D Gómez Cabello (2009) Role of ING1 in gene expression profile: connection with microRNA processor DGCR8 and functional implications Biomedical Research Institute, University Autonomous of Madrid Abstract: The ING family of proteins are involved in tumor suppression mechanisms such as apoptosis, senescence, DNA repair and cell cycle arrest, usually in connection with the tumor suppressor p53 pathway. The best characterized member of the family is p33Ing1b. This protein has a largely conserved C-terminus, with a PHD domain involved in interaction with modified histones, specifically histone H3 trimethylated at lysine 4. Its N-terminal region is specific to this protein, and interacts with histone acetyltransferase (HATs) and histone deacetylases (HDACs) complexes that they are responsible for the remodeling of chromatin. This implies the participation of p33Ing1b in chromatin-modifying activities, which affect changes in gene expression. In this study, we have analysed the global effects of Ing1 on gene expression, using mouse embryonic fibroblasts deficient in the Ing1 locus (MEFs g/g). Our data has shown that, p33Ing1b mainly plays a role as a transcriptional repressor, regulating genes involved in a variety of cellular processes, including stress-related response and gene repression. One of the genes regulated by Ing1 is Dgcr8. This protein is involved in the machinery processing microRNAs and it is a key regulator of microRNA biogenesis. We have shown that p33Ing1b represses DGCR8 through direct binding to its promoter and epigenetic changes. We have observed that DGCR8 deficiency causes a antiproliferative response in mouse embryonic fibroblasts and various tumor cell lines. In this antiproliferative effect, our data suggest the involvement of the tumor suppressor p21 and p53. The p21 protein increases their levels when DGCR8 is silenced, and could be involved in proliferation decrease. Our results reflect a role of p53 in antiproliferative response in Dgcr8-deficient cells, in primary cells but not in the context of tumor cell line. Therefore, this study shows the involvement of the p33Ing1b tumor suppressor in regulation of a microARNs processor, known as DGCR8.
Notes: 1. Gómez-Cabello D, Callejas S, Benguria A, Moreno A, Alonso J and Palmero I (2009). Regulation of the microRNA processor DGCR8 by the tumor suppressor ING1. (In press on Cancer Research).
