BADERC- Maria Alexander-Bridges

Maria Alexander-Bridges, M.D., PhD.

Insulin Regulation of Gene Expression

The overall goal of our work is to identify the downstream targets of insulin (and insulin- sensitizing agents) action on metabolic pathways that contribute to obesity, diabetes and longevity.

Two major areas of investigation are underway in Dr. Alexander-Bridges’ laboratory. First we want to understand how insulin and insulin-sensitizing agents regulate the activity of the DAF-16 family of transcription regulators in C. elegans and in mammalian cells and to identify the targets of this family of factors. Genetic studies in C. elegans predict that insulin signaling via PI3 kinase reverses the effect of DAF-16 and its mammalian homologs (FKHR, FKHRL1 and AFX). Dr. Alexander-Bridges? laboratory and others have shown that, in mammalian cells, DAF-16- like factors activate the transcription of genes that control gluconeogenesis, growth arrest and apoptosis while insulin inhibits this effect. In the presence of glucorticoids and other activators DAF-16 recruits co-activators to its target genes; the interaction of DAF-16 and co-activators and insulin inhibits this effect. More recent observations from Dr. Alexander-Bridges? laboratory indicate that insulin also activates DAF-16 like factors. In this case, DAF-16 acts as a repressor of basal promoter function and insulin activates gene transcription by reversing this effect.

Accordingly, as a visiting scientist at Millinneum Pharmaceuticals Incorporated (MPI) in the Partners Fellowship Program, Dr. Alexander-Bridges’ spent a year identifying genes that are regulated by insulin and sensitize the cell to insulin. A subset of genes involved in regulating glucose utilization is inhibited by DAF-16/FKHR and positively regulated by insulin in adipose cells. These findings show that DAF-16 can is involved in mediating the positive effect of insulin on genes that regulate metabolic pathways. In addition, these studies identify novel genes that are activated by FKHR and inhibited by insulin as has been previously described. These observations have far reaching implications for the role of DAF-16 like factors in mediating the transcriptional response of metabolic pathways to insulin.

A second area of interest is to determine whether activation of AMP kinase underlies the effect of caloric restriction to prolong lifespan and if so whether these effects are, in turn, dependent or independent of insulin signaling to DAF-16 homologs (in worms disruption of insulin signaling prolongs lifespan).

References:

1. Nasrin, N., Ogg, S., Calvo, D. Cahill, C. Dore, J., Nui, S., Shi, Y., Ruvkun, G., Alexander-Bridges, M.C. DAF-16 Recruits the CBP Co-Activator Complex to the IGFBP Promoter in HepG2 Cells. Proc. Natl Acad Sci. 2000; 97:10412-10417.

2. C.M. Cahill, G. Tzivion, S. Ogg, N. Nasrin, J. Dore, G. Ruvkun, J. Avruch and M. Alexander-Bridges. Insulin and PI3 kinase regulates DAF-16 DNA binding through 14-3-3 dependent and independent pathways. J.Biol. Chem. 2001; 276:13402-13410.






			Maria Alexander-Bridges, M.D., PhD. Insulin Regulation of Gene Expression The overall goal of our work is to identify the downstream targets of insulin (and insulin- sensitizing agents) action on metabolic pathways that contribute to obesity, diabetes and longevity. Two major areas of investigation are underway in Dr. Alexander-Bridges’ laboratory. First we want to understand how insulin and insulin-sensitizing agents regulate the activity of the DAF-16 family of transcription regulators in C. elegans and in mammalian cells and to identify the targets of this family of factors. Genetic studies in C. elegans predict that insulin signaling via PI3 kinase reverses the effect of DAF-16 and its mammalian homologs (FKHR, FKHRL1 and AFX). Dr. Alexander-Bridges? laboratory and others have shown that, in mammalian cells, DAF-16- like factors activate the transcription of genes that control gluconeogenesis, growth arrest and apoptosis while insulin inhibits this effect. In the presence of glucorticoids and other activators DAF-16 recruits co-activators to its target genes; the interaction of DAF-16 and co-activators and insulin inhibits this effect. More recent observations from Dr. Alexander-Bridges? laboratory indicate that insulin also activates DAF-16 like factors. In this case, DAF-16 acts as a repressor of basal promoter function and insulin activates gene transcription by reversing this effect. Accordingly, as a visiting scientist at Millinneum Pharmaceuticals Incorporated (MPI) in the Partners Fellowship Program, Dr. Alexander-Bridges’ spent a year identifying genes that are regulated by insulin and sensitize the cell to insulin. A subset of genes involved in regulating glucose utilization is inhibited by DAF-16/FKHR and positively regulated by insulin in adipose cells. These findings show that DAF-16 can is involved in mediating the positive effect of insulin on genes that regulate metabolic pathways. In addition, these studies identify novel genes that are activated by FKHR and inhibited by insulin as has been previously described. These observations have far reaching implications for the role of DAF-16 like factors in mediating the transcriptional response of metabolic pathways to insulin. A second area of interest is to determine whether activation of AMP kinase underlies the effect of caloric restriction to prolong lifespan and if so whether these effects are, in turn, dependent or independent of insulin signaling to DAF-16 homologs (in worms disruption of insulin signaling prolongs lifespan). References: 1. Nasrin, N., Ogg, S., Calvo, D. Cahill, C. Dore, J., Nui, S., Shi, Y., Ruvkun, G., Alexander-Bridges, M.C. DAF-16 Recruits the CBP Co-Activator Complex to the IGFBP Promoter in HepG2 Cells. Proc. Natl Acad Sci. 2000; 97:10412-10417. 2. C.M. Cahill, G. Tzivion, S. Ogg, N. Nasrin, J. Dore, G. Ruvkun, J. Avruch and M. Alexander-Bridges. Insulin and PI3 kinase regulates DAF-16 DNA binding through 14-3-3 dependent and independent pathways. J.Biol. Chem. 2001; 276:13402-13410.