas ligand, but not TNF-alpha-mediated apoptosis. Glucagon, CPT-cAMP, and CPT-2-Me-cAMP all activated Rap 1, a downstream effector of cAMP-GEF. These results suggest that a PKA-independent cAMP/cAMP-GEF/Rap pathway exists in hepatocytes and that activation of cAMP-GEFs promotes Akt phosphorylation and hepatocyte survival. Thus a cAMP/cAMP-GEF/Rap/PI3-kinase/Akt signaling pathway may confer protection against bile acid- and Fas-induced apoptosis in hepatocytes.
机译：先前已证明cAMP可以促进多种细胞类型的细胞存活，但是这种抗凋亡作用的下游信号传导途径尚不清楚。因此，本研究研究了通过PKA和cAMP调节的鸟嘌呤核苷酸交换因子（cAMP-GEFs）产生的cAMP信号在cAMP的抗凋亡作用中的作用。 cAMP对胆汁酸，Fas配体和TNF-α诱导的大鼠肝细胞凋亡的保护作用在很大程度上不受选择性PKA抑制剂Rp-8-（4-氯苯硫基）-cAMP（Rp-cAMP）的影响。相比之下，一种新型的cAMP类似物8-（4-氯苯硫基）-2'-O-甲基（CPT-2-Me）-cAMP激活了肝细胞中的cAMP-GEF，而没有激活PKA，可以保护肝细胞免受胆汁诱导的细胞凋亡。酸，Fas配体和TNF-α。研究了cAMP-GEF和PKA在激活Akt方面的作用，Akt是一种与cAMP生存信号有关的激酶。用RP-cAMP抑制PKA对cAMP介导的Akt磷酸化没有影响，而没有激活PKA的CPT-2-Me-​​cAMP诱导了磷脂酰肌醇3-激酶（PI3-激酶）依赖性的Akt激活。用PI3激酶抑制剂Ly-294002预处理肝细胞可阻止CPT-2-Me-​​cAMP对胆汁酸和Fas配体的保护作用，但不能阻止TNF-α介导的细胞凋亡。胰高血糖素，CPT-cAMP和CPT-2-Me-​​cAMP均激活了Rap 1，它是cAMP-GEF的下游效应子。这些结果表明，肝细胞中存在独立于PKA的cAMP / cAMP-GEF / Rap途径，而cAMP-GEFs的激活可促进Akt磷酸化和肝细胞存活。因此，cAMP / cAMP-GEF / Rap / PI3-激酶/ Akt信号传导途径可能赋予抗胆汁酸和Fas诱导的肝细胞凋亡的保护作用。

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