Loss of G_sα impairs liver regeneration through a defect in the crosstalk between cAMP and growth factor signaling

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• 作者：Changli Lu¹ ; ² ; ^&dagger ; ; Jie Xia¹ ; ^&dagger ; ; Yongjie Zhou¹ ; ³ ; Xufeng Lu¹ ; Lei Zhang¹ ; ³ ; Maling Gou⁴ ; Lei Li⁵ ; Xiaoyun Zhang⁵ ; Hongjie Ji¹ ; ³ ; Keting Zhu¹ ; ³ ; Li Li¹ ; Jie Zhang¹ ; Ping Yu⁶ ; Jiayin Yang⁵ ; Hong Bu¹ ; ² ; ^{hongbu@scu.edu.cn" class="auth_mail" title="E-mail the corresponding author} ; Yujun Shi¹ ; ³ ; ^{shiyujun@scu.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：cAMP ; cyclic adenosine monophosphate ; CCl4 ; carbon tetrachloride ; CDK ; cyclin-dependent kinase ; CREB ; cAMP-responsive element-binding protein ; Erk ; extracellular signal-regulated kinase ; GPCR ; G-protein-coupled receptor ; Gsα ; the stimulatory G protein α subunit ; JNK ; c-Jun N-terminal kinases ; MAPK ; mitogen-activated protein kinases ; PH ; partial hepatectomy ; PKA ; protein kinase A ; Rb ; retinoblastoma protein
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：64
• 期：2
• 页码：342-351
• 全文大小：4669 K

文摘

The stimulatory G protein α subunit (G_sα) activates the cAMP-dependent pathway by stimulating the production of cAMP and participates in diverse cell processes. Aberrant expression of G_sα results in various pathophysiological disorders, including tumorigenesis, but little is known about its role in liver regeneration.

Methods

We generated a hepatocyte-specific G_sα gene knockout mouse to demonstrate the essential role of G_sα in liver regeneration using a mouse model with 70% partial hepatectomy (PH) or an intraperitoneal injection of carbon tetrachloride (CCl₄).

Results

G_sα inactivation dramatically impaired liver regeneration and blocked proliferating hepatocytes in G1/S transition due to the simultaneous depression of cyclin-dependent kinase 2 (CDK2) and cyclin E1. Loss of G_sα led to a fundamental alteration in gene profiles. Among the altered signaling cascades, the MAPK/Erk pathway, which is downstream of growth factor signaling, was disrupted secondary to a defect in phosphorylated Raf1 (pRaf1), resulting in a deficiency in phosphorylated CREB (pCREB) and CDK2 ablation. The lack of pRaf1 also resulted in a failure to phosphorylate retinoblastoma, which releases and activates E2F1, and a decrease in cyclin E1. Although these factors could be phosphorylated through both G_sα and growth factor signaling, the unique function of Raf1 in the growth factor cascade collapsed in response to the lack of G_sα.

Conclusion

The growth factor signaling pathway that promotes hepatocyte proliferation is dependent on G_sα signaling. Loss of G_sα leads to a breakdown of the crosstalk between cAMP and growth factor signaling and dramatically impairs liver regeneration.