| Abstract: |
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 G1 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 farnesyl-transferase 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. |
| Keywords: |
mitogen activated protein kinase; controlled study; protein expression; human cell; cell cycle; mitogenesis; tumor cells, cultured; protein tyrosine kinase; phosphatidylinositol 3 kinase; messenger rna; rna, messenger; 1-phosphatidylinositol 3-kinase; immunoprecipitation; immunoblotting; rna translation; protein biosynthesis; heat shock protein 90; quinones; down regulation; protein-tyrosine kinases; cyclin d1; cyclins; growth factor; rapamycin; benzoquinones; lactams, macrocyclic; 2 morpholino 8 phenylchromone; wortmannin; rna processing, post-transcriptional; transferase; herbimycin a; oncogene protein v-akt; humans; human; priority journal; article; retroviridae proteins, oncogenic
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