Retinoic acid-stimulated sequential phosphorylation, PML recruitment, and SUMOylation of nuclear receptor TR2 to suppress Oct4 expression

• Published in: Proceedings of the National Academy of Sciences - PNAS 2008-08, Vol.105 (32), p.11424-11429
• Main Authors: Gupta, Pawan, Ho, Ping-Chih, Huq, MD Mostaqul, Ha, Sung Gil, Park, Sung Wook, Khan, Amjad Ali, Tsai, Nien-Pei, Wei, Li-Na
• Format: Article
• Language: English
• Subjects: Actins; Adaptor Proteins, Signal Transducing - metabolism; Animals; Antineoplastic Agents - pharmacology; Biological Sciences; Cell Line; Embryonic stem cells; Embryonic Stem Cells - cytology; Embryonic Stem Cells - metabolism; Gene expression regulation; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Genes; Genomics; Homeostasis - drug effects; Homeostasis - physiology; MAP Kinase Kinase Kinases - metabolism; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; Mice; Mitogen-Activated Protein Kinase 1 - metabolism; Nuclear Proteins - metabolism; Nuclear Receptor Interacting Protein 1; Nuclear Receptor Subfamily 2, Group C, Member 1; Octamer Transcription Factor-3 - biosynthesis; Orphans; p300-CBP Transcription Factors - metabolism; Phosphorylation; Phosphorylation - drug effects; Pluripotent stem cells; Promyelocytic Leukemia Protein; Receptors; Receptors, Thyroid Hormone - metabolism; Repressor Proteins - metabolism; Stem cells; SUMO-1 Protein - metabolism; Transcription Factors - metabolism; Tretinoin - pharmacology; Tumor Suppressor Proteins - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0710561105

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.