Evidence for a p27 tumor suppressive function independent of its role regulating cell proliferation in the prostate. Academic Article uri icon

Overview

abstract

  • 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.

publication date

  • December 22, 2004

Research

keywords

  • Cell Cycle Proteins
  • Cell Division
  • Prostate
  • Tumor Suppressor Proteins

Identity

PubMed Central ID

  • PMC539141

Scopus Document Identifier

  • 11844259459

Digital Object Identifier (DOI)

  • 10.1073/pnas.0407362102

PubMed ID

  • 15615849

Additional Document Info

volume

  • 102

issue

  • 1