Evaluating Effects of Hypomorphic Thoc1 Alleles on Embryonic Development in Rb1 Null Mice

Abstract

The Rb1 tumor suppressor protein is a molecular adaptor that physically links transcription factors like E2f with various proteins acting on DNA or RNA to repress gene expression. Loss of Rb1 liberates E2f to activate the expression of genes mediating resulting phenotypes. Most Rb1 binding proteins, including E2f, interact through carboxyl-terminal protein interaction domains, but genetic evidence suggests that an amino-terminal protein interaction domain is also important. One protein that binds Rb1 through the amino-terminal domain is encoded by Thoc1, a required component of the THO ribonucleoprotein complex important for RNA processing and transport. The physiological relevance of this interaction is unknown. Here we tested whether Thoc1 mediates effects of Rb1 loss on mouse embryonic development. We found that Thoc1 deficiency delays embryo death, and this delay correlates with reduced apoptosis in the brain. E2f protein levels are reduced in Rb1:Thoc1-deficient brain tissue. Expression of apoptotic regulatory genes regulated by E2f, like Apaf1 and Bak1, is also reduced. These observations suggest that Thoc1 is required to support increased expression of E2f and apoptotic regulatory genes that trigger apoptosis upon Rb1 loss. These findings implicate Rb1 in the regulation of the THO ribonucleoprotein complex.

Pan-cancer molecular analysis of the RB tumor suppressor pathway

“…Therefore, these tumors could be selectively sensitive to agents that target these processes (e.g., proteasome inhibition or unfolded protein stress). This concept has been tested in limited contexts evaluating either genetic interactions (e.g., between RB1 deletion and targeting RNA processing) 47 or drug sensitivities specific to RB-deficient tumors 48 . Conversely, we identify a host of processes that would appear to be more engaged in indolent tumors or those that have forced out of the cell cycle therapeutically.…”

Identification of drug targets and potential molecular mechanisms for Wantong Jingu Tablet extract in treatment of rheumatoid arthritis: bioinformatics analysis of fibroblast-like synoviocytes

“…The human protein THO complex 1 (THOC1) was originally identi ed as a nuclear matrix component that binds to the tumor suppressor retinoblastoma (RB) protein [40,41]. Recent research found that high levels of THOC1 were associated with tumor size and aggressiveness in breast and lung cancer cells, and that down-regulation of THOC1 was essential for the NO-mediated cytotoxicity induced by CCL-34 in cancer cells [40].…”

Identification of drug targets and potential molecular mechanisms for Wantong Jingu Tablet extract in treatment of rheumatoid arthritis: bioinformatics analysis of fibroblast-like synoviocytes

“…The human protein THO complex 1 (THOC1) was originally identified as a nuclear matrix component that binds to the tumor suppressor retinoblastoma (RB) protein [36,37]. Recent research found that high levels of THOC1 were associated with tumor size and aggressiveness in breast and lung cancer cells, and that down-regulation of THOC1 was essential for the NO-mediated cytotoxicity induced by CCL-34 in cancer cells [36].…”