Laboratories > Dr. Renato Baserga

Laboratories - Dr. Renato Baserga

1. micro RNAs targeting the IGF-I receptor pathway. We have identified and experimentally validated that miR145 targets the 3’UTR of the insulin receptor substrate-1 (IRS-1) and down-regulates it. IRS-1 is a docking protein of the IGF- receptor (IGF-IR) that transmits a strong mitogenic, anti-differentiation signal. Accordingly, miR145 causes a dramatic inhibition of growth in human breast cancer cell lines and human colon cancer cell lines. This is the first miR shown to inhibit the IGF-IR/IRS-1 signaling pathway and to have an effect on tumor cells growth (antibodies to the IGF-IR are now in phase 1 clinical trials). Collaborators at Merck are developing methods to deliver miRs to pathological targets, like cancers. In the meantime, we are investigating the possibility of regulating miR145 levels from outside the cell. It seems that miR145 is up-regulated by retinoic acid and other differentiating agents, which also explains the anti-differentiation effect of IRS-1.
   
   
2. Caveolin-1 project. This has been done in collaboration with Michael Lisanti, using his cells with a deletion of the caveolin-1 genes. We found that deletion of cav1 in mouse embryo fibroblasts (cav1-/- MEFs) causes down-regulation of IRS-1; re-introduction of cav1 in cav1-/- MEFs rescues the expression of IRS-1. The stabilization is reciprocal as down-regulation of IRS-1 causes down-regulation of cav1. The mechanism is based on an interaction between tyrosine 14 nof cav1 and phosphotyrosine binding domain of IRS-1. This is a totally novel mechanism for the regulation of IRS-1 levels in cells.
   
   
3. Role of IRS-1 in oncogenesis. Evidence is rapidly accumulating that IRS-1 plays a significant role in oncogenesis. We have found that down-regulation of IRS-1 reverses the transformed phenotype of cells transformed by SV40 T antigen, v-src and Ha-ras. We are not claiming that IRS-1 is the only or even the most important component of oncogenesis, but we do believe that it is one of several proteins that are required for transformation. It could become a target of cancer therapy.
   
   
4. Acetylation of IRS-1. This is done in collaboration with Steve McMahon. Posttranslational modifications of IRS-1 (tyrosine and serine phosphorylation) play a crucial role in IRS-1 activity. We have found that IRS-1 is acetylated, and acetylation is known to play a very important role in regulation of gene expression. We have also found that acetylation of IRS-1 inhibits its nuclear translocation. This is the first functional modification of IRS-1 by acetylation.