MCB Accepts, published online ahead of print on 14 July 2008

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Mol. Cell. Biol. doi:10.1128/MCB.00245-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Retinoic acid utilizes CREB and USF-1 in a transcriptional feed-forward loop in order to stimulate MKP1 expression in HIV-infected podocytes

Ting-Chi Lu, Zhaohui Wang, Xiaobei Feng, Peter Chuang, Wei Fang, Yibang Chen, Susana Neves, Avi Maayan, Huabao Xiong, Yusen Liu, Ravi Iyengar, Paul E Klotman, and John Cijiang He^*

Department of Medicine, Department of Pharmacology and Systems Therapeutics, Immunobiology Center, Mount Sinai School of Medicine, New York, NY; James J. Peters VA Medical Center, Bronx, NY; Department of Nephrology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai; Children's Research Institute, The Ohio State University, OH

^* To whom correspondence should be addressed. Email: Cijiang.he{at}mssm.edu.

Nef induced podocyte proliferation and dedifferentiation via MAPK1,2 activation plays a role in HIV nephropathy pathogenesis. All-trans retinoic acid (atRA) reverses the HIV-induced podocyte phenotype by activating cAMP/PKA and inhibiting MAPK1,2. Here we show that atRA, through cAMP and PKA, triggers a feed-forward loop involving CREB and USF1 to induce biphasic stimulation of MKP1. AtRA stimulated CREB and USF1 binding to the MKP1 gene promoter as shown by gel shifting and Chromatin immunoprecipitation assays. CREB directly mediated the early phase of atRA-induced MKP1 stimulation; whereas the later phase was mediated by CREB indirectly through induction of USF1. These findings were confirmed by reporter gene assay using MKP1 promoter with mutation of CRE or Ebox binding sites. Consistent with these findings, the biological effects of atRA on podocytes were inhibited by silencing either MKP1, CREB, or USF1 with siRNA. AtRA also induced CREB phosphorylation, MKP1 expression, and reduced MAPK1,2 phosphorylation in kidneys of HIV-1 transgenic mice. We conclude that atRA induces sustained activation of MKP1 to suppress Nef-induced activation of Src-MAPK1,2 pathway, thus returning the podocyte to a more differentiated state. The mechanism involves a feed-forward loop where activation of one TF (CREB) leads to induction of a second TF (USF1).