Retinoic acid utilizes CREB and USF1 in a transcriptional feed-forward loop in order to stimulate MKP1 expression in human immunodeficiency virus-infected podocytes

Mol Cell Biol. 2008 Sep;28(18):5785-94. doi: 10.1128/MCB.00245-08. Epub 2008 Jul 14.


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).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cells, Cultured
  • Cyclic AMP / genetics
  • Cyclic AMP / metabolism
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / genetics
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Dual Specificity Phosphatase 1 / genetics
  • Dual Specificity Phosphatase 1 / metabolism*
  • Gene Expression Regulation
  • Genes, Reporter
  • HIV Infections / metabolism
  • HIV Infections / pathology
  • HIV-1 / genetics
  • HIV-1 / metabolism*
  • Humans
  • Mice
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Podocytes / cytology
  • Podocytes / physiology
  • Podocytes / virology*
  • Promoter Regions, Genetic
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Signal Transduction / physiology
  • Transcription, Genetic*
  • Tretinoin / metabolism*
  • Upstream Stimulatory Factors / genetics
  • Upstream Stimulatory Factors / metabolism*


  • Cyclic AMP Response Element-Binding Protein
  • RNA, Small Interfering
  • Upstream Stimulatory Factors
  • Usf1 protein, mouse
  • Tretinoin
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Dual Specificity Phosphatase 1
  • Dusp1 protein, mouse