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J. Biol. Chem., Vol. 282, Issue 10, 7154-7163, March 9, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/10/7154    most recent M611599200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Choi, W.-T. Articles by Huang, Z. Search for Related Content PubMed PubMed Citation Articles by Choi, W.-T. Articles by Huang, Z. Social Bookmarking                      What's this?

Neuronal Apoptotic Signaling Pathways Probed and Intervened by Synthetically and Modularly Modified (SMM) Chemokines^*

Won-Tak Choi, Marcus Kaul, Santosh Kumar, Jun Wang^¶, I. M. Krishna Kumar^¶, Chang-Zhi Dong, Jing An^¶||, Stuart A. Lipton, and Ziwei Huang^¶**1

From the Departments of Biochemistry and ^**Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, Center for Neurosciences and Aging and ^¶Cancer Center, The Burnham Institute for Medical Research, La Jolla, California 92037, and ^||Raylight Corporation, Chemokine Pharmaceutical Inc., La Jolla, California 92037

As the main coreceptors for human immunodeficiency virus type 1 (HIV-1) entry, CXCR4 and CCR5 play important roles in HIV-associated dementia (HAD). HIV-1 glycoprotein gp120 contributes to HAD by causing neuronal damage and death, either directly by triggering apoptotic pathways or indirectly by stimulating glial cells to release neurotoxins. Here, to understand the mechanism of CXCR4 or CCR5 signaling in neuronal apoptosis associated with HAD, we have applied synthetically and modularly modified (SMM)-chemokine analogs derived from natural stromal cell-derived factor-1 or viral macrophage inflammatory protein-II as chemical probes of the mechanism(s) whereby these SMM-chemokines prevent or promote neuronal apoptosis. We show that inherently neurotoxic natural ligands of CXCR4, such as stromal cell-derived factor-1 or viral macrophage inflammatory protein-II, can be modified to protect neurons from apoptosis induced by CXCR4-preferring gp120_IIIB, and that the inhibition of CCR5 by antagonist SMM-chemokines, unlike neuroprotective CCR5 natural ligands, leads to neurotoxicity by activating a p38 mitogen-activated protein kinase (MAPK)-dependent pathway. Furthermore, we discover distinct signaling pathways activated by different chemokine ligands that are either natural agonists or synthetic antagonists, thus demonstrating a chemical biology strategy of using chemically engineered inhibitors of chemokine receptors to study the signaling mechanism of neuronal apoptosis and survival.

Received for publication, December 19, 2006

^* This work was supported in part by National Institutes of Health Grants R01 GM5776105 (to Z. H.), R01 NS050621 (to M. K.), and P01 HD29587, R01 EY09024, and R01 NS41207 (to S. A. L.). 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.

¹ To whom correspondence should be addressed: The Burnham Inst. for Medical Research, 10901 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-713-9928; E-mail: ziweihuang{at}burnham.org.

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