p53與Mcl-1蛋白於保護肝臟免於損傷、纖維化及癌症之協同效應研究

Synergism between p53 and Mcl-1 in protecting from hepatic injury, fibrosis and cancer

翁仕彥(Shih-Yen Weng)

指導教授 ： 楊性芳

國立臺灣大學/醫學院/分子醫學研究所/博士(2010年)

https://doi.org/10.6342/NTU.2010.03252

摘要

Mcl-1缺失的肝臟細胞有細胞凋亡的傾向。而腫瘤抑制因子p53則於細胞凋亡控制以及其他細胞的反應上扮演重要的角色。本研究目的在於檢視在Mcl-1缺失導致的細胞凋亡，p53是否參與其中。本研究利用專一性剔除肝臟Mcl-1的小鼠(Alb-Mcl-1-/-)，並比較其於p53存在與否之下的特性。
Alb-Mcl-1-/-小鼠雖可正常存活，其肝臟細胞卻傾向細胞凋亡，且發現p53稍微上升的現象。為了檢視p53在其間的功能，Alb-Mcl-1-/-及p53-/- 雙重突變 (DKO)的小鼠因此被分析及檢視。出乎意料的是，雖然p53缺失的小鼠發育是正常的，大約60%的DKO小鼠卻在新生的期間相繼死亡。進一步分析更顯示這樣的死亡可能與肝臟細胞分化的減損進而導致機能喪失有關。此外，相較於Alb-Mcl-1-/-小鼠，存活至成鼠的DKO小鼠顯現更為嚴重的肝臟損傷，顯示p53在Alb-Mcl-1-/-小鼠的肝臟中活化並促進細胞存活。在微陣列及定量PCR的實驗結果中顯示p53下游中一個促進存活的分子p21，有可能在其間參與p53保護Alb-Mcl-1-/-小鼠肝臟的角色。最後，我們也發現p53的缺失，加劇了Alb-Mcl-1-/-小鼠的肝臟纖維化及肝癌的進程。
綜合以上，本研究發現在保護免於肝臟損傷、纖維化及肝癌上，Mcl-1及p53之間存在著非預期的協同效應。

關鍵字

肝臟 ； Mcl-1 ； p53 ； 細胞凋亡 ； 腫瘤

並列摘要

Mcl-1-deficient hepatocytes are prone to undergo apoptosis. The tumor suppressor protein p53 plays an important role in apoptosis control as well as other cellular responses. To test whether p53 was involved in Mcl-1 deficiency-induced apoptosis of hepatocytes, hepatocyte-specific Mcl-1 knockout (Alb-Mcl-1-/-) mice and Alb-Mcl-1-/- mice in wild-type or p53-deficient background were generated and characterized. The results showed that Alb-Mcl-1-/- mice were viable, but their liver cells were prone to undergo apoptosis and manifested a slightly elevated level of p53. To examine the role of p53 in Alb-Mcl-1-/- livers, Alb-Mcl-1-/- mice without p53 (DKO mice) were characterized. Unexpectedly, although p53-deficient mice appeared to be developmentally normal, DKO mice were highly susceptible to neonatal death (~60%). Further analysis revealed that such early lethality was likely due to hepatic failure caused by a marked reduction of fully-differentiated hepatocytes at the perinatal/neonatal stage. Moreover, those DKO mice that did survive to adulthood manifested more severe liver damage than Alb-Mcl-1-/- mice, suggesting that p53 was activated in Alb-Mcl-1-/- livers to promote cell survival. Microarray followed by quantitative PCR analysis suggests that p21Waf1/Cip1, one p53 target gene with apoptosis-inhibitory function, is likely involved in the protective role of p53 in Alb-Mcl-1-/- livers. Last, we demonstrated that loss of p53 exacerbated liver fibrosis and tumor development in Alb-Mcl-1-/- mice. In summary, this study revealed an unexpected synergism between Mcl-1 and p53 in protecting from hepatic injury, fibrosis and cancer.

並列關鍵字

Liver ； Mcl-1 ； p53 ； apoptosis ； tumor

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