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1
Hypo-phosphorylation of the retinoblastoma protein (pRb) by cyclin D:Cdk4/6 complexes results in active pRb.细胞周期蛋白D:细胞周期蛋白依赖性激酶4/6复合物对视网膜母细胞瘤蛋白(pRb)的低磷酸化导致活性pRb的产生。
Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10699-704. doi: 10.1073/pnas.94.20.10699.
2
Differential regulation of retinoblastoma tumor suppressor protein by G(1) cyclin-dependent kinase complexes in vivo.体内G1期细胞周期蛋白依赖性激酶复合物对视网膜母细胞瘤肿瘤抑制蛋白的差异性调控
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Interaction of retinoblastoma protein and D cyclins during cell-growth inhibition by hexamethylenebisacetamide in TM2H mouse epithelial cells.六亚甲基双乙酰胺在TM2H小鼠上皮细胞中抑制细胞生长期间视网膜母细胞瘤蛋白与D型细胞周期蛋白的相互作用
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Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin-cdk complexes.视网膜母细胞瘤蛋白的功能失活需要至少两种不同的细胞周期蛋白 - 细胞周期蛋白依赖性激酶复合物进行顺序修饰。
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Expression of cyclin E renders cyclin D-CDK4 dispensable for inactivation of the retinoblastoma tumor suppressor protein, activation of E2F, and G1-S phase progression.细胞周期蛋白E的表达使得细胞周期蛋白D - CDK4对于视网膜母细胞瘤肿瘤抑制蛋白的失活、E2F的激活以及G1 - S期进程而言不再是必需的。
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Molecular mechanisms underlying interferon-alpha-induced G0/G1 arrest: CKI-mediated regulation of G1 Cdk-complexes and activation of pocket proteins.α干扰素诱导G0/G1期阻滞的分子机制:细胞周期蛋白依赖性激酶抑制剂介导的G1期细胞周期蛋白依赖性激酶复合物调控及口袋蛋白激活。
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本文引用的文献

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CDK-independent activation of estrogen receptor by cyclin D1.细胞周期蛋白D1对雌激素受体的细胞周期蛋白依赖性激酶非依赖性激活
Cell. 1997 Feb 7;88(3):405-15. doi: 10.1016/s0092-8674(00)81879-6.
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Cancer cell cycles.癌细胞周期。
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Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer.人类癌症中细胞周期蛋白、细胞周期蛋白依赖性激酶及细胞周期蛋白依赖性激酶抑制剂的基因改变。
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Temperature-sensitive mutants of p16CDKN2 associated with familial melanoma.与家族性黑色素瘤相关的p16CDKN2温度敏感突变体。
Mol Cell Biol. 1996 Jul;16(7):3844-52. doi: 10.1128/MCB.16.7.3844.
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E2F-4 switches from p130 to p107 and pRB in response to cell cycle reentry.E2F-4在细胞周期重新进入时从p130转变为p107和pRB。
Mol Cell Biol. 1996 Apr;16(4):1436-49. doi: 10.1128/MCB.16.4.1436.
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Negative regulation of cell growth by TGF beta.转化生长因子β对细胞生长的负调控
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Physical interaction of the retinoblastoma protein with human D cyclins.视网膜母细胞瘤蛋白与人D型细胞周期蛋白的物理相互作用。
Cell. 1993 May 7;73(3):499-511. doi: 10.1016/0092-8674(93)90137-f.
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Sequences within the conserved cyclin box of human cyclin A are sufficient for binding to and activation of cdc2 kinase.人细胞周期蛋白A保守细胞周期蛋白框内的序列足以与cdc2激酶结合并激活该激酶。
Mol Cell Biol. 1993 Feb;13(2):1194-201. doi: 10.1128/mcb.13.2.1194-1201.1993.
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Independent regulation of human D-type cyclin gene expression during G1 phase in primary human T lymphocytes.原代人T淋巴细胞G1期人D型细胞周期蛋白基因表达的独立调控
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10
Distinct sub-populations of the retinoblastoma protein show a distinct pattern of phosphorylation.视网膜母细胞瘤蛋白的不同亚群呈现出不同的磷酸化模式。
EMBO J. 1994 Jan 1;13(1):118-27. doi: 10.1002/j.1460-2075.1994.tb06241.x.

细胞周期蛋白D:细胞周期蛋白依赖性激酶4/6复合物对视网膜母细胞瘤蛋白(pRb)的低磷酸化导致活性pRb的产生。

Hypo-phosphorylation of the retinoblastoma protein (pRb) by cyclin D:Cdk4/6 complexes results in active pRb.

作者信息

Ezhevsky S A, Nagahara H, Vocero-Akbani A M, Gius D R, Wei M C, Dowdy S F

机构信息

Howard Hughes Medical Institute and Division of Molecular Oncology, Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA.

出版信息

Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10699-704. doi: 10.1073/pnas.94.20.10699.

DOI:10.1073/pnas.94.20.10699
PMID:9380698
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC23451/
Abstract

In cycling cells, the retinoblastoma protein (pRb) is un- and/or hypo-phosphorylated in early G1 and becomes hyper-phosphorylated in late G1. The role of hypo-phosphorylation and identity of the relevant kinase(s) remains unknown. We show here that hypo-phosphorylated pRb associates with E2F in vivo and is therefore active. Increasing the intracellular concentration of the Cdk4/6 specific inhibitor p15(INK4b) by transforming growth factor beta treatment of keratinocytes results in G1 arrest and loss of hypo-phosphorylated pRb with an increase in unphosphorylated pRb. Conversely, p15(INK4b)-independent transforming growth factor beta-mediated G1 arrest of hepatocellular carcinoma cells results in loss of Cdk2 kinase activity with continued Cdk6 kinase activity and pRb remains only hypo-phosphorylated. Introduction of the Cdk4/6 inhibitor p16(INK4a) protein into cells by fusion to a protein transduction domain also prevents pRb hypo-phosphorylation with an increase in unphosphorylated pRb. We conclude that cyclin D:Cdk4/6 complexes hypo-phosphorylate pRb in early G1 allowing continued E2F binding.

摘要

在循环细胞中,视网膜母细胞瘤蛋白(pRb)在G1早期未磷酸化和/或低磷酸化,而在G1晚期则过度磷酸化。低磷酸化的作用以及相关激酶的身份仍然未知。我们在此表明,低磷酸化的pRb在体内与E2F结合,因此具有活性。通过用转化生长因子β处理角质形成细胞来增加细胞内Cdk4/6特异性抑制剂p15(INK4b)的浓度,会导致G1期停滞以及低磷酸化pRb的丧失,同时未磷酸化的pRb增加。相反,肝细胞癌细胞中不依赖p15(INK4b)的转化生长因子β介导的G1期停滞会导致Cdk2激酶活性丧失,而Cdk6激酶活性持续存在,并且pRb仅保持低磷酸化状态。通过与蛋白质转导结构域融合将Cdk4/6抑制剂p16(INK4a)蛋白导入细胞也会阻止pRb的低磷酸化,同时未磷酸化的pRb增加。我们得出结论,细胞周期蛋白D:Cdk4/6复合物在G1早期使pRb低磷酸化,从而允许E2F持续结合。