Inactivation of TGF-β signaling in hepatocytes results in an increased proliferative response after partial hepatectomy
Inactivation of TGF-β signaling in hepatocytes results in an increased proliferative response after partial hepatectomy
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DOI：
10.1038/sj.onc.1208475
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发表时间：
2005-04-21
期刊：
影响因子：
8
通讯作者：
Grady, WM
中科院分区：
文献类型：
--
作者：
Romero-Gallo, J;Sozmen, EG;Grady, WM
转化生长因子β（TGF-β）信号通路由I型和II型TGF-β受体（TGFBR 1和TGFBR 2）组成的TGF-β受体复合物激活，调节细胞生长和死亡。TGF-β及其信号传导途径的组分，特别是TGFBR 2，已经被认为是胃肠道和肝脏中的肿瘤抑制基因和重要的抗有丝分裂因子。研究这些作用的体内方法受到Tgfbr 2（-/-）小鼠胚胎致死率和Tgfb 1（-/-）小鼠生存能力差的阻碍。因此，我们开发了一种肝细胞特异性Tgfbr 2基因敲除小鼠，Alb-cre Tgfbr 2（flx/flx）小鼠，以研究TGF-β信号传导对体内上皮细胞增殖的生理相关影响。70%肝切除后，我们观察到与Tgfbr 2（flx/flx）小鼠相比，Alb-cre Tgfbr 2（flx/flx）小鼠的增殖增加和肝脏质量：体重比增加。我们还观察到在Alb-cre Tgfbr 2（flx/flx）小鼠肝脏中p130的表达减少和磷酸化增加，以及细胞周期蛋白E的表达增加，细胞周期蛋白E在转录上部分受p130：E2 F4调节。与这些结果一致，在来自Tgfbr 2（flx/flx）小鼠的肝细胞系中，我们发现TGF-β增加了E2 F4的核定位，并可能增加了p130：E2 F4复合物的转录抑制。因此，我们已经证明，TGF-β信号在体内调节有丝分裂的反应，在再生的肝脏，影响肝部分切除术后的肝脏质量：体重比，这些有丝分裂反应伴随着改变p130的表达和磷酸化，暗示p130作为一种蛋白质调节在体内的TGF-β在肝再生过程中。
The transforming growth factor beta (TGF-beta) signaling pathway, which is activated by the TGF-beta receptor complex consisting of type I and type II TGF-beta receptors (TGFBR1 and TGFBR2), regulates cell growth and death. TGF-beta and components of its signaling pathway, particularly TGFBR2, have been implicated as tumor suppressor genes and important antimitogenic factors in the gastrointestinal tract and liver. An in vivo approach to study these effects has been hindered by the embryonic lethality of Tgfbr2(-/-) mice and poor viability of the Tgfb1(-/-) mice. Consequently, we have developed a hepatocyte-specific Tgfbr2 knockout mouse, the Alb-cre Tgfbr2(flx/flx) mouse, to study the physiologically relevant effects of TGF-beta signaling on epithelial cell proliferation in vivo. After 70% hepatectomy, we observed increased proliferation and an increased liver mass : body weight ratio in the Alb-cre Tgfbr2(flx/flx) mice compared to Tgfbr2(flx/flx) mice. We also observed decreased expression and increased phosphorylation of p130 in the livers from the Alb-cre Tgfbr2(flx/flx) mice as well as increased expression of cyclin E, which is transcriptionally regulated, in part, by p130:E2F4. Consistent with these results, in a hepatocyte cell line derived from the Tgfbr2(flx/flx) mice, we found that TGF-beta increases the nuclear localization of E2F4, and presumably the transcriptional repression of the p130: E2F4 complex. Thus, we have demonstrated that TGF-beta signaling in vivo regulates the mitogenic response in the regenerating liver, affecting the liver mass : body weight ratio after partial hepatectomy, and that these mitogenic responses are accompanied by alterations in p130 expression and phosphorylation, implicating p130 as one of the proteins regulated in vivo by TGF-beta during liver regeneration.