p53 may positively regulate hepatocyte proliferation in rats
p53 may positively regulate hepatocyte proliferation in rats
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DOI：
10.1053/jhep.2002.34942
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发表时间：
2002-08-01
期刊：
影响因子：
13.5
通讯作者：
Fujiwara, K
中科院分区：
文献类型：
--
作者：
Inoue, Y;Tomiya, T;Fujiwara, K
p53是一种肿瘤抑制基因，是一种调节多种细胞功能的转录因子。最近，几种生长因子基因启动子，包括转化生长因子α（TGF-α）的启动子，被证明是p53介导的转录的直接靶点。大鼠肝再生过程中肝脏p53 mRNA表达上调本研究的目的是研究p53在肝细胞增殖中的作用。在含有肝细胞生长因子（HGF）的培养基中培养的大鼠肝细胞中检测p53蛋白水平。p53水平在孵育6小时后开始增加，在18小时达到最大值，此后下降。DNA合成在12小时增加，并在30小时达到峰值。当肝细胞与p53反义寡核苷酸孵育时，除了HGF外，p53和TGF-α水平的增加被抑制，DNA合成减少。TGF-α水平和DNA合成的增加也被p53的化学抑制剂pifithrin-alpha抑制。在三分之二部分肝切除术后的大鼠中，肝p53增加并在16小时左右达到最大水平，此时肝HGF水平已显示达到最大值，随后肝TGF-α水平增加或肝细胞增殖。与此相反，假手术大鼠肝脏p53水平略有升高。总之，p53的产生是由HGF刺激，并可能有助于大鼠肝细胞的增殖。考虑到先前的研究结果表明内源性TGF-α对HGF刺激的肝细胞增殖的重要性，TGF-α可能在HGF-p53介导的肝细胞增殖中起作用。
p53, known as a tumor suppressor gene, is a transcription factor that regulates various cellular functions. Recently, several growth factor gene promoters, including that of transforming growth factor alpha (TGF-alpha), were shown to be direct targets of p53-mediated transcription. Hepatic p53 mRNA is up-regulated during liver regeneration in rats. The aim of this study is to examine the role of p53 in hepatocyte proliferation. p53 protein levels were examined in rat hepatocytes cultured in the medium containing hepatocyte growth factor (HGF). p53 levels began to increase after 6 hours of incubation, reached a maximum at 18 hours, and decreased thereafter. DNA synthesis increased at 12 hours and peaked at 30 hours. When hepatocytes were incubated with p53 antisense oligonucleotide in addition to HGF, increases of p53 and TGF-alpha levels were suppressed, and DNA synthesis was reduced. The increases of TGF-alpha levels and DNA synthesis were also suppressed by a chemical inhibitor of p53, pifithrin-alpha. In rats after two-thirds partial hepatectomy, hepatic p53 increased and reached maximal levels around 16 hours when hepatic HGF levels have been shown to reach a maximum followed by an increase in hepatic TGF-alpha levels or hepatocyte proliferation. In contrast, sham-operated rats showed minor elevations of hepatic p53 levels. In conclusion, p53 production is stimulated by HGF and may contribute to the proliferation of rat hepatocytes. Considering previous findings indicating the importance of endogenous TGF-alpha for the proliferation of hepatocytes stimulated by HGF, TGF-alpha might play a role in HGF-p53 mediated hepatocyte proliferation.