Cyclin D expression is controlled post-transcriptionally via a phosphatidylinositol 3-kinase/Akt-dependent pathway.
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 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.
Muise-Helmericks
R C
RC
Program in Cell Biology and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Grimes
H L
HL
Bellacosa
A
A
Malstrom
S E
SE
Tsichlis
P N
PN
Rosen
N
N
D016227:Benzoquinones; D056741:Cyclin D; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047029:Lactams, Macrocyclic; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014176:Protein Biosynthesis; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011809:Quinones / Q000494:pharmacology; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015682:Retroviridae Proteins, Oncogenic / Q000378:metabolism*; D017828:Rifabutin / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured
D016227:Benzoquinones; D056741:Cyclin D; D016213:Cyclins; D047029:Lactams, Macrocyclic; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D011809:Quinones; D012333:RNA, Messenger; D015682:Retroviridae Proteins, Oncogenic; D017828:Rifabutin; C020754:herbimycin