Elimination of C/EBPα through the ubiquitin-proteasome system promotes the development of liver cancer in mice
Elimination of C/EBPα through the ubiquitin-proteasome system promotes the development of liver cancer in mice
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DOI：
10.1172/jci41933
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发表时间：
2010-07-01
影响因子：
15.9
通讯作者：
Timchenko, Nikolai A.
中科院分区：
文献类型：
--
作者：
Wang, Guo-Li;Shi, Xiurong;Timchenko, Nikolai A.
尽管我们对癌症发展的理解取得了重大进展，但肝癌形成的分子机制在很大程度上仍然未知。C/EBP α是调节肝脏静止的转录因子。C/EBP α在丝氨酸193（S193-ph）的磷酸化在老年小鼠中上调，并被认为有助于年龄相关的肝功能障碍。由于肝肿瘤的发展与年龄的增长有关，我们研究了S193-ph在肝癌发展中的作用，使用表达磷酸模拟天冬氨酸残基代替C/EBP α 193位丝氨酸（S193 D）的敲入小鼠。在部分肝切除术后，C/EBP α的S193 D亚型能够完全抑制体内肝增殖。然而，用二乙基亚硝胺/苯巴比妥（DEN/PB）治疗这些小鼠，诱导肝癌的形成，实际上导致了肝肿瘤的早期发展。DEN/PB处理通过激活泛素-蛋白酶体系统（UPS）与C/EBP α的S193-ph和S193 D亚型的特异性降解相关。在致癌过程中UPS介导的C/EBP α消除机制涉及Gankyrin水平升高，Gankyrin是一种与C/EBP α的S193-ph亚型相互作用并靶向其进行UPS介导的降解的蛋白质。这项研究确定了支持老年小鼠肝癌发展的分子机制和预防肝癌的潜在治疗靶点。
Despite significant advancements in our understanding of cancer development, the molecular mechanisms that underlie the formation of liver cancer remain largely unknown. C/EBP alpha is a transcription factor that regulates liver quiescence. Phosphorylation of C/EBP alpha at serine 193 (S193-ph) is upregulated in older mice and is thought to contribute to age-associated liver dysfunction. Because development of liver tumors is associated with increasing age, we investigated the role of S193-ph in the development of liver cancer using knockin mice expressing a phospho-mimetic aspartic acid residue in place of serine at position 193 (S193D) of C/EBP alpha. The S193D isoform of C/EBP alpha was able to completely inhibit liver proliferation in vivo after partial hepatectomy. However, treatment of these mice with diethylnitrosamine/phenobarbital (DEN/PB), which induces formation of liver cancer, actually resulted in earlier development of liver tumors. DEN/PB treatment was associated with specific degradation of both the S193-ph and S193D isoforms of C/EBP alpha through activation of the ubiquitin-proteasome system (UPS). The mechanism of UPS-mediated elimination of C/EBP alpha during carcinogenesis involved elevated levels of gankyrin, a protein that was found to interact with the S193-ph isoform of C/EBP alpha and target it for UPS-mediated degradation. This study identifies a molecular mechanism that supports the development of liver cancer in older mice and potential therapeutic targets for the prevention of liver cancer.