HMG box transcriptional repressor HBP1 maintains a proliferation barrier in differentiated liver tissue
HMG box transcriptional repressor HBP1 maintains a proliferation barrier in differentiated liver tissue
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DOI：
10.1128/mcb.21.17.5723-5732.2001
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发表时间：
2001-09-01
影响因子：
5.3
通讯作者：
Yee, AS
中科院分区：
文献类型：
--
作者：
Shih, HH;Xiu, M;Yee, AS
我们以前分离HBP 1作为视网膜母细胞瘤（RB）和p130家族成员的目标，并作为第一个HMG盒转录抑制因子。我们随后的工作表明，HBP 1协调细胞培养模型中的分化。在本研究中，我们发现HBP 1调节动物分化组织的增殖。使用转基因小鼠，其中HBP 1的表达在甲状腺素运载蛋白启动子控制下的肝细胞中特异性增加，我们确定了HBP 1对部分肝切除术后同步细胞周期再入的影响。HBP 1的适度过表达产生了可检测的细胞周期表型。在三分之二部分肝切除诱导的促有丝分裂刺激后，表达HBP 1转基因的小鼠表现出从G（1）期到S期高峰的10- 12-h延迟。伴随着中G（1）事件的延迟，如细胞周期蛋白E的诱导。虽然G（1）和S期的延迟与转基因HBP 1的轻微过表达相关，但内源性HBP 1蛋白本身的水平在S期下降。相比之下，HBP 1转基因小鼠肝部分切除术后即刻早期反应的发生没有变化。这一观察结果表明，观察到的S期延迟不是由导致G（0）到G（1）转变的信号通路变化引起的。最后，转基因小鼠表达突变HBP 1缺乏N-末端RB相互作用域表现出更强的S期反应后，部分肝切除术。这些结果提供了第一个证据表明，HBP 1可以调节分化组织中的细胞周期进程。
We previously isolated HBP1 as a target of the retinoblastoma (RB) and p130 family members and as the first of the HMG box transcriptional repressors. Our subsequent work demonstrated that HBP1 coordinates differentiation in cell culture models. In the present study, we show that HBP1 regulates proliferation in a differentiated tissue of an animal. Using transgenic mice in which HBP1 expression was specifically increased in hepatocytes under control of the transthyretin promoter, we determined the impact of HBP1 on synchronous cell cycle reentry following partial hepatectomy. Modest overexpression of HBP1 yielded a detectable cell cycle phenotype. Following a mitogenic stimulus induced by two-thirds partial hepatectomy, mice expressing the HBP1 transgene showed a 10- to 12-h delay in progression through G(1) to the peak of S phase. There was a concomitant delay in mid-G(1) events, such as the induction of cyclin E. While the delay in G(1) and S phases correlated with the slight overexpression of transgenic HBP1, the level of the endogenous HBP1 protein itself declined in S phase. In contrast, the onset of the immediate-early response following partial hepatectomy was unchanged in HBP1 transgenic mice. This observation indicated that the observed delay in S phase did not result from changes in signaling pathways leading into the G(0)-to-G(1) transition. Finally, transgenic mice expressing a mutant HBP1 lacking the N-terminal RB interacting domain showed a stronger S-phase response following partial hepatectomy. These results provide the first evidence that HBP1 can regulate cell cycle progression in differentiated tissues.