Marie-Louise Hammarskjold, MD, PhD
Post-translational regulation of RNA expression and derangement in cancer
Marie-Louise Hammarskjold (Department of Microbiology) studies post-transcriptional regulation of RNA with special emphasis on alternative splicing, nucleo-cytoplasmic export, localization and translation and links between these processes. This is to a large extent an ongoing collaborative effort with another Cancer Center investigator, Dr. David Rekosh, that has lasted over 20 years. Recent efforts have focused on the functions of two cellular proteins of relevance for cancer, Sam68 and the Wilms' tumor gene 1 protein. Sam68 is regulated by Src, Brk and other cellular kinases of importance in human cancer. Sam68 provides a link between signal transduction and RNA metabolism. Specifically, we have shown a novel function for the Sam68 protein in regulation of translation and have demonstrated that Sam68 associates with polyribosomes. This appears to be of special importance for translation of RNA with retained introns. The regulation of export and translation of mRNA with retained introns represents a novel mechanism for post-transcriptional control of gene expression that is likely to play an important role function in both viral and cellular gene regulation. Sam68 is also believed to be involved in alternative splicing and the protein has recently been shown to potentially interact with COBRA, a protein that is important for function of BRACA1. We are presently determining how the role of Sam68 in translation relates to the role of this protein in other steps in RNA metabolism. Recently, we have demonstrated that the WT1(+KTS) protein, one of the major isoforms of WT1, also serves to regulate translation of alternatively spliced mRNAs and that this protein associates with polyribosomes as well. This is the first time a definite function has been described for the +KTS protein, previously hypothesized to function at the post-transcriptional level because of its association with splicing factors. Furthermore, the function is modulated by the other major isoform, WT1(-KTS), in a transdominant manner. Since this isoform also functions as a transcriptional regulator, our results suggest coordinated regulation of transcriptional and post-transcriptional events by the different isoforms of the WT1 protein. Since the ratios between the +KTS and -KTS isoforms are regulated by alternative splicing, these studies highlight the intricate regulation of mammalian gene expression at multiple levels. WT1 is perturbed in many human cancers and thus these studies will have potential direct impact on human disease.