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

In human prostate cancer, the frequent down-regulation of p27(kip1) protein expression is correlated with poor clinical outcome, yet p27(kip1) rarely undergoes mutational inactivation. Here, we investigate the consequences of reducing or eliminating p27(kip1) 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 p27(kip1) null allele (Nkx3.1(+/- or -/-); Pten(+/-); p27(+/-)) display enhanced prostate carcinogenesis, whereas mice that are homozygous null for p27(kip1) (Nkx3.1(+/- or -/-); Pten(+/-); p27(-/-)) show inhibition of cancer progression. Expression profiling reveals that Cyclin D1 is highly up-regulated in compound p27(kip1) heterozygotes, but is down-regulated in the compound p27(kip1) homozygous mutants. Using RNA interference in prostate cancer cell lines with distinct p27(kip1) gene doses, we show that prostate tumorigenicity depends on levels of p27(kip1) and that the consequences of p27(kip1) gene dosage can be attributed, in part, to altered levels of Cyclin D1. Our findings suggest that p27(kip1) possesses dosage-sensitive positive as well as negative modulatory roles in prostate cancer progression.
AuthorsHui Gao, Xuesong Ouyang, Whitney Banach-Petrosky, Alexander D Borowsky, Yong Lin, Minjung Kim, Hansol Lee, Weichung-Joseph Shih, Robert D Cardiff, Michael M Shen, Cory Abate-Shen
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 101 Issue 49 Pg. 17204-9 (Dec 7 2004) ISSN: 0027-8424 [Print] United States
PMID15569926 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Cdkn1b protein, mouse
  • Cell Cycle Proteins
  • Homeodomain Proteins
  • Nkx3-1 protein, mouse
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Cyclin D1
  • Cyclin-Dependent Kinase Inhibitor p27
  • Protein Tyrosine Phosphatases
  • Pten protein, mouse
  • PTEN Phosphohydrolase
  • Animals
  • Cell Cycle Proteins (genetics)
  • Cyclin D1 (genetics)
  • Cyclin-Dependent Kinase Inhibitor p27
  • Disease Models, Animal
  • Disease Progression
  • Gene Dosage
  • Gene Expression Regulation, Neoplastic
  • Genotype
  • Homeodomain Proteins
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Mutant Strains
  • PTEN Phosphohydrolase
  • Prostatic Neoplasms (etiology, genetics)
  • Protein Tyrosine Phosphatases (deficiency)
  • Transcription Factors (deficiency)
  • Tumor Suppressor Proteins (deficiency, genetics)

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