Evidence for a p27 tumor suppressive function independent of its role regulating cell proliferation in the prostate.
Reduced p27 levels correlate with poor prognosis in a wide spectrum of human tumors and can accelerate tumorigenesis in mouse tissues. To determine whether p27 deficiency can accelerate tumorigenesis in tissues with inactive Rb and p53 pathways, we examined the effect of p27 status on prostate tumorigenesis in mice expressing simian virus 40 large T antigen (LT). In p27-deficient mice expressing LT, tumors progressed from high-grade prostatic intraepithelial neoplasia to poorly differentiated carcinoma at a greatly accelerated rate. p27 deficiency could not collaborate with a mutant of LT that fails to inactivate the Rb pathway alone. Furthermore, p27 deficiency does not increase the proliferation index, reduce the apoptotic index, or affect the expression of E2F-dependent genes in cells expressing LT at any stage of the disease. Expression of LT alone leads to maximal proliferation, but p27 deficiency still increases the amount of cyclin A and cyclin-dependent kinase 2-associated kinase activity in tissues. Interestingly, this model recapitulates an important feature of the human disease, specifically a high frequency of allelic loss of chromosome 16q, which is syntenic to mouse chromosome 8. Loss of heterozygosity may accelerate the inactivation of other tumor suppressors, such as E-cadherin, which are located in this interval. These experiments provide direct physiological and causal evidence that p27 has tumor suppressive functions independent of its role regulating cell proliferation.
Shaffer
David R
DR
Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
Viale
Agnes
A
Ishiwata
Ryota
R
Leversha
Margaret
M
Olgac
Semra
S
Manova
Katia
K
Satagopan
Jaya
J
Scher
Howard
H
Koff
Andrew
A
D000818:Animals; D000957:Antigens, Viral, Tumor / Q000276:immunology; D042846:CDC2-CDC28 Kinases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002455:Cell Division / Q000502:physiology*; D002869:Chromosome Aberrations; D019925:Cyclin A / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D042822:Genomic Instability; D008297:Male; D051379:Mice; D011467:Prostate / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000276:immunology / Q000378:metabolism / Q000821:virology; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D013539:Simian virus 40 / Q000276:immunology; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D000957:Antigens, Viral, Tumor; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D019925:Cyclin A; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2