Rapid hepatocyte nuclear translocation of the Forkhead Box M1B (FoxM1B) transcription factor caused a transient increase in size of regenerating transgenic hepatocytes.
Rapid hepatocyte nuclear translocation of the Forkhead Box M1B (FoxM1B) transcription factor caused a transient increase in size of regenerating transgenic hepatocytes.
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DOI：
10.3727/000000003108749044
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发表时间：
2003
期刊：
影响因子：
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通讯作者：
Xinhe Wang;Dibyendu Bhattacharyya;Margaret B. Dennewitz;V. Kalinichenko;Yan Zhou;R. Lepe;R. Costa
中科院分区：
文献类型：
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作者：
Xinhe Wang;Dibyendu Bhattacharyya;Margaret B. Dennewitz;V. Kalinichenko;Yan Zhou;R. Lepe;R. Costa
叉头盒（Fox）蛋白是在有翼螺旋DNA结合结构域中共享同源性的广泛的转录因子家族。肝再生的研究与-3 kb转甲状腺素蛋白（TTR）启动子驱动的FoxM 1B转基因（TG）小鼠证明，过早的肝细胞核定位的FoxM 1B转基因蛋白在16小时后部分肝切除术（PHx）引起8小时的加速启动肝细胞DNA复制（S期）和有丝分裂刺激细胞周期基因的早期表达。FoxM 1B转基因蛋白是否参与肝再生过程中的立即早期事件仍有待确定。在这里，我们发现FoxM 1B转基因蛋白易位到肝细胞核后立即PHx，其核染色持续前6小时手术后，这种易位与再生TG肝细胞的大小增加。然而，再生的TTR-FoxM 1B肝脏没有表现出与介导细胞大小增加有关的蛋白质表达的改变，包括血清和糖皮质激素诱导的蛋白激酶（SGK），蛋白激酶B/Akt，肿瘤抑制基因PTEN（PI 3 K/Akt通路的负调节因子），c-Myc或过氧化物酶体增殖。此外，我们证明了FoxM 1B转基因蛋白的肝细胞核转位在肝脏急性期反应期间被迅速诱导，这发生在肝脏再生的早期阶段。cDNA表达阵列的分析鉴定了许多基因，如立即早期转录因子（ID-3，Stat 3，Nur 77），基质金属蛋白酶-9（MMP-9），和几种谷胱甘肽S-转移酶（GST）亚型和应激反应基因，与再生野生型（WT）肝脏相比，其表达在再生TTR-FoxM 1B TG肝脏中升高。这些肝再生研究表明，肝细胞核转位的FoxM 1B转基因蛋白持续PHx后的第一个6小时，并与瞬时肥大的再生TG肝细胞和基因的表达增加，可能会提高肝细胞增殖。
The Forkhead Box (Fox) proteins are an extensive family of transcription factors that shares homology in the winged helix DNA binding domain. Liver regeneration studies with the -3 kb transthyretin (TTR) promoter-driven FoxM1B transgenic (TG) mice demonstrated that premature hepatocyte nuclear localization of the FoxM1B transgene protein at 16 h following partial hepatectomy (PHx) caused an 8-h acceleration in the onset of hepatocyte DNA replication (S-phase) and mitosis by stimulating earlier expression of cell cycle genes. Whether the FoxM1B transgene protein participates in immediate early events during liver regeneration remains to be determined. Here, we found that the FoxM1B transgene protein translocated to hepatocyte nuclei immediately following PHx, that its nuclear staining persisted for the first 6 h after surgery, and that this translocation was associated with an increase in size of regenerating TG hepatocytes. However, regenerating TTR-FoxM1B liver did not exhibit altered expression of proteins that have been implicated in mediating increased cell size, including serum-and-gucocorticoid-inducible protein kinase (SGK), protein kinase-B/Akt, the tumor suppresser gene PTEN (negative regulator of the PI3K/Akt pathway), c-Myc, or peroxisome proliferation. Moreover, we demonstrated that hepatocyte nuclear translocation of the FoxM1B transgene protein was rapidly induced during the hepatic acute phase response, which occurs during the immediate early stages of liver regeneration. Analysis of cDNA expression arrays identified a number of genes such as immediate early transcription factors (ID-3, Stat3, Nur77), matrix metalloproteinase-9 (MMP-9), and several glutathione S-transferase (GST) isoforms and stress response genes, whose expression is elevated in regenerating TTR-FoxM1B TG livers compared with regenerating wild-type (WT) liver. These liver regeneration studies demonstrate that hepatocyte nuclear translocation of the FoxM1B transgene protein was sustained for the first 6 h after PHx, and was associated with transient hypertrophy of regenerating TG hepatocytes and increased expression of genes that may enhance hepatocyte proliferation.