Cyclin D Expression Is Controlled Post-transcriptionally via a Phosphatidylinositol 3-Kinase/Akt-dependent Pathway

Abstract

Growth factors elicit their biological effects by activating a complex network of receptors and signaling pathways. Activation of transmembrane tyrosine kinases by serum or polypeptide growth factors results in the transit of cells through the G 1 phase of the cell cycle into S-phase. Several lines of evidence suggest that the D-type cyclins and their associated kinases (Cdks) 1 are among the targets of these growth signals (1). The D-type cyclins, D1, D2 and D3, are closely related proteins whose expression is induced by mitogens and growth factors (2-6) and down-regulated by growth factor deprivation or by antimitogens (7,8). The D-type cyclins associate with cyclindependent protein kinase Cdk4 or Cdk6 to form an active complex that phosphorylates and inactivates the retinoblastoma protein, pRb (9, 10). Inhibition of cyclin D1 expression either by antisense methodology or antibody microinjection lengthens the duration of the G 1 phase and causes a reduction in proliferation (11,12). Aberrant overexpression of D-type cyclins resulting from upstream growth factor receptor activation, gene amplification or rearrangement, or an increase in mRNA stability seems to be a common feature of a number of human cancers and may reduce the cell's dependence on physiologic growth stimuli (13-16).Changes in cyclin D expression integrate the proliferative effects of an array of extracellular factors, including cytokines, polypeptide growth factors, and steroid hormones (2-4, 7). Cellular stress results in the loss of cyclin D1 expression, with a concomitant arrest in the G 1 phase of the cell cycle (8, 17). The networks of pathways responsible for the transduction of these signals are complex and not completely understood. There is some evidence suggesting that a Ras-and MAP kinasedependent signaling pathway is involved. Expression of activated Ras is associated with the increased expression of cyclin D1 in both epithelial cells (12) and fibroblasts (11). Moreover, in the absence of growth factors, activation of the Raf1 3 MEK 3 MAP kinase pathway has been shown to be sufficient to induce cyclin D1 transcription (5). Herbimycin A is a natural product that binds to a specific site in Hsp90 and causes the degradation of transmembrane tyrosine protein kinases, Raf1, and steroid hormone receptors (18 -23). We found that treatment of tumor cells with this drug causes a decrease in the expression of D-type cyclins and an Rb-dependent G 1 block. 2 We report here that the reduction in the level of D-type cyclins induced by herbimycin A is due to inhibition of translation of cyclin D mRNAs. Furthermore, the increase in the level of D-type cyclins in cells treated with serum is due to an increase in the translation of their mRNAs. These effects are due to the regulation of a PI 3-kinase/Akt kinase-dependent, Raf1-and MAP kinase-independent pathway. This pathway is activated by serum and is blocked by the drug herbimycin A. EXPERIMENTAL PROCEDURESCells and Antibodies-Colo205, a human colon carcinoma cell line, and MCF7, a breast cancer c...

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