Cyclin D expression is controlled post-transcriptionally via a phosphatidylinositol 3-kinase Akt-dependent pathway
Cyclin D expression is controlled post-transcriptionally via a phosphatidylinositol 3-kinase Akt-dependent pathway
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DOI：
10.1074/jbc.273.45.29864
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发表时间：
1998-11-06
影响因子：
4.8
通讯作者：
Rosen, N
中科院分区：
文献类型：
--
作者：
Muise-Helmericks, RC;Grimes, HL;Rosen, N
细胞周期蛋白D的表达受生长因子的调节，是诱导有丝分裂所必需的。Herbimycin A是一种与Hsp 90结合的药物，可诱导酪氨酸激酶的破坏，并导致细胞周期蛋白D的下调和细胞周期G（1）期的Rb依赖性生长停滞。我们发现，诱导的D细胞周期蛋白的表达由血清和抑制除草霉素A调节在mRNA的翻译水平。血清对细胞周期蛋白D的诱导发生在其mRNA的诱导之前，并且不需要转录。Herbimycin A抑制的特征在于在mRNA表达变化之前D-细胞周期蛋白的合成速率降低，并且蛋白质的半衰期没有变化。这种对D-细胞周期蛋白翻译的影响是通过磷脂酰肌醇3-激酶（PI 3-激酶）依赖性途径介导的。PI 3-激酶抑制剂，如渥曼青霉素和LY 294002，和雷帕霉素，FRAP/TOR的抑制剂，导致D-细胞周期蛋白水平的下降，而丝裂原活化蛋白激酶激酶和法尼基转移酶的抑制剂不会。表达活化的、豆蔻酰化形式的Akt激酶（PI 3-激酶的靶点）的细胞对除莠霉素A或血清饥饿对D-细胞周期蛋白表达的影响是难治的。这些数据表明，血清诱导细胞周期蛋白D表达的结果从其mRNA的翻译增强，这是从依赖于PI 3-激酶和Akt激酶的途径激活的结果。
Cyclin D expression is regulated by growth factors and is necessary for the induction of mitogenesis. Herbimycin A, a drug that binds to Hsp90, induces the destruction of tyrosine kinases and causes the down-regulation of cyclin D and an Rb-dependent growth arrest in the G(1) phase of the cell cycle. We find that the induction of D cyclin expression by serum and its repression by herbimycin A are regulated at the level of mRNA translation. Induction of cyclin D by serum occurs prior to the induction of its mRNA and does not require transcription. Herbimycin A repression is characterized by a decrease in the synthetic rate of D-cyclins prior to changes in mRNA expression and in the absence of changes in the half-life of the protein, This effect on D-cyclin translation is mediated via a phosphatidylinositol 3-kinase (PI 3-kinase)-dependent pathway. PI 3-kinase inhibitors such as wortmannin and LY294002, and rapamycin, an inhibitor of FRAP/TOR, cause a decline in the level of D-cyclins, whereas inhibitors of mitogen-activated protein kinase kinase and farnesyltransferase do not. Cells expressing the activated, myristoylated form of Akt kinase, a target of PI 3-kinase, are refractory to the effects of herbimycin A or serum starvation on D-cyclin expression. These data suggest that serum induction of cyclin D expression results from enhanced translation of its mRNA and that this results from activation of a pathway that is dependent upon PI 3-kinase and Akt kinase.