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Signal Pathway of Hypoxia-Inducible Factor-1 Phosphorylation and its Interaction with von Hippel-Lindau Tumor Suppressor Protein During Ischemia in MiaPaCa-2 Pancreatic Cancer Cells

Authors' Affiliation: Departments of Surgery and Pharmacology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

Requests for reprints: Yong J. Lee, Department of Surgery, University of Pittsburgh, Hillman Cancer Center, Room 1.19, 5117 Centre Avenue, Pittsburgh, PA 15213. Phone: 412-623-3268; Fax: 412-623-1415; E-mail: leeyj{at}msx.upmc.edu.

Purpose and Experimental Design: Previously, we observed that the activation of p38 mitogen-activated protein kinase (MAPK) and c-Jun NH₂-terminal kinase (JNK1) is mediated through the activation of apoptosis signal–regulating kinase 1 (ASK1) as a result of the reactive oxygen species–mediated dissociation of glutaredoxin and thioredoxin from ASK1. In this study, we examined whether p38 MAPK and JNK1 are involved in the accumulation of hypoxia-inducible factor-1 (HIF-1) during ischemia. Human pancreatic cancer MiaPaCa-2 cells were exposed to low glucose (0.1 mmol/L) with hypoxia (0.1% O₂).

Results and Conclusions: During ischemia, p38 MAPK and JNK1 were activated in MiaPaCa-2 pancreatic cancer cells. The activated p38 MAPK, but not JNK1, phosphorylated HIF-1. Data from in vivo binding assay of von Hippel-Lindau tumor suppressor protein with HIF-1 suggests that the p38-mediated phosphorylation of HIF-1 contributed to the inhibition of HIF-1 and von Hippel-Lindau tumor suppressor protein interaction during ischemia. SB203580, a specific inhibitor of p38 MAPK, inhibited HIF-1 accumulation during ischemia, probably resulting from the ubiquitination and degradation of HIF-1.

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