A dual role of p21 in liver regeneration and hepatocarcinogenesis.
A dual role of p21 in liver regeneration and hepatocarcinogenesis.
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DOI：
10.1002/hep.22588
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发表时间：
2008-11-01
期刊：
影响因子：
--
通讯作者：
Trautwein, Christian
中科院分区：
文献类型：
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作者：
Liedtke, Christian;Trautwein, Christian
遗传性酪氨酸血症I型（HT1）患者体内毒性代谢产物的积累导致慢性DNA损伤，是任何人类疾病中肝细胞癌（HCC）的最高风险。在这里，我们表明，肝细胞的HT1小鼠表现出深刻的细胞周期停滞，尽管伴随着细胞凋亡阻力，导致死亡率受损的肝再生。然而，HT1小鼠中p21的额外损失恢复了肝细胞和肾近端小管细胞的增殖能力。这种生长反应补偿了由于不受抑制的细胞凋亡引起的细胞损失，使动物能够存活，但迅速导致HCC、肾囊肿和肾癌。因此，p21的抗增殖功能对于抑制慢性损伤的肝脏和肾脏上皮细胞的致癌作用是不可或缺的，并且不能通过细胞凋亡来补偿。
Accumulation of toxic metabolites in hereditary tyrosinemia type I (HT1) patients leads to chronic DNA damage and the highest risk for hepatocellular carcinomas (HCCs) of any human disease. Here we show that hepatocytes of HT1 mice exhibit a profound cell-cycle arrest that, despite concomitant apoptosis resistance, causes mortality from impaired liver regeneration. However, additional loss of p21 in HT1 mice restores the proliferative capabilities of hepatocytes and renal proximal tubular cells. This growth response compensates cell loss due to uninhibited apoptosis and enables animal survival but rapidly leads to HCCs, renal cysts, and renal carcinomas. Thus, p21's antiproliferative function is indispensable for the suppression of carcinogenesis from chronically injured liver and renal epithelial cells and cannot be compensated by apoptosis.