Role of co-regulators in cell growth and gene expression

Derek Solum

Appointment Period: 2001-2002 / Grant Year: [17]

Nuclear receptors belong to a family of structurally related, ligand-activated regulators of a complex array of genes involved in cell proliferation, differentiation, morphogenesis, and homeostasis. Regulation of gene expression by nuclear receptors requires the recruitment of proteins characterized as coregulators, with ligand-dependent exchange of corepressors for coactivators serving as the basic mechanism for switching gene repression to activation. A diverse group of proteins have emerged as potential coactivators for nuclear receptors. These proteins are recruited in a ligand-dependent fashion and have the capacity to enhance transcriptional activation. Several insights into the mechanisms by which coactivator complexes are recruited to nuclear receptors in a ligand-dependent manner have been provided by the initial identification of the p160 family of nuclear receptor coactivators, referred to as SRC-1/NCOA1, TIF2/GRIP1, and p/CIP/AIB1/ACTR/TRAM-1. These members of the p160 family have been suggested to function as coactivators, at least in part, by serving as adapter molecules that recruit CBP and/or p300 complexes to promoter bound nuclear receptors in a ligand-dependent manner. These and other factors, acting in large complexes, have emerged as chromatin remodelers through intrinsic histone-modifying activites such as acetylation or methylation. In addition, other ligand recruited complexes appear to act more directly on the transcriptional apparatus, suggesting that transcriptional regulation by nuclear receptors may involve a process of both chromatin alterations and direct recruitment of key initiation components at regulated promoters. My current research interests are focused on the way by which nuclear receptors, coregulatory proteins, as well as other chromatin modifying factors influence cell proliferation and differentiation. Additionally, I am interested in how these factors influence neural fate determination through alteration of gene expression by studying their roles in neural progenitor cells.

PUBLICATIONS (resulting from this training)

Ju BG, Solum D, Song EJ, Lee KJ, Rose DW, Glass CK, Rosenfeld MG. (2004) Activating the PARP-1 sensor component of the groucho/ TLE1 corepressor complexmediates a CaMKinase IIdelta-dependent neurogenic gene activation pathway. Cell 119:815-29.