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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.

Publication ,  Journal Article
Lee, SJ; Ha, MJ; Lee, J; Nguyen, P; Choi, YH; Pirnia, F; Kang, WK; Wang, XF; Kim, SJ; Trepel, JB
Published in: J Biol Chem
April 24, 1998

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.

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Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

April 24, 1998

Volume

273

Issue

17

Start / End Page

10618 / 10623

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Tumor Cells, Cultured
  • Transcription, Genetic
  • Transcription Factors
  • Transcription Factor DP1
  • Retinoblastoma-Binding Protein 1
  • Retinoblastoma Protein
  • RNA, Messenger
  • Prostatic Neoplasms
  • Promoter Regions, Genetic
 

Citation

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Lee, S. J., Ha, M. J., Lee, J., Nguyen, P., Choi, Y. H., Pirnia, F., … Trepel, J. B. (1998). 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. J Biol Chem, 273(17), 10618–10623. https://doi.org/10.1074/jbc.273.17.10618
Lee, S. J., M. J. Ha, J. Lee, P. Nguyen, Y. H. Choi, F. Pirnia, W. K. Kang, X. F. Wang, S. J. Kim, and J. B. Trepel. “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.J Biol Chem 273, no. 17 (April 24, 1998): 10618–23. https://doi.org/10.1074/jbc.273.17.10618.
Lee, S. J., et al. “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.J Biol Chem, vol. 273, no. 17, Apr. 1998, pp. 10618–23. Pubmed, doi:10.1074/jbc.273.17.10618.
Lee SJ, Ha MJ, Lee J, Nguyen P, Choi YH, Pirnia F, Kang WK, Wang XF, Kim SJ, Trepel JB. 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. J Biol Chem. 1998 Apr 24;273(17):10618–10623.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

April 24, 1998

Volume

273

Issue

17

Start / End Page

10618 / 10623

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Tumor Cells, Cultured
  • Transcription, Genetic
  • Transcription Factors
  • Transcription Factor DP1
  • Retinoblastoma-Binding Protein 1
  • Retinoblastoma Protein
  • RNA, Messenger
  • Prostatic Neoplasms
  • Promoter Regions, Genetic