Selective activation of p38 alpha and p38 gamma by hypoxia - Role in regulation of cyclin D1 by hypoxia in PC12 cells

Hypoxic/ischemic trauma is a primary factor in the pathology of a multitude of disease states, The effects of hypoxia on the stress- and mitogen-activ ated protein kinase signaling pathways were studied in PC12 cells. Exposure to moderate hypoxia (5% O-2) progressively stimulated phosphorylation and activation of p38 gamma in particular, and also p38 alpha, two stress-activ ated protein kinases, In contrast, hypoxia had no effect on enzyme activity of p38 beta, p38 beta(2), p38 delta, or on c-Jun N-terminal kinase, anothe r stress-activated protein kinase. Prolonged hypoxia also induced phosphory lation and activation of p42/p44 mitogen-activated protein kinase, although this activation was modest compared with nerve growth factor- and ultravio let light-induced activation. Hypoxia also dramatically down-regulated immu noreactivity of cyclin D1, a gene that is known to be regulated negatively by p38 at the level of gene expression (Lavoie, J, N., L'Allemain, G,, Brun et, A., Muller, R., and Pouyssegur, J. (1996) J. Biol. Chem. 271, 20608-206 16). This effect was partially blocked by SB203580, an inhibitor of p38 alp ha but not p38 gamma, Overexpression of a kinase-inactive form of p38 gamma was also able to reverse in part the effect of hypoxia on cyclin D1 levels , suggesting that p38 alpha and p38 gamma converge to regulate cyclin D1 du ring hypoxia, These studies demonstrate that an extremely typical physiolog ical stress (hypoxia) causes selective activation of specific p38 signaling elements; and they also identify a downstream target of these pathways.