SUMOylation of Tr2 orphan receptor involves Pml and fine-tunes Oct4 expression in stem cells.
The Tr2 orphan nuclear receptor can be SUMOylated, resulting in the replacement of coregulators recruited to the regulatory region of its endogenous target gene, Oct4. UnSUMOylated Tr2 activates Oct4, enhancing embryonal carcinoma-cell proliferation, and is localized to the promyelocytic leukemia (Pml) nuclear bodies. When its abundance is elevated, Tr2 is SUMOylated at Lys238 and seems to be released from the nuclear bodies to act as a repressor. SUMOylation of Tr2 induces an exchange of its coregulators: corepressor Rip140 replaces coactivator Pcaf, which switches Tr2 from an activator to a repressor. This involves dynamic partitioning of Tr2 into Pml-containing and Pml-free pools. These results support a model where SUMOylation-dependent partitioning and differential coregulator recruitment contribute to the maintenance of a homeostatic supply of activating, as opposed to repressive, Tr2, thus fine-tuning Oct4 expression and regulating stem-cell proliferation.
Park
Sung Wook
SW
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.
Hu
Xinli
X
Gupta
Pawan
P
Lin
Ya-Ping
YP
Ha
Sung Gil
SG
Wei
Li-Na
LN
D000818:Animals; D022003:Cell Nucleus Structures / Q000378:metabolism*; D049109:Cell Proliferation; D054278:Embryonal Carcinoma Stem Cells; D051379:Mice; D014411:Neoplastic Stem Cells / Q000166:cytology; D057107:Nuclear Receptor Subfamily 2, Group C, Member 1; D050814:Octamer Transcription Factor-3 / Q000235:genetics*; D011401:Promoter Regions, Genetic; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism*; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D000098843:Ubiquitin-Conjugating Enzyme UBC9
C539823:Nr2c1 protein, mouse; D057107:Nuclear Receptor Subfamily 2, Group C, Member 1; D050814:Octamer Transcription Factor-3; C494211:Pias1 protein, mouse; C494174:Pou5f1 protein, mouse; D050828:Protein Inhibitors of Activated STAT; D011988:Receptors, Thyroid Hormone; D025841:Small Ubiquitin-Related Modifier Proteins; D044763:Ubiquitin-Conjugating Enzymes; D000098843:Ubiquitin-Conjugating Enzyme UBC9