INVESTIGADORES
CERUTI Julieta Maria
congresos y reuniones científicas
Título:
Hepatic Nuclear Factor 3 and Nuclear Factor 1 Regulate the 5-Aminolevulinate Synthase Gene Expression and Are Involved in Insulin Repression
Autor/es:
MARÍA E. SCASSA; JULIETA M. CERUTI; ALEJANDRA S. GUBERMAN; EDUARDO T. CÁNEPA
Lugar:
Iguazú, Misiones, Argentina
Reunión:
Simposio; ICGEB Symposium. "Gene Expression and RNA Processing"; 2003
Institución organizadora:
ICGEB
Resumen:
Insulin performs a central role in homeostasis regulating the expression of over one hundred genes. Many of these genes are regulated by insulin at the transcriptional level, but the details by which this regulation is achieved are poorly understood. Progress in this area has been restricted by the fact that no unique consensus insulin-responsive element (IRE) has been reported. However, an IRE sequence has been associated with insulin-induced transcriptional repression of a number of metabolic genes. Several genes involved in carbohydrate metabolism are negatively regulated by insulin through members of the C/EBP, NF-1 and HNF3 transcription factor families. However, in no case does the binding of one of these proteins correlate with the effect of insulin. Thus, the actual function of this consensus motif and the proteins that are relevant for the negative insulin effect are still under investigation. Because of the complexity of insulin action at the gene level, it is important to delineate the actual contribution of the regulatory sequences in several promoters to identify common themes in signalling by this hormone. The purpose of this study was to examine the molecular mechanism underlying insulin-inhibited expression of 5-aminolevulinate synthase (ALAS). Our results show the presence of a functional binding site for the transcription factor HNF3 and a putative response sequence for NF1 in the proximal ALAS promoter. Both transcription factors appear to be necessary to achieve complete basal ALAS expression, although NF1 would need the presence of HNF3 factor. In addition to the transcription factor-binding sites, this region includes an IRE-like sequence, localized at position -383 to -389 bp, overlapping the HNF3 site in an inverted orientation. Mutation of IRE is required to abrogate the insulin effect. From the data reported in this paper, it is apparent that insulin could interfere with HNF3 and NF1 binding or transactivation potential necessary, but not sufficient, to mediate its negative effect on ALAS gene transcription. Likewise, the participation of an unknown IRE-dependent binding inhibitory factor on ALAS promoter is hypothesized.