The role of p27 in gliomagenesis.

摘要

P27 is a cyclin-dependent kinase (cdk) inhbitor that regulates the cell cycle in response to anti-proliferative signals. Defects in p27 function are associated with enhanced proliferation in many types of cancer. However, in other cancers, including oligodendrogliomas, p27 deficiency is not associated with changes in proliferation, suggesting that p27 has cell cycle independent functions. The work presented here characterizes two cell cycle independent functions of p27 that operate in oligodendrogliomas: regulation of chromosomal stability and regulation of cell migration.;We used the RCAS/tv-a system to induce PDGF-expressing gliomas in mice. To determine if loss of p27 affected oligodendroglioma tumor formation, we crossed nestin-tv-a positive mice onto a p27 null background and injected PDGF-expressing virus producing DF1 cells into the frontal cortex of newborn mice. Loss of p27 caused a dramatic decrease in survival. Wild type (WT) and p27 deficient PDGF-expressing glial cell lines were then generated. Early passage p27 deficient and WT cells exhibited similar PDGF signaling and growth properties. However, after continued passage, p27 deficient cells grew much faster than WT cells. Early passage p27 deficient cells demonstrated karyotype abnormalities, defects in Rad51 function, and, upon gamma-irradiation, contained more unrepaired double stranded breaks. These results support a model wherein p27 deficiency leads to chromosomal instability and the outgrowth of cells with enhanced proliferation.