A critical role for p27kip1 gene dosage in a mouse model of prostate carcinogenesis

Hui Gao, Xuesong Ouyang, Whitney Banach-Petrosky, Alexander D Borowsky, Yong Lin, Minjung Kim, Hansol Lee, Weichung Joseph Shih, Robert Cardiff, Michael M. Shen, Cory Abate-Shen

Research output: Contribution to journalArticle

96 Scopus citations

Abstract

In human prostate cancer, the frequent down-regulation of p27 kip1 protein expression is correlated with poor clinical outcome, yet p27kip1 rarely undergoes mutational inactivation. Here, we investigate the consequences of reducing or eliminating p27kip1 function for prostate carcinogenesis in the context of a mouse modeling lacking the Nkx3.1 homeobox gene and the Pten tumor suppressor. Unexpectedly, we find that triple mutant mice heterozygous for a p27kip1 null allele (Nkx3.1+/- or -/-; Pten+/-; p27+/-) display enhanced prostate carcinogenesis, whereas mice that are homozygous null for p27kip1 (Nkx3.1+/- or -/-; Pten+/-; p27 -/-) show inhibition of cancer progression. Expression profiling reveals that Cyclin D1 is highly up-regulated in compound p27kip1 heterozygotes, but is down-regulated in the compound p27kip1 homozygous mutants. Using RNA interference in prostate cancer cell lines with distinct p27kip1 gene doses, we show that prostate tumorigenicity depends on levels of p27kip1 and that the consequences of p27 kip1 gene dosage can be attributed, in part, to altered levels of Cyclin D1. Our findings suggest that p27kip1 possesses dosage-sensitive positive as well as negative modulatory roles in prostate cancer progression.

Original languageEnglish (US)
Pages (from-to)17204-17209
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number49
DOIs
StatePublished - Dec 7 2004

Keywords

  • Cyclin D1
  • Expression profiling
  • p27
  • Prostate cancer

ASJC Scopus subject areas

  • Genetics
  • General

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