{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T07:33:43Z","timestamp":1768548823845,"version":"3.49.0"},"reference-count":34,"publisher":"The Endocrine Society","issue":"12","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The retinoic acid receptor-\u03b1 (Rara) gene is critical for germ cell development in the testis, as demonstrated by infertile Rara knockout male mice. The encoded protein for Rara (RARA) is expressed in both Sertoli cells and germ cells, but it is not always in the nucleus. Previously, all-trans retinoic acid (ATRA) was shown to increase the nuclear localization and transcriptional activity of RARA in Sertoli cells. Here, we identified a small ubiquitin-like modifier-2 (SUMO-2) modification as a novel posttranslational regulatory mechanism controlling the ATRA-dependent RARA subcellular localization and transcription. ATRA increased the SUMO-2 modification of RARA. In the presence of ATRA, lysine 166 (K166) and K171 of RARA were modified at a physiological concentration of SUMO-2, whereas in the absence of ATRA, K399 was the only site that was modified, but at a higher SUMO-2 concentration. However, K399 was critical for ATRA-controlled nuclear trafficking of RARA. In the presence of ATRA, a K399 mutation to arginine resulted in the cytoplasmic localization of K399R mutant, indicating that K166 and K171 sumoylations were inhibitory to nuclear localization. This may be due to SUMO\/sentrin-specific peptidase 6 (SENP6) not being able to bind K399R mutant to desumoylate K166 and K171 in Sertoli cells, whereas it can bind RARA with intact K399. On the other hand, functional K166 and K171 sites for sumoylation were required for a full transcriptional activity, when K399 was intact. These results together suggest that both K166 and K171 sumoylation and desumoylation are critical for optimal RARA function.<\/jats:p>","DOI":"10.1210\/en.2009-0868","type":"journal-article","created":{"date-parts":[[2009,10,23]],"date-time":"2009-10-23T01:53:14Z","timestamp":1256262794000},"page":"5586-5595","source":"Crossref","is-referenced-by-count":28,"title":["Small Ubiquitin-Like Modifier-2 Modification of Retinoic Acid Receptor-\u03b1 Regulates Its Subcellular Localization and Transcriptional Activity"],"prefix":"10.1210","volume":"150","author":[{"given":"Li","family":"Zhu","sequence":"first","affiliation":[{"name":"School of Molecular Biosciences, Center for Reproductive Biology, Washington State University, Pullman, Washington 99164"}]},{"given":"Nadine C.","family":"Santos","sequence":"additional","affiliation":[{"name":"School of Molecular Biosciences, Center for Reproductive Biology, Washington State University, Pullman, Washington 99164"}]},{"given":"Kwan Hee","family":"Kim","sequence":"additional","affiliation":[{"name":"School of Molecular Biosciences, Center for Reproductive Biology, Washington State University, Pullman, Washington 99164"}]}],"member":"80","published-online":{"date-parts":[[2009,10,22]]},"reference":[{"key":"2020071613284723400_R1","doi-asserted-by":"crossref","first-page":"7225","DOI":"10.1073\/pnas.90.15.7225","article-title":"High postnatal lethality and testis degeneration in retinoic acid receptor \u03b1 mutant mice.","volume":"90","author":"Lufkin","year":"1993","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071613284723400_R2","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1196\/annals.1411.008","article-title":"Potential functions of retinoic acid receptor A in Sertoli cells and germ cells during spermatogenesis.","volume":"1120","author":"Doyle","year":"2007","journal-title":"Ann NY Acad Sci"},{"key":"2020071613284723400_R3","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1095\/biolreprod56.2.549","article-title":"Retinoic acid receptor \u03b1 gene expression in the rat testis: potential role during the prophase of meiosis and in the transition from round to elongating spermatids.","volume":"56","author":"Akmal","year":"1997","journal-title":"Biol Reprod"},{"key":"2020071613284723400_R4","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1095\/biolreprod61.5.1300","article-title":"Cellular and subcellular localization of six retinoid receptors in rat testis during postnatal development: identification of potential heterodimeric receptors.","volume":"61","author":"Dufour","year":"1999","journal-title":"Biol Reprod"},{"key":"2020071613284723400_R5","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1210\/endo.139.3.5775","article-title":"Ligand-dependent regulation of retinoic acid receptor \u03b1 in rat testis: in vivo response to depletion and 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retinoic acid receptor \u03b1 activity by means of increasing interaction with and phosphorylation by cyclin H\/cdk7.","volume":"103","author":"Gaillard","year":"2006","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071613284723400_R9","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.tcb.2007.04.003","article-title":"Protein kinases and the proteasome join in the combinatorial control of transcription by nuclear retinoic acid receptors.","volume":"17","author":"Bour","year":"2007","journal-title":"Trends Cell Biol"},{"key":"2020071613284723400_R10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.molcel.2005.03.012","article-title":"SUMO: a history of modification.","volume":"18","author":"Hay","year":"2005","journal-title":"Mol Cell"},{"key":"2020071613284723400_R11","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/j.bbrc.2005.09.090","article-title":"A proline-90 residue unique to SUMO-4 prevents maturation and sumoylation.","volume":"337","author":"Owerbach","year":"2005","journal-title":"Biochem Biophys Res Commun"},{"key":"2020071613284723400_R12","doi-asserted-by":"crossref","first-page":"27233","DOI":"10.1074\/jbc.M402273200","article-title":"A M55V polymorphism in a novel SUMO gene (SUMO-4) differentially activates heat shock transcription factors and is associated with susceptibility to type I diabetes mellitus.","volume":"279","author":"Bohren","year":"2004","journal-title":"J Biol Chem"},{"key":"2020071613284723400_R13","doi-asserted-by":"crossref","first-page":"1422","DOI":"10.1042\/BST0351422","article-title":"Small ubiquitin-related modifiers in chains.","volume":"35","author":"Vertegaal","year":"2007","journal-title":"Biochem Soc Trans"},{"key":"2020071613284723400_R14","doi-asserted-by":"crossref","first-page":"6310","DOI":"10.1021\/ac058019d","article-title":"Fourier transform ion cyclotron resonance mass spectrometry for the analysis of small ubiquitin-like modifier (SUMO) 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elements.","volume":"18","author":"Callewaert","year":"2004","journal-title":"Mol 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