Opposing early and late effects of insulin-like growth factor I on differentiation and the cell cycle regulatory retinoblastoma protein in skeletal myoblasts.
Opposing early and late effects of insulin-like growth factor I on differentiation and the cell cycle regulatory retinoblastoma protein in skeletal myoblasts.
复制标题
胰岛素样生长因子 I 对骨骼肌母细胞分化和细胞周期调节视网膜母细胞瘤蛋白的早期和晚期作用相反。
DOI：
10.1073/pnas.92.22.10307
复制
发表时间：
1995
影响因子：
11.1
通讯作者：
Cheng,ZQ
中科院分区：
文献类型：
--
作者：
Rosenthal,SM;Cheng,ZQ
胰岛素样生长因子（IGF）在骨骼肌成肌细胞中促进有丝分裂和促进分化的机制尚不清楚，因为这两个过程被认为在该组织中是相互排斥的。普遍存在的核视网膜母细胞瘤蛋白 (Rb) 的磷酸化状态在决定成肌细胞是否增殖或分化方面起着重要作用：磷酸化的 Rb 促进有丝分裂，而非（或低）磷酸化的 Rb 促进细胞周期退出和分化。我们假设 IGF 可能通过调节 Rb 的磷酸化来影响成肌细胞的命运。尽管已知长期 IGF 治疗可刺激分化，但我们发现 IGF 最初的作用是抑制分化，并且仅具有促有丝分裂作用。 IGF 的这些早期作用与增殖细胞典型的 Rb 磷酸化的维持有关。上调细胞周期蛋白依赖性激酶 4 和细胞周期蛋白 D1 的基因表达，它们是在介导 Rb 磷酸化中起主要作用的全酶成分；显着抑制肌细胞生成素的基因表达，肌细胞生成素是骨骼肌特异性转录因子 MyoD 家族的成员，对肌肉分化至关重要。我们还发现 IGF 诱导的分化抑制是通过一个与其促有丝分裂作用无关的过程发生的。因此，我们证明 IGF 调节 Rb 磷酸化以及细胞周期蛋白 D1 和细胞周期蛋白依赖性激酶 4 基因表达；连同它们对肌细胞生成素表达的双相作用，这些结果表明IGF最初是促有丝分裂的，随后在骨骼肌中促进分化的机制。
The mechanisms by which insulin-like growth factors (IGFs) can be both mitogenic and differentiation-promoting in skeletal myoblasts are unclear because these two processes are believed to be mutually exclusive in this tissue. The phosphorylation state of the ubiquitous nuclear retinoblastoma protein (Rb) plays an important role in determining whether myoblasts proliferate or differentiate: Phosphorylated Rb promotes mitogenesis, whereas un- (or hypo-) phosphorylated Rb promotes cell cycle exit and differentiation. We hypothesized that IGFs might affect the fate of myoblasts by regulating the phosphorylation of Rb. Although long-term IGF treatment is known to stimulate differentiation, we find that IGFs act initially to inhibit differentiation and are exclusively mitogenic. These early effects of IGFs are associated with maintenance of Rb phosphorylation typical of proliferating cells; upregulation of the gene expression of cyclin-dependent kinase 4 and cyclin D1, components of a holoenzyme that plays a principal role in mediating Rb phosphorylation; and marked inhibition of the gene expression of myogenin, a member of the MyoD family of skeletal muscle-specific transcription factors that is essential in muscle differentiation. We also find that IGF-induced inhibition of differentiation occurs through a process that is independent of its mitogenic effects. We demonstrate, thus, that IGFs regulate Rb phosphorylation and cyclin D1 and cyclin-dependent kinase 4 gene expression; together with their biphasic effects on myogenin expression, these results suggest a mechanism by which IGFs are initially mitogenic and subsequently differentiation-promoting in skeletal muscle.