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).
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.
Bianconcini
Adriana
A
Dipartimento di Scienze Biologiche ed Ambientali, Facoltà di Scienze MM.FF.NN., Università del Sannio, Via Port'Arsa 11, 82100 Benevento, Italy.
Lupo
Angelo
A
Capone
Silvana
S
Quadro
Loredana
L
Monti
Maria
M
Zurlo
Diana
D
Fucci
Alessandra
A
Sabatino
Lina
L
Brunetti
Antonio
A
Chiefari
Eusebio
E
Gottesman
Max E
ME
Blaner
William S
WS
Colantuoni
Vittorio
V
D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D024003:HMGA Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008957:Models, Genetic; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000378:metabolism; D034521:Nuclear Matrix-Associated Proteins / Q000378:metabolism*; D000072670:PTB-Associated Splicing Factor; D010957:Plasmids / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D016601:RNA-Binding Proteins / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D054839:Retinol-Binding Proteins, Plasma / Q000235:genetics* / Q000378:metabolism; D054339:Steroidogenic Factor 1 / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics*; D004268:DNA-Binding Proteins
D000242:Cyclic AMP; D004247:DNA; D024003:HMGA Proteins; D046912:Multiprotein Complexes; D034521:Nuclear Matrix-Associated Proteins; D000072670:PTB-Associated Splicing Factor; D016601:RNA-Binding Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D054839:Retinol-Binding Proteins, Plasma; D054339:Steroidogenic Factor 1; C431936:Nr5a2 protein, mouse; C502487:Rbp4 protein, mouse; C500331:Nono protein, mouse; D004268:DNA-Binding Proteins