Selective activation of p38α and p38γ 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-activated 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-activated 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, another stress-activated protein kinase. Prolonged hypoxia also induced phosphorylation and activation of p42/p44 mitogen-activated protein kinase, although this activation was modest compared with nerve growth factor- and ultraviolet light-induced activation. Hypoxia also dramatically down-regulated immunoreactivity 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,, Brunet, A., Muller, R., and Pouyssegur, J. (1996) J. Biol. Chem. 271, 20608-20616). This effect was partially blocked by SB203580, an inhibitor of p38 alpha 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 during hypoxia, These studies demonstrate that an extremely typical physiological stress (hypoxia) causes selective activation of specific p38 signaling elements; and they also identify a downstream target of these pathways.