title: Retinoic acid utilizes CREB and USF1 in a transcriptional feed-forward loop in order to stimulate MKP1 expression in human immunodeficiency virus-infected podocytes.
abstract: 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).
authors.affiliation: Department of Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.
authors.forename: Ting-Chi
authors.initials: TC
authors.lastname: Lu
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Wang
authors.forename: Xiaobei
authors.initials: X
authors.lastname: Feng
authors.forename: Peter
authors.initials: P
authors.lastname: Chuang
authors.forename: Wei
authors.initials: W
authors.lastname: Fang
authors.forename: Yibang
authors.initials: Y
authors.lastname: Chen
authors.forename: Susana
authors.initials: S
authors.lastname: Neves
authors.forename: Avi
authors.initials: A
authors.lastname: Maayan
authors.forename: Huabao
authors.initials: H
authors.lastname: Xiong
authors.forename: Yusen
authors.initials: Y
authors.lastname: Liu
authors.forename: Ravi
authors.initials: R
authors.lastname: Iyengar
authors.forename: Paul E
authors.initials: PE
authors.lastname: Klotman
authors.forename: John Cijiang
authors.initials: JC
authors.lastname: He
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D015658:HIV Infections / Q000378:metabolism / Q000473:pathology; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D050199:Podocytes / Q000166:cytology / Q000502:physiology / Q000821:virology*; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic; D014212:Tretinoin / Q000378:metabolism*; D051720:Upstream Stimulatory Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D034741:RNA, Small Interfering; D051720:Upstream Stimulatory Factors; C497183:Usf1 protein, mouse; D014212:Tretinoin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse