Dianne R. Soprano, PhD

Research in Dr. Soprano's laboratory focuses on the mechanism of action of retinoic acid (RA) at the molecular level. RA exerts its action by the transcriptional regulation of specific genes via a family of nuclear receptors called retinoic acid receptors, RARs, and retinoid X receptors, RXRs. Three distinct but highly homologous RAR isotypes have been described termed RARα, RARβ and RARγ. In addition, several isoforms of each RAR isotype, which vary in both the length and amino acid sequence of the N-terminal A domain, have been identified. Specifically, we are interested in the structure, function and regulation of RARs particularly during development and in tumors.

First, the mRNA and protein levels of pre-B cell leukemia transcription factors (PBXs) are elevated by RA in mouse limb buds and in P19 embryonal carcinoma cells. Abrogation of the RA-dependent increase in PBX expression in P19 cells results in a failure of these cells to differentiate to either endodermal or neuronal cells demonstrating the importance of PBX in the cascade of RA-dependent changes in gene expression during differentiation. Microarray analysis has resulted in the identification of a number of genes whose expression is regulated by RA treatment in wild type cells but not in cells that fail to increase PBX expression. Currently we are addressing the role of these genes during RA-dependent differentiation of P19 cells to endodermal and neuronal cells.

These studies are aimed at the elucidation of the sequence of events involved in RA-mediating differentiation of pluripotent embryonal carcinoma cells to endodermal and neuronal cells. Second, little is known about the functional importance of the unique A/B domains associated with each of the isoforms of the three RAR isotypes. Yeast 2-hybrid screening has resulted in the identification of several unique cDNAs that encode proteins including Acinus and HACE1 that interact with the amino terminal A/B domain of RARs. Acinus has been suggested to be a splicing factor and HACE1 has E3 ubiquitin ligase activity. The role of these proteins in the regulation of RA-dependent gene expression is being explored with the goal of further understanding the functional importance of the A/B domains of RARs. Third, RA can inhibit the growth of many tumor cells including the CAOV3 ovarian tumor cell line. In addition, several synthetic retinoids induce apoptosis in ovarian tumor cells. Studies are currently underway examining the steps in the apoptotic pathway induced by several synthetic retinoids and the mechanism of regulation of the protein levels of the tumor suppressor gene, Rb2, during RA-induced growth inhibition of these cells. Elucidation of the mechanism of action underlying RA-dependent inhibition of tumor cell growth may lead to the development of unique retinoid treatments for cancer chemotherapy and chemoprevention.