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.
Gao
Hui
H
Center for Advanced Biotechnology and Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
Ouyang
Xuesong
X
Banach-Petrosky
Whitney
W
Borowsky
Alexander D
AD
Lin
Yong
Y
Kim
Minjung
M
Lee
Hansol
H
Shih
Weichung-Joseph
WJ
Cardiff
Robert D
RD
Shen
Michael M
MM
Abate-Shen
Cory
C
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics*; D019938:Cyclin D1 / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004195:Disease Models, Animal; D018450:Disease Progression; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D018398:Homeodomain Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D051059:PTEN Phosphohydrolase; D011471:Prostatic Neoplasms / Q000209:etiology / Q000235:genetics*; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency; D014157:Transcription Factors / Q000172:deficiency; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics*
C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D018398:Homeodomain Proteins; C102837:Nkx3-1 protein, mouse; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017027:Protein Tyrosine Phosphatases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse