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Inhibition of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase pathway induces p53-independent transcriptional regulation of p21(WAF1/CIP1) in human prostate carcinoma cells.

Lee, SJ; Ha, MJ; Lee, J; Nguyen, P; Choi, YH; Pimia, F; Kang, WK; Wang, XF; Kim, SJ; Trepel, JB
The Journal of biological chemistry, 273(17):10618-10623, 1998
Journal Title
The Journal of biological chemistry
Progression through the cell cycle is controlled by the induction of cyclins and the activation of cognate cyclin-dependent kinases. The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor lovastatin induces growth arrest and cell death in certain cancer cell types. We have pursued the mechanism of growth arrest in PC-3-M cells, a p53-null human prostate carcinoma cell line. Lovastatin treatment increased protein and mRNA levels of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1), increased binding of p21 with Cdk2, markedly inhibited cyclin E- and Cdk2-associated phosphorylation of histone H1 or GST-retinoblastoma protein, enhanced binding of the retinoblastoma protein to the transcription factor E2F-1 in vivo, and induced the activation of a p21 promoter reporter construct. By using p21 promoter deletion constructs, the lovastatin-responsive element was mapped to a region between -93 and -64 relative to the transcription start site. Promoter mutation analysis indicated that the lovastatin-responsive site coincided with the previously identified transforming growth factor-beta-responsive element. These data indicate that in human prostate carcinoma cells an inhibitor of the HMG-CoA reductase pathway can circumvent the loss of wild-type p53 function and induce critical downstream regulatory events leading to transcriptional activation of p21.
MeSH terms
Apoptosis/drug effectsBase Sequence*Carrier Proteins*Cell Cycle ProteinsCyclin-Dependent Kinase Inhibitor p21Cyclin-Dependent Kinases/antagonists & inhibitorsCyclins/*genetics*DNA-Binding ProteinsE2F Transcription FactorsE2F1 Transcription FactorG1 Phase/drug effects*Gene Expression Regulation, NeoplasticHumansHydroxymethylglutaryl CoA Reductases/*metabolismHydroxymethylglutaryl-CoA Reductase Inhibitors/*pharmacologyLovastatin/pharmacologyMaleMolecular Sequence DataPhosphorylationPromoter Regions, GeneticProstatic Neoplasms/*genetics/metabolism/pathologyRNA, Messenger/biosynthesis/geneticsRetinoblastoma Protein/metabolismRetinoblastoma-Binding Protein 1Transcription Factor DP1Transcription Factors/metabolism*Transcription, GeneticTumor Cells, CulturedTumor Suppressor Protein p53/*metabolism
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Journal Papers > School of Medicine / Graduate School of Medicine > Anatomy
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하, 만준
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