Suppression of the dual-specificity phosphatase MKP-1 enhances HIF-1 trans-activation and increases expression of EPO

• Published in: Biochemical and biophysical research communications 2003-12, Vol.312 (3), p.780-786
• Main Authors: Liu, Changjiang, Shi, Yongquan, Han, Zheyi, Pan, Yanglin, Liu, Na, Han, Shuang, Chen, Yu, Lan, Mei, Qiao, Taidong, Fan, Daiming
• Format: Article
• Language: English
• Subjects: Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Cell Cycle Proteins; Cell Line, Tumor; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Down-Regulation; Dual Specificity Phosphatase 1; Enzyme Activation; EPO; Erythropoietin - biosynthesis; Erythropoietin - genetics; Gene Expression Regulation, Neoplastic; HIF-1α; Homeostasis; Humans; Hypoxia; Hypoxia - metabolism; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Immediate-Early Proteins - antagonists & inhibitors; Immediate-Early Proteins - genetics; Immediate-Early Proteins - metabolism; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; MKP-1; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; p38 protein; Phosphoprotein Phosphatases; Phosphorylation; Protein Phosphatase 1; Protein Tyrosine Phosphatases - antagonists & inhibitors; Protein Tyrosine Phosphatases - genetics; Protein Tyrosine Phosphatases - metabolism; Sensitivity and Specificity; siRNA; Transcription Factors; Transcriptional Activation
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2003.10.186

Hypoxia-inducible factor 1 (HIF-1) is a phosphorylated protein and its phosphorylation is involved in HIF-1α subunit stabilization as well as in the regulation of HIF-1 transcriptional activity. In a variety of cell lines, the phosphorylation of HIF-1α is dependent on ERK or p38, two members of the mitogen-activated protein kinase (MAPK) superfamily. In addition, active MAPK could be inactivated through dephosphorylation by mitogen-activated protein kinase phosphatase-1 (MKP-1). MKP-1 has been identified as a hypoxia responsive gene, but its role in the response of cells to hypoxia is poorly understood. Here we found that hypoxia induces MKP-1 expression in human hepatoma cells HepG2 in a time-dependent manner. Inhibition of MKP-1 expression using siRNA technique could enhance HIF-1α phosphorylation, accompanied by an increase in transcriptionally active HIF-1 as well as a rise in the levels of HIF-1-induced erythropoietin expression.