Abstract
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
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Apoptosis / drug effects
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Base Sequence
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Carrier Proteins*
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Cell Cycle Proteins*
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclin-Dependent Kinases / antagonists & inhibitors
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Cyclins / genetics*
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DNA-Binding Proteins*
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E2F Transcription Factors
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E2F1 Transcription Factor
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G1 Phase / drug effects
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Gene Expression Regulation, Neoplastic*
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Humans
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Hydroxymethylglutaryl CoA Reductases / metabolism*
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
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Lovastatin / pharmacology
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Male
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Molecular Sequence Data
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Phosphorylation
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Promoter Regions, Genetic
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Prostatic Neoplasms / genetics*
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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Retinoblastoma Protein / metabolism
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Retinoblastoma-Binding Protein 1
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Transcription Factor DP1
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Transcription Factors / metabolism
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Transcription, Genetic*
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Tumor Cells, Cultured
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Tumor Suppressor Protein p53 / metabolism*
Substances
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CDKN1A protein, human
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Carrier Proteins
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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DNA-Binding Proteins
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E2F Transcription Factors
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E2F1 Transcription Factor
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E2F1 protein, human
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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RNA, Messenger
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Retinoblastoma Protein
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Retinoblastoma-Binding Protein 1
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Transcription Factor DP1
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Transcription Factors
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Tumor Suppressor Protein p53
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Lovastatin
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Hydroxymethylglutaryl CoA Reductases
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Cyclin-Dependent Kinases