CYCLIN-D EXPRESSION IS CONTROLLED POSTTRANSCRIPTIONALLY VIA A PHOSPHATIDYLINOSITOL 3-KINASE AKT-DEPENDENT PATHWAY

Cyclin D expression is regulated by growth factors and is necessary fo r the induction of mitogenesis. Herbimycin A, a drug that binds to Hsp 90, induces the destruction of tyrosine kinases and causes the down-re gulation of cyclin D and an Rb-dependent growth arrest in the G(1) pha se of the cell cycle. We find that the induction of D cyclin expressio n by serum and its repression by herbimycin A are regulated at the lev el of mRNA translation. Induction of cyclin D by serum occurs prior to the induction of its mRNA and does not require transcription. Herbimy cin 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 tran slation is mediated via a phosphatidylinositol 3-kinase (PI 3-kinase)- dependent pathway. PI 3-kinase inhibitors such as wortmannin and LY294 002, and rapamycin, an inhibitor of FRAP/TOR, cause a decline in the l evel of D-cyclins, whereas inhibitors of mitogen-activated protein kin ase kinase and farnesyltransferase do not. Cells expressing the activa ted, myristoylated form of Akt kinase, a target of PI 3-kinase, are re fractory to the effects of herbimycin A or serum starvation on D-cycli n expression. These data suggest that serum induction of cyclin D expr ession results from enhanced translation of its mRNA and that this res ults from activation of a pathway that is dependent upon PI 3-kinase a nd Akt kinase.