Inhibition of the 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase Pathway Induces p53-independent Transcriptional Regulation of p21 in Human Prostate Carcinoma Cells

• DOI: 10.1074/jbc.273.17.10618
• Publication Date: 2002-07-26T15:04:43Z
• Authors: Su Jae Lee; Mahn Joon Ha; Jeen Lee; PhuongMai Nguyen; Yung Hyun Choi; Farzaneh Pirnia; Won-Ki Kang; Xiao-Fan Wang; Seong-Jin Kim; Jane B. Trepel
• Keywords: Cyclin-Dependent Kinase Inhibitor p21; Male; 0301 basic medicine; Base Sequence; Molecular Sequence Data; G1 Phase; Apoptosis; Cell Cycle Proteins; Cyclin-Dependent Kinases; E2F Transcription Factors; 3. Good health; DNA-Binding Proteins; Gene Expression Regulation, Neoplastic; 03 medical and health sciences; Cyclins; Humans; Hydroxymethylglutaryl CoA Reductases; Lovastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Phosphorylation; Carrier Proteins; Promoter Regions, Genetic; E2F1 Transcription Factor

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.