Retinoic acid-stimulated sequential phosphorylation, PML recruitment, and SUMOylation of nuclear receptor TR2 to suppress Oct4 expression.
We previously reported an intricate mechanism underlying the homeostasis of Oct4 expression in normally proliferating stem cell culture of P19, mediated by SUMOylation of orphan nuclear receptor TR2. In the present study, we identify a signaling pathway initiated from the nongenomic activity of all-trans retinoic acid (atRA) to stimulate complex formation of extracellular signal-regulated kinase 2 (ERK2) with its upstream kinase, mitogen-activated protein kinase kinase (MEK). The activated ERK2 phosphorylates threonine-210 (Thr-210) of TR2, stimulating its subsequent SUMOylation. Dephosphorylated TR2 recruits coactivator PCAF and functions as an activator for its target gene Oct4. Upon phosphorylation at Thr-210, TR2 increasingly associates with promyelocytic leukemia (PML) nuclear bodies, becomes SUMOylated, and recruits corepressor RIP140 to act as a repressor for its target, Oct4. To normally proliferating P19 stem cell culture, exposure to a physiological concentration of atRA triggers a rapid nongenomic signaling cascade to suppress Oct4 gene and regulate cell proliferation.
Gupta
Pawan
P
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Ho
Ping-Chih
PC
Huq
Md Mostaqul
MM
Ha
Sung Gil
SG
Park
Sung Wook
SW
Khan
Amjad Ali
AA
Tsai
Nien-Pei
NP
Wei
Li-Na
LN
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D006706:Homeostasis / Q000187:drug effects* / Q000502:physiology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D000078723:Nuclear Receptor Interacting Protein 1; D057107:Nuclear Receptor Subfamily 2, Group C, Member 1; D050814:Octamer Transcription Factor-3 / Q000096:biosynthesis*; D010766:Phosphorylation / Q000187:drug effects; D000071156:Promyelocytic Leukemia Protein; D011988:Receptors, Thyroid Hormone / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D025842:SUMO-1 Protein / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D020930:MAP Kinase Kinase Kinases; D019950:Mitogen-Activated Protein Kinase 1; D009687:Nuclear Proteins; D000078723:Nuclear Receptor Interacting Protein 1; D057107:Nuclear Receptor Subfamily 2, Group C, Member 1; D050814:Octamer Transcription Factor-3; D000071156:Promyelocytic Leukemia Protein; D011988:Receptors, Thyroid Hormone; D012097:Repressor Proteins; D025842:SUMO-1 Protein; D014157:Transcription Factors; D014212:Tretinoin; D025521:Tumor Suppressor Proteins; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C539823:Nr2c1 protein, mouse; C513293:Pml protein, mouse; C494174:Pou5f1 protein, mouse