Transcriptional activity of the murine retinol-binding protein gene is regulated by a multiprotein complex containing HMGA1, p54 nrb/NonO, protein-associated splicing factor (PSF) and steroidogenic factor 1 (SF1)/liver receptor homologue 1 (LRH-1)

Int J Biochem Cell Biol. 2009 Nov;41(11):2189-203. doi: 10.1016/j.biocel.2009.04.011. Epub 2009 Apr 21.

Abstract

Retinol-binding protein (RBP4) transports retinol in the circulation from hepatic stores to peripheral tissues. Since little is known regarding the regulation of this gene, we analysed the cis-regulatory sequences of the mouse RBP4 gene. Our data show that transcription of the gene is regulated through a bipartite promoter: a proximal region necessary for basal expression and a distal segment responsible for cAMP-induction. This latter region contains several binding sites for the structural HMGA1 proteins, which are important to promoter regulation. We further demonstrate that HMGA1s play a key role in basal and cAMP-induction of Rbp4 transcription and the RBP4 and HMGA1 genes are coordinately regulated in vitro and in vivo. HMGA1 acts to recruit transcription factors to the RBP4 promoter and we specifically identified p54(nrb)/NonO and protein-associated splicing factor (PSF) as components that interact with this complex. Steroidogenic factor 1 (SF1) or the related liver receptor homologue 1 (LRH-1) are also associated with this complex upon cAMP-induction. Depletion of SF1/LRH-1 by RNA interference resulted in a dramatic loss of cAMP-induction. Collectively, our results demonstrate that basal and cAMP-induced Rbp4 transcription is regulated by a multiprotein complex that is similar to ones that modulate expression of genes of steroid hormone biosynthesis. Since genes related to glucose metabolism are regulated in a similar fashion, this suggests that Rbp4 expression may be regulated as part of a network of pathways relevant to the onset of type 2 diabetes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Cell Line, Tumor
  • Cyclic AMP / pharmacology
  • DNA / metabolism
  • HMGA Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Models, Genetic
  • Molecular Sequence Data
  • Multiprotein Complexes / metabolism
  • Nuclear Matrix-Associated Proteins / metabolism*
  • PTB-Associated Splicing Factor
  • Plasmids / genetics
  • Promoter Regions, Genetic / genetics
  • Protein Binding / drug effects
  • Protein Biosynthesis / drug effects
  • RNA-Binding Proteins / metabolism*
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Retinol-Binding Proteins, Plasma / genetics*
  • Retinol-Binding Proteins, Plasma / metabolism
  • Steroidogenic Factor 1 / metabolism*
  • Transcription, Genetic / drug effects
  • Transcriptional Activation / drug effects
  • Transcriptional Activation / genetics*

Substances

  • HMGA Proteins
  • Multiprotein Complexes
  • Nr5a2 protein, mouse
  • Nuclear Matrix-Associated Proteins
  • PTB-Associated Splicing Factor
  • RNA-Binding Proteins
  • Rbp4 protein, mouse
  • Receptors, Cytoplasmic and Nuclear
  • Retinol-Binding Proteins, Plasma
  • Steroidogenic Factor 1
  • p54nrb protein, mouse
  • DNA
  • Cyclic AMP