title: Negative regulation of transcription coactivator p300 by orphan receptor TR3.
abstract: p300 regulates the transcriptional activity of a variety of transcription factors by forming an activation complex and/or promoting histone acetylation. Here, we show a unique characteristic of orphan receptor TR3 in negatively regulating the function of p300. TR3 was found to interact with p300 and inhibited the acetylation of transcription factors induced by p300, resulting in the repression of their transcriptional activity. Further analysis revealed that both a conserved transcriptional adapter motif (TRAM) in p300 and a specific sequence FLELFIL in TR3 were critical for their interaction. TR3 binding completely covered the histone acetyltransferase (HAT) domain of p300 and resulted in suppression of the HAT activity, as the p300-induced histone H3 acetylation and transcription were inhibited with the presence TR3. Furthermore, an agonist of TR3, a natural octaketide isolated from Dothiorella sp. HTF3 of an endophytical fungus, was shown to be a potent compound for inhibiting p300 HAT activity (IC(50) = 1.5 microg/ml) in vivo. More importantly, this agonist could repress the transcriptional activity of transcription factors, and proliferation of cancer cells. Taken together, our results not only delineate a novel transcriptional repressor function for TR3, but also reveal its modulation on p300 HAT activity as the underlying mechanism.
authors.affiliation: Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian Province, China.
authors.forename: Gui-deng
authors.initials: GD
authors.lastname: Li
authors.forename: Jin-xu
authors.initials: JX
authors.lastname: Fang
authors.forename: Hang-zi
authors.initials: HZ
authors.lastname: Chen
authors.forename: Jie
authors.initials: J
authors.lastname: Luo
authors.forename: Zhong-hui
authors.initials: ZH
authors.lastname: Zheng
authors.forename: Yue-mao
authors.initials: YM
authors.lastname: Shen
authors.forename: Qiao
authors.initials: Q
authors.lastname: Wu
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D001665:Binding Sites; D002460:Cell Line; D015536:Down-Regulation; D005786:Gene Expression Regulation; D006801:Humans; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011987:Receptors, Steroid / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*; D012097:Repressor Proteins / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D012097:Repressor Proteins; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C539821:NR4A1 protein, human