Dual-specificity phosphatase DUSP1 protects overactivation of hypoxia-inducible factor 1 through inactivating ERK MAPK.
Hypoxia-inducible factor 1 (HIF-1) plays a critical role in controlling oxygen delivery and metabolic adaptation to hypoxic conditions in hypoxic tumor cells. HIF-1 activation is initiated by several factors including mitogen-activated protein kinase ( MAPK) superfamily. We have previously reported that mitogen-activated protein kinase phosphatase DUSP1 (MKP-1) was implicated in the negative regulation of HIF-1alpha subunit phosphorylation and HIF-1 activity. However, the molecular basis by which MKP-1 influences HIF-1 activity is not clarified. In this paper, we show that hypoxia transcriptionally induces MKP-1 expression in a time-dependent manner. Meanwhile, hypoxia also activates extracellular signal-regulated kinase ( ERK) whose activity is enhanced or reduced by MKP-1 suppression or MKP-1 overexpression, respectively. We also show that suppression of MKP-1 expression facilitates the interaction between HIF-1alpha subunit and p300, a co-activator of HIF-1. Moreover, MKP-1 suppression leads to enhanced HIF-1 activity, which can be counteracted by PD98059, an ERK kinase inhibitor. Taken together, the results presented here suggest that hypoxia-induced MKP-1 protects overactivation of HIF-1 activation through inhibiting ERK kinase activity.[1]References
- Dual-specificity phosphatase DUSP1 protects overactivation of hypoxia-inducible factor 1 through inactivating ERK MAPK. Liu, C., Shi, Y., Du, Y., Ning, X., Liu, N., Huang, D., Liang, J., Xue, Y., Fan, D. Exp. Cell Res. (2005) [Pubmed]
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