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TENT5C has been proposed to mediate the susceptibility of multiple myeloma to treatment with dexamethasone, a steroid hormone analog that binds to the glucocorticoid receptor (GR). However, the relationship between TENT5C and nuclear receptor (NR) signaling remains unclear. In this study, we investigate the regulatory role of TENT5C in the GR and estrogen receptor \u03b1 (ER\u03b1) ligand complexes. We find that TENT5C acts as a corepressor of both GR and ER\u03b1. Molecular dynamics simulations indicate that the third TENT5C LXXLL motif directly interacts with ER\u03b1, but not GR. The physical interaction of TENT5C and ER\u03b1 is supported by co\u2010immunoprecipitation assays. Reporter assays show that mutations to the third TENT5C LXXLL motif disrupt TENT5C\u2010mediated repression of ER\u03b1 but do not affect the repression of the GR complex. In addition, the disruption of TENT5C poly(A) polymerase activity does not appear to affect TENT5C repression of ER\u03b1 in the cell lines studied. Taken together, our findings highlight a role of TENT5C as an NR corepressor, differentially modulating GR\u2010 and ER\u03b1\u2010induced transcriptional activity.<\/jats:p>","DOI":"10.1111\/febs.70137","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T06:06:42Z","timestamp":1748326002000},"page":"5168-5184","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<scp>TENT5C<\/scp> functions as a corepressor in the ligand\u2010bound glucocorticoid receptor and estrogen receptor \u03b1 complexes"],"prefix":"10.1111","volume":"292","author":[{"given":"Yin","family":"Li","sequence":"first","affiliation":[{"name":"Reproductive and Developmental Biology Laboratory National Institute of Environmental Health Sciences  Durham NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lalith","family":"Perera","sequence":"additional","affiliation":[{"name":"Genomic Integrity and 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