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Adenovirus-mediated Overexpression of p15^INK4B Inhibits Human Glioma Cell Growth, Induces Replicative Senescence, and Inhibits Telomerase Activity Similarly to p16^INK4A

Ludwig Institute for Cancer Research, Stockholm Branch, S-17177 Stockholm [J. F., H. M. G., V. P. C., R. F. P.]; Department of Medical Immunology and Microbiology, Uppsala University, 75123 Uppsala [G. A.]; and Department of Pathology, Umeå University, 90187 Umeå [G. R.], Sweden

Abstract

The genes encoding the cyclin-dependent kinase inhibitors p16^INK4A (CDKN2A) and p15^INK4B (CDKN2B) are frequently homozygously deleted in a variety of tumor cell lines and primary tumors, including glioblastomas in which 40–50% of primary tumors display homozygous deletions of these two loci. Although the role of p16 as a tumor suppressor has been well documented, it has remained less well studied whether p15 plays a similar growth-suppressing role. Here, we have used replication-defective recombinant adenoviruses to compare the effects of expressing wild-type p16 and p15 in glioma cell lines. After infection, high levels of p16 and p15 were observed in two human glioma cell lines (U251 MG and U373 MG). Both inhibitors were found in complex with CDK4 and CDK6. Expression of p16 and p15 had indistinguishable effects on U251 MG, which has homozygous deletion of CDKN2A and CDKN2B, but a wild-type retinoblastoma (RB) gene. Cells were growth-arrested, showed no increased apoptosis, and displayed a markedly altered cellular morphology and repression of telomerase activity. Transduced cells became enlarged and flattened and expressed senescence-associated ß-galactosidase, thus fulfilling criteria for replicative senescence. In contrast, the growth and morphology of U373 MG, which expresses p16 and p15 endogenously, but undetectable levels of RB protein, were not affected by exogenous overexpression of either inhibitor. Thus, we conclude that overexpression of p15 has a similar ability to inhibit cell proliferation, to cause replicative senescence, and to inhibit telomerase activity as p16 in glioma cells with an intact RB protein pathway.

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