Cyclin D1 is an early target in hepatocyte proliferation induced by thyroid hormone (T3)
Cyclin D1 is an early target in hepatocyte proliferation induced by thyroid hormone (T3)
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DOI：
10.1096/fj.00-0416com
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发表时间：
2001-04-01
期刊：
影响因子：
4.8
通讯作者：
Columbano, A
中科院分区：
文献类型：
--
作者：
Pibiri, M;Ledda-Columbano, GM;Columbano, A
甲状腺激素（T3）通过与甲状腺激素核受体（TR）的相互作用影响细胞生长、分化并调节代谢功能。TRs介导细胞生长的机制尚不清楚。为了研究T3的促有丝分裂作用的机制，我们确定了转录因子激活、立即早期基因的mRNA水平和参与细胞周期从G1期到S期进展的蛋白质水平的变化。我们发现，在没有AP-1，NF-κ B和STAT 3激活或立即早期基因c-fos，c-jun和c-myc的mRNA水平变化的情况下，单次给药T3诱导Wistar大鼠肝细胞增殖。这些基因被认为是部分肝切除术（PH）后肝再生所必需的。另一方面，T3处理引起细胞周期蛋白D1 mRNA和蛋白水平的增加，与2/3 PH后的肝再生相比，这种增加发生得更快。细胞周期蛋白D1表达的早期增加与DNA合成的加速开始有关，T3处理后12小时溴脱氧尿苷阳性肝细胞增加20倍，18 h时有丝分裂活性增加一倍。在用萘诺平治疗后也观察到细胞周期蛋白D1表达的早期增加，萘诺平是类固醇/甲状腺受体的同一超家族的核受体（过氧化物酶体增殖物激活受体α）的配体。T3处理还导致细胞周期蛋白E、E2 F和p107的表达增加以及pRb的磷酸化增强，pRb是导致从G1期过渡到S期的途径中的最终底物。结果表明，细胞周期蛋白D1的诱导是T3诱导的肝细胞增殖的早期事件之一，并建议，这种细胞周期蛋白可能是一个共同的目标负责核受体的配体的促有丝分裂活性。
The thyroid hormone (T3) affects cell growth, differentiation, and regulates metabolic functions via its interaction with the thyroid hormone nuclear receptors (TRs). The mechanism by which TRs mediate cell growth is unknown. To investigate the mechanisms responsible for the mitogenic effect of T3, we have determined changes in activation of transcription factors, mRNA levels of immediate early genes, and levels of proteins involved in the progression from G1 to S phase of the cell cycle. We show that hepatocyte proliferation induced by a single administration of T3 to Wistar rats occurred in the absence of activation of AP-1, NF-kappaB, and STAT3 or changes in the mRNA levels of the immediate early genes c-fos, c-jun, and c-myc These genes are considered to be essential for liver regeneration after partial hepatectomy (PH). On the other hand, T3 treatment caused an increase in cyclin D1 mRNA and protein levels that occurred much more rapidly compared to liver regeneration after 2/3 PH. The early increase in cyclin D1 expression was associated with accelerated onset of DNA synthesis, as demonstrated by a 20-fold increase of bromodeoxyuridine-positive hepatocytes at 12 h after T3 treatment and by a 20-fold increase in mitotic activity at 18 h. An early increase of cyclin D1 expression was also observed after treatment with nafenopin, a ligand of a nuclear receptor (peroxisome proliferator-activated receptor alpha) of the same superfamily of steroid/thyroid receptors. T3 treatment also resulted in increased expression of cyclin E, E2F, and p107 and enhanced phosphorylation of pRb, the ultimate substrate in the pathway leading to transition from G1 to S phase. The results demonstrate that cyclin D1 induction is one of the earlier events in hepatocyte proliferation induced by T3 and suggest that this cyclin might be a common target responsible for the mitogenic activity of ligands of nuclear receptors.