2007. Vol. 49, N 2. p. 115-124
ROLE OF p38α KINASE IN ACTIVATION OF PREMATURE SENESCENCE PROGRAM IN TRANSFORMED MOUSE FIBROBLASTS

S. G. Zubova, T. V. Bykova, J. G. Zubova, V. S. Romanov, N. D. Aksenov, V. A. Pospelov, T. V. Pospelova

Institute of Cytology RAS, St. Petersburg;
e-mail: egretta_julia@mail.ru

We investigated the role of p38α stress-kinase in regulation of premature senescence program, stimulated by histone deacetylase inhibitor - sodium butyrate (NaB) - after application to rodent transformed cell lines. Investigation was performed on the E1A + cHa-ras transformants selected from mice embryonic fibroblasts null at the p38α kinase gene or null fibroblasts at the PPM1D gene, which encoded phosphatase Wip1. Absence of Wip1 led to constitutive activation of p38α kinase. It was revealed that after NaB treatment both cell lines completely stopped proliferation due to irreversible cell cycle arrest in G1/S phase. In both cell lines sodium butyrate induced sustained block of prolifaration due to irreversible cell cycle arrest in G1/S phase. Following sodium butyrate treatment cells expressed marker of senescence - β-galactosidase activity (SA-β-Gal). Long-term (during several days) NaB treatment of cells led to partial restoration of actin cytoskeleton, focal adhesion contacts and heterochromatin focus formation (SAHF) in the nucleus of senescent cells. Obtained data allow us to suppose that irreversible process of cellular senescence activated by sodium butyrate can occur in the absence of functionally active p38 kinase by means of other ways of cell cycle suppression.

Key words:  oncogenes E1A and cHa-ras, transformation, p38α kinase, Wip1 hosphatase, senescence, cell cycle, sodium butyrate


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