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Molecular and Cellular Biology, September 2008, p. 5785-5794, Vol. 28, No. 18
0270-7306/08/$08.00+0     doi:10.1128/MCB.00245-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Retinoic Acid Utilizes CREB and USF1 in a Transcriptional Feed-Forward Loop in Order To Stimulate MKP1 Expression in Human Immunodeficiency Virus-Infected Podocytes{triangledown}

Ting-Chi Lu,1 Zhaohui Wang,2 Xiaobei Feng,2 Peter Chuang,1 Wei Fang,1 Yibang Chen,3 Susana Neves,3 Avi Maayan,3 Huabao Xiong,4 Yusen Liu,5 Ravi Iyengar,3 Paul E. Klotman,1 and John Cijiang He1,3,6*

Department of Medicine,1 Department of Pharmacology and Systems Therapeutics,3 Immunobiology Center, Mount Sinai School of Medicine, New York, New York,4 James J. Peters VA Medical Center, Bronx, New York,6 Department of Nephrology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China,2 Children's Research Institute, The Ohio State University, Columbus, Ohio5

Received 13 February 2008/ Returned for modification 25 March 2008/ Accepted 16 June 2008

Nef-induced podocyte proliferation and dedifferentiation via mitogen-activated protein kinase 1,2 (MAPK1,2) activation plays a role in human immunodeficiency virus (HIV) nephropathy pathogenesis. All-trans retinoic acid (atRA) reverses the HIV-induced podocyte phenotype by activating cyclic AMP (cAMP)/protein kinase A (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 a reporter gene assay using the 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 small interfering RNA. atRA also induced CREB phosphorylation and MKP1 expression and reduced MAPK1,2 phosphorylation in kidneys of HIV type 1-infected transgenic mice. We conclude that atRA induces sustained activation of MKP1 to suppress Nef-induced activation of the Src-MAPK1,2 pathway, thus returning the podocyte to a more differentiated state. The mechanism involves a feed-forward loop where activation of one transcription factor (TF) (CREB) leads to induction of a second TF (USF1).

* Corresponding author. Mailing address: Box 1243, Division of Nephrology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029. Phone: (212) 241-8004. Fax: (212) 987-0389. E-mail: Cijiang.he{at}mssm.edu

{triangledown} Published ahead of print on 14 July 2008.

Molecular and Cellular Biology, September 2008, p. 5785-5794, Vol. 28, No. 18
0270-7306/08/$08.00+0     doi:10.1128/MCB.00245-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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