Role of N-Cor During Normal Mammary Gland Development

摘要

Understanding the regulation of N-CoR and its associated co- repressors, in concert with defining the molecular mechanisms that underlie regulation by estrogen receptors, offers a reasonable prospect of achieving new approaches to diagnosis and treatment of breast cancer. The authors demonstrate that estrogen receptors recruit at least two distinct N-CoR-containing complexes as mSin3/HDAC1/2 and the novel TAB2/HDAC3/N-CoR complex that bind to agonist. The inflammatory signals such as IL-1 cause export of the TAB2/N- CoR/HDAC3 complex from nucleus to cytoplasm by MEKK1 action. Among the N-CoR target genes, c-myc and KAI1 play important roles in cell cycle control and metastasis during breast cancer. Therefore, the authors suggest that N-CoR is linked to the beta-catenin signaling pathway and N-CoR/TAB2 might be involved in the regulation of the expression of an important metastasis suppressor gene(s). Furthermore, they demonstrate that specific N-CoR complexes containing TBL1/TBLR1 serve as specific adaptors for the recruitment of the ubiquitin conjugating/19S proteasome complex, with TBLR1 selectively serving to mediate a required exchange of the ER co-repressors, N-CoR and SMRT, for co-activators upon ligand binding. Therefore, TBL1 and TBLR1 constitute a specific class of co-regulators that play important roles in both activation and repression, acting as nuclear receptor co-repressor/co-activator exchange factors (N-CoEx), required for modulating regulated gene transcription by ER.