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SHP-1 Inhibition by 4-Hydroxynonenal Activates Jun N-Terminal Kinase and Glutamate Cysteine Ligase

¹ School of Natural Sciences, University of California Merced, Merced, California; and ² Department of Pharmacobiology, School of Pharmacy, University of Messina, Messina, Italy

Correspondence and requests for reprints should be addressed to Henry Jay Forman, PhD, School of Natural Sciences, University of California Merced, P. O. Box 2039, Merced, CA 95344. E-mail: hjforman{at}gmail.com

4-Hydroxy-2-nonenal (HNE), a major lipid peroxidation product, is toxic at high concentrations, but at near-physiological concentrations it induces detoxifying enzymes. Previous data established that in human bronchial epithelial (HBE1) cells, both genes for glutamate cysteine ligase (GCL) are induced by HNE through the c-Jun N-terminal kinase (JNK) pathway. The protein-tyrosine phosphatase SH2 domain containing phosphatase-1 (SHP-1) is thought to play a role as a negative regulator of cell signaling, and has been implicated as such in the JNK pathway. In the present study, SHP-1 was demonstrated to contribute to HNE-induced-gclc expression via regulation of the JNK pathway in HBE1 cells. Treatment of HBE1 cells with HNE induced phosphorylation of mitogen-activated protein kinase kinase 4 (MKK4), JNK, and c-Jun. HNE was able to inhibit protein tyrosine phosphatase activity of SHP-1 through increased degradation of the protein. Furthermore, transfection with small interference RNA SHP-1 showed an enhancement of JNK and c-Jun phosphorylation, but not of MKK4, leading to increased gclc expression. These results demonstrate that SHP-1 plays a role as a negative regulator of the JNK pathway and that HNE activated the JNK pathway by inhibiting SHP-1. Thus, SHP-1 acts as a sensor for HNE and is responsible for an important adaptive response to oxidative stress.

Key Words: SHP-1 • 4-hydroxynonenal • glutamate cysteine ligase • protein degradation • protein tyrosine phosphatase

CLINICAL RELEVANCE 4-hydroxynonenal (HNE), a lipid peroxidation product, mediates adaptation to oxidative stress. HNE caused degradation of the protein tyrosine phosphatase SHP-1, leading to activation of c-Jun N-terminal kinase and expression of the first enzyme in glutathione synthesis.