A Requirement for Cyclin D3–Cyclin-dependent Kinase (cdk)-4 Assembly in the Cyclic Adenosine Monophosphate–dependent Proliferation of Thyrocytes
A Requirement for Cyclin D3–Cyclin-dependent Kinase (cdk)-4 Assembly in the Cyclic Adenosine Monophosphate–dependent Proliferation of Thyrocytes
复制标题
甲状腺细胞环磷酸腺苷依赖性增殖中细胞周期蛋白 D3 细胞周期蛋白依赖性激酶 (CDK)-4 组装的要求
作者：
F. Depoortere;A. Van Keymeulen;J. Lukas;S. Costagliola;J. Bártková;J. Dumont;J. Bartek;P. Roger;S. Dremier
在不同的系统中，环磷酸腺苷（cAMP）可以阻断或促进细胞周期的进展，在中期至晚期G1期。狗甲状腺上皮细胞在原代培养构成了一个模型的DNA合成启动和G 0-S复制前期进展的cAMP作为促甲状腺激素（TSH）的第二信使的积极控制。cAMP依赖性有丝分裂途径是独特的，因为它不依赖于有丝分裂原活化的蛋白激酶活化，并且在几种原癌基因/转录因子的表达水平上与生长因子依赖性途径不同。本研究检测了D型G1期细胞周期蛋白及其相关的细胞周期蛋白依赖性激酶（cdk 4）在犬甲状腺细胞cAMP依赖性G1期进展中的参与。与表皮生长因子（EGF）+血清和其他cAMP-非依赖性有丝分裂原，TSH不诱导细胞周期蛋白D1和D2的积累，并部分抑制最丰富的细胞周期蛋白D3的基础表达。然而，促甲状腺激素刺激增强细胞周期蛋白D3的核检测。这种效应与G1期和S期进展相关。发现它反映了接近其与cdk 4相互作用的结构域的细胞周期蛋白D3的表位的暴露，以及细胞周期蛋白D3的核转位。TSH和EGF+血清也诱导了以前未描述的cdk 4核转位，可沉淀的细胞周期蛋白D3-cdk 4复合物的组装，以及这些复合物的Rb激酶活性。以前，发现cdk 4活性在狗甲状腺细胞的cAMP依赖性促有丝分裂途径中是必需的，如在生长因子途径中一样。在这里，细胞周期蛋白D3抗体的显微注射表明，细胞周期蛋白D3是必不可少的TSH/cAMP依赖的有丝分裂，但不是在生长因子诱导细胞周期蛋白D1和D2的途径。本研究（a）提供了在正常细胞中刺激G1期进展的第一个例子，其发生独立于细胞周期蛋白D的增强的积累，（B）鉴定了细胞周期蛋白D3和cdk 4通过其增强的组装和/或核转位的激活，作为平行的cAMP依赖性和生长因子促有丝分裂途径的第一个会聚步骤，和（c）强烈地表明这种新的机制在cAMP依赖的有丝分裂中是必需的，这提供了在G1期进展中对细胞周期蛋白D3的需要的第一个直接证明。
In different systems, cyclic adenosine monophosphate (cAMP) either blocks or promotes cell cycle progression in mid to late G1 phase. Dog thyroid epithelial cells in primary culture constitute a model of positive control of DNA synthesis initiation and G0-S prereplicative phase progression by cAMP as a second messenger for thyrotropin (TSH). The cAMP-dependent mitogenic pathway is unique as it is independent of mitogen-activated protein kinase activation and differs from growth factor-dependent pathways at the level of the expression of several protooncogenes/transcription factors. This study examined the involvement of D-type G1 cyclins and their associated cyclin-dependent kinase (cdk4) in the cAMP-dependent G1 phase progression of dog thyroid cells. Unlike epidermal growth factor (EGF)+serum and other cAMP-independent mitogens, TSH did not induce the accumulation of cyclins D1 and D2 and partially inhibited the basal expression of the most abundant cyclin D3. However, TSH stimulation enhanced the nuclear detection of cyclin D3. This effect correlated with G1 and S phase progression. It was found to reflect both the unmasking of an epitope of cyclin D3 close to its domain of interaction with cdk4, and the nuclear translocation of cyclin D3. TSH and EGF+serum also induced a previously undescribed nuclear translocation of cdk4, the assembly of precipitable cyclin D3-cdk4 complexes, and the Rb kinase activity of these complexes. Previously, cdk4 activity was found to be required in the cAMP-dependent mitogenic pathway of dog thyrocytes, as in growth factor pathways. Here, microinjections of a cyclin D3 antibody showed that cyclin D3 is essential in the TSH/ cAMP-dependent mitogenesis, but not in the pathway of growth factors that induce cyclins D1 and D2. The present study (a) provides the first example in a normal cell of a stimulation of G1 phase progression occurring independently of an enhanced accumulation of cyclins D, (b) identifies the activation of cyclin D3 and cdk4 through their enhanced assembly and/or nuclear translocation, as first convergence steps of the parallel cAMP-dependent and growth factor mitogenic pathways, and (c) strongly suggests that this new mechanism is essential in the cAMP-dependent mitogenesis, which provides the first direct demonstration of the requirement for cyclin D3 in a G1 phase progression.
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影响因子：
10.5
作者：
LaBaer, J;Garrett, MD;Harlow, E
通讯作者：
Harlow, E
DOI：
10.1073/pnas.90.24.11513
发表时间：
1993-12-15
影响因子：
11.1
作者：
KATO, JY;SHERR, CJ
通讯作者：
SHERR, CJ
影响因子：
10.5
作者：
Lukas, J;Herzinger, T;Bartek, J
通讯作者：
Bartek, J
影响因子：
8
作者：
Y. Geng;E. Eaton;M. Picón;J. Roberts;A. Lundberg;A. Gifford;C. Sardet;R. Weinberg
通讯作者：
Y. Geng;E. Eaton;M. Picón;J. Roberts;A. Lundberg;A. Gifford;C. Sardet;R. Weinberg
DOI：
10.1002/dvg.1020160209
发表时间：
1995-01-01
期刊：
DEVELOPMENTAL GENETICS
影响因子：
--
作者：
RAVNIK, SE;RHEE, K;WOLGEMUTH, DJ
通讯作者：
WOLGEMUTH, DJ