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J. Biol. Chem., Vol. 279, Issue 47, 49199-49205, November 19, 2004

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Cystathionine -Lyase Overexpression Inhibits Cell Proliferation via a H₂S-dependent Modulation of ERK1/2 Phosphorylation and p21^Cip/WAK-1*

Guangdong Yang, Kun Cao¶, Lingyun Wu||**, and Rui Wang, Supported by an Investigator Award from CIHR

From the Department of Physiology, College of Medicine, The Cardiovascular Research Group and the ^||Department of Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada

Cystathionine -lyase (CSE) is a key enzyme in the trans-sulfuration pathway. CSE uses L-cysteine as a substrate to produce hydrogen sulfide (H₂S). The CSE/H₂S system has been shown to play an important role in regulating cellular functions in different systems. In the present study, we used CSE stably overexpressed HEK-293 cells to explore the effect of the CSE/H₂S system on cell growth and proliferation. The overexpression of CSE resulted in increases in CSE mRNA levels, CSE proteins, and intracellular H₂S production rates, as well as the inhibition of cell proliferation and DNA synthesis. These effects were accompanied by a sustained ERK activation and up-regulation of the cyclin-dependent kinase inhibitor p21^Cip/WAK-1. Blocking the action of ERK with U0126 inhibited the induction of p21^Cip/WAK-1, suggesting that ERK activation functions upstream of p21^Cip/WAK-1 activation to initiate the CSE overexpression-induced cell growth inhibition. The antiproliferative effect of CSE is likely mediated by endogenously produced H₂S because the H₂S scavenger methemoglobin (10 µM) significantly decreased the H₂S production rate and reversed the antiproliferative effect afforded by CSE. Exogenous H₂S (100 µM) also inhibited cell proliferation. However, the other CSE-catalyzed products, ammonium and pyruvate, failed to inhibit cell proliferation. Methemoglobin also abolished the inhibitory effect of exogenous H₂S on cell proliferation. Moreover, exogenous H₂S induced a sustained ERK and p21^Cip/WAK-1 activation. These findings support the hypothesis that endogenously produced H₂S may play a fundamental role in cell proliferation and survival.

Received for publication, August 6, 2004 , and in revised form, September 2, 2004.

^* This study was supported in part by the Natural Sciences and Engineering Research Council of Canada. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a post-doctoral fellowship award from the Saskatchewan Health Research Foundation, Canada.

^¶ Supported by a post-doctoral fellowship award from the Canadian Institutes of Health Research (CIHR) and Canadian Hypertension Society.

^** Supported by a New Investigator Award from CIHR.

To whom correspondence should be addressed: Dept. of Physiology, University of Saskatchewan, 107 Wiggins Rd., Saskatoon, Saskatchewan S7N 5E5, Canada. Tel.: 306-966-6592; Fax: 306-966-6532; E-mail: wangrui{at}duke.usask.ca.

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