James A. DeCaprio
Our laboratory studies tumor suppressor proteins and their mechanisms of action. The broad class of tumor suppressors serves in a variety of ways to prevent the development of cancer.
Our laboratory studies the retinoblastoma family (RB) including pRB, p107 and p130. The RB family represses E2F target genes through mechanisms that are not fully understood. Using an integrated approach combining proteomics, genomics and bioinformatic analyses, we recently identified a p130 complex termed DREAM (DP, RB-like, E2F and MuvB) that contains mammalian homologues of synMuvB proteins LIN-9, LIN-37, LIN-52, LIN-54 and LIN-53/RBBP4. Using chromatin immunoprecipitation combined with genome arrays we determined that DREAM bound to more than 800 human promoters in G0 and was required for repression of E2F target genes. In S phase, DREAM dissociated to form a distinct sub-module interacting with MYB. This work reveals an evolutionarily conserved multi-subunit protein complex that contains p130 and E2F4 but not pRB and mediates the repression of cell-cycle dependent genes in quiescence. We are currently exploring the mechanism of action of the DREAM complex and how it serves to regulate the quiescent state. In addition, we are studying the ability of p107 and pRB to bind to different transcription repressor complexes and their ability to regulate E2F dependent regulation on a genome scale.
Our laboratory also studies the CUL7 E3 ubiquitin ligase. CUL7 is unique to vertebrates and appears to function as a novel tumor suppressor. We initially identified CUL7 as a specific binding partner of SV40 large T antigen and we determined that T Antigen binding to CUL7 is necessary for full transformation activity of T Ag. We have also determined that CUL7 binds specifically to a large number of proteins including SKP1, RBX1, FBXW8, p53, PARC, GLMN as well as SV40 large T antigen. We have generated several knockout strains of mice to explore the function of CUL7 in vivo and have evidence that FBXW8 serves as a novel tumor suppressor in an animal model of cancer. Our current goals include identifying substrates that are specifically targeted for degradation by the SKP1-CUL7-FBXW8 SCF like complex.
Arai T, Kasper JS, Skaar JR, Ali SH, Takahashi C, DeCaprio JA. Targeted disruption of p185/Cul7 gene results in abnormal vascular morphogenesis. Proc Natl Acad Sci U S A. 2003;100(17):9855-60.
Poulin DL, Decaprio JA. The carboxyl-terminal domain of large T antigen rescues SV40 host range activity in trans independent of acetylation. Virology. 2006;349(1):212-21.
Skaar JR, Florens L, Tsutsumi T, Arai T, Tron A, Swanson SK, Washburn MP, DeCaprio JA. PARC and CUL7 form atypical cullin RING ligase complexes. Cancer Res. 2007;67(5):2006-14.
Litovchick L, Sadasivam S, Florens L, Zhu X, Swanson SK, Velmurugan S, Chen R, Washburn MP, Liu XS, Decaprio JA. Evolutionarily Conserved Multisubunit RBL2/p130 and E2F4 Protein Complex Represses Human Cell Cycle-Dependent Genes in Quiescence. Mol Cell. 2007;26(4):539-551.