Hypoxia differentially regulates the mitogen- and stress-activated protein kinases. Role of Ca2+/CaM in the activation of MAPK and p38 gamma

Hypoxic/ischemic trauma is a primary factor in the pathology of various vascular, pulmonary, and cerebral disease states. Yet, the signaling mechanisms by which cells respond and adapt to changes in oxygen levels are not clearly established. The effects of hypoxia on the stress- and mitogen-activate...

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Bibliographic Details
Published inAdvances in experimental medicine and biology Vol. 475; p. 293
Main Authors Conrad, P W, Millhorn, D E, Beitner-Johnson, D
Format Journal Article
LanguageEnglish
Published United States 2000
Subjects
Animals
Calcium - metabolism
Calmodulin - metabolism
Cell Hypoxia - physiology
Enzyme Activation
JNK Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinase 1 - metabolism
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinases - metabolism
p38 Mitogen-Activated Protein Kinases
PC12 Cells
Rats
Signal Transduction
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Summary:Hypoxic/ischemic trauma is a primary factor in the pathology of various vascular, pulmonary, and cerebral disease states. Yet, the signaling mechanisms by which cells respond and adapt to changes in oxygen levels are not clearly established. The effects of hypoxia on the stress- and mitogen-activated protein kinase (SAPK and MAPK) signaling pathways were studied in PC12 cells. Exposure to moderate hypoxia (5% O2) was found to progressively stimulate phosphorylation and activation of p38 gamma in particular, and also p38 alpha, two isoforms of the p38 family of stress-activated protein kinases. In contrast, hypoxia had no effect on enzyme activity of p38 beta, p38 beta 2, p38 delta, or on JNK, another stress-activated protein kinase. Prolonged hypoxia also induced phosphorylation and activation of p42/p44 MAPK, although this activation was modest when compared to NGF and UV-induced activation. We further showed that activation of p38 gamma and MAPK during hypoxia requires calcium, as treatment with Ca(2+)-free media or the calmodulin antagonist, W13, blocked the activation of p38 gamma and MAPK, respectively. These studies demonstrate that an extremely typical physiological stress (hypoxia) causes selective activation of specific elements of the SAPKs and MAPKs, and identifies Ca+2/CaM as a critical upstream activator.
ISSN:0065-2598