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Vol. 17, Issue 4, 1995-2008, April 2006
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Attenuates Hypoxia-induced Proliferation of Fibroblasts by Regulating MAP Kinase Phosphatase-1 Expression
Developmental Lung Biology Research Laboratory, Department of Pediatrics, University of Colorado Health Sciences Center, Denver, CO 80262
Submitted September 20, 2005;
Revised January 5, 2006;
Accepted January 31, 2006
Monitoring Editor: Richard Assoian
We have previously found that hypoxia stimulates proliferation of vascular fibroblasts through G
i-mediated activation of ERK1/2. Here, we demonstrate that hypoxia also activates the atypical protein kinase C
(PKC) isozyme and stimulates the expression of ERK1/2-specific phosphatase, MAP kinase phosphatase-1 (MKP-1), which attenuates ERK1/2-mediated proliferative signals. Replication repressor activity is unique to PKC because the blockade of classical and novel PKC isozymes does not affect fibroblast proliferation. PKC is phosphorylated upon prolonged (24 h) exposure to hypoxia, whereas ERK1/2, the downstream kinases, are maximally activated in fibroblasts exposed to acute (10 min) hypoxia. However, PKC blockade results in persistent ERK1/2 phosphorylation and marked increase in hypoxia-induced replication. Similarly prolonged ERK1/2 phosphorylation and increase in hypoxia-stimulated proliferation are also observed upon blockade of MKP-1 activation. Because of the parallel suppressive actions of PKC and MKP-1 on ERK1/2 phosphorylation and proliferation, the role of PKC in the regulation of MKP-1 expression was evaluated. PKC attenuation reduces MKP-1 expression, whereas PKC overexpression increases MKP-1 levels. In conclusion, our results indicate for the first time that hypoxia activates PKC, which acts as a terminator of ERK1/2 activation through the regulation of downstream target, MKP-1 expression and thus serves to limit hypoxia-induced proliferation of fibroblasts.
Address correspondence to: Mita Das (Mita.Das{at}uchsc.edu).
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