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Tissue‐Specific Roles of MED1/TRAP220 Nuclear Receptor‐Interacting LxxLL Motifs in vivo
Author(s) -
Zhang Xiaoting
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.lb55
Subject(s) - mediator , microbiology and biotechnology , biology , coactivator , transcription factor , nuclear receptor , progenitor cell , estrogen receptor , cancer research , stem cell , genetics , gene , cancer , breast cancer
Mediator recently has emerged as a central player in the direct transduction of signals from transcription factors to the general transcriptional machinery. In the case of nuclear receptors, in vitro studies have shown that the transcriptional coactivator function of the Mediator involves direct ligand‐dependent interactions of the MED1 (a.k.a. TRAP220) subunit, through its two classical LxxLL motifs, with the receptor AF2 domain. However, despite the strong in vitro evidence, there currently is no information regarding in vivo functions of the LxxLL motifs either in MED1 or in other coactivators. Towards this end, we have generated MED1 LxxLL motif‐mutant knockin mice. Interestingly, these mice are both viable and fertile, and do not exhibit any apparent gross abnormalities. However, they do exhibit severe defects in pubertal mammary gland development. This was manifested as a significant impairment in duct elongation and branching morphogenesis and a decrease in mammary epithelial cell proliferation in the mutant mice. Consistent with this phenotype, as well as a loss of the strong ligand‐dependent estrogen receptor (ER)α‐Mediator interaction, expression of a number of known ERα‐regulated genes was down‐regulated in MED1‐mutant mammary epithelial cells and could no longer respond to estrogen stimulation. Related, estrogen‐stimulated mammary duct growth in MED1‐mutant mice was also greatly diminished. Finally, additional studies show that MED1 is differentially expressed in different types of mammary epithelial cells and that its LxxLL motifs play a role in mammary luminal epithelial cell differentiation and progenitor/stem cell determination. Our results establish a key nuclear receptor‐ and cell‐ specific in vivo role for MED1 LxxLL motifs, through Mediator‐ERα interactions, in mammary gland development.