Published ahead of print on February 14, 2008 Am. J. Respir. Cell Mol. Biol. 2008, doi:10.1165/rcmb.2007-0371OC
Submitted on October 13, 2007 SHP-1 Inhibition by 4-hydroxynonenal Activates Jun N-terminal Kinase and Glutamate Cysteine LigaseAlessandra Rinna1 and Henry Jay Forman2*1 University of California Merced, School of Natural Sciences, Merced, CA, USA; Department of Pharmacobiology, University of Messina, School of Pharmacy, Messina, Italy, 2 University of California Merced, School of Natural Sciences, Merced, CA, USA * To whom correspondence should be addressed. 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, 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 JNK pathway. The protein-tyrosine phosphatase 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 MKK4, JNK and c-Jun. HNE was able to inhibit PTP activity of SHP-1 through increased degradation of the protein. Furthermore transfection with siRNA 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.
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