title: Requirement of protein l-isoaspartyl O-methyltransferase for transcriptional activation of trefoil factor 1 (TFF1) gene by estrogen receptor alpha.
abstract: Lysine- and arginine-specific methyltransferases have been shown to act as either direct or secondary transcriptional co-activator of the estrogen receptor (ERα). However, little is known about the role of protein l-isoaspartyl O-methyltransferase (PIMT) on transcriptional regulation. Here, we show that PIMT acts as a co-activator for ERα-mediated transcription. Activation of the estrogen response element (ERE) promoter by β-estradiol (E(2)) was suppressed by knockdown of PIMT, and enhanced by overexpression of wild-type PIMT. However, the ERE promoter activity was resistant to E(2) stimulation in cells overexpressing a catalytically inactive PIMT mutant, G88A. Consistent with these results, the expression of the endogenous ERα response gene trefoil factor 1 (TFF1) by E(2) was completely abrogated by PIMT depletion and decreased to approximately 50% when PIMT mutant G88A was expressed. In addition, over-expression of PIMT significantly increased the levels of TFF1 mRNA in the presence or absence of E(2). Interestingly, PIMT interacted with ERα and was distributed to the cytosol and the nucleus. The chromatin immunoprecipitation analysis revealed that PIMT was recruited to the promoter of TFF1 gene together with ERα in an E(2)-dependent manner, which was accompanied by uploading of RNA polymerase II on the promoter. Taken together, the results suggest that PIMT may act as a co-activator in ERα-mediated transcription through its recruitment to the promoter via interacting with ERα.
authors.affiliation: Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University, Republic of Korea.
authors.forename: Jong Woo
authors.initials: JW
authors.lastname: Park
authors.forename: Jae Cheol
authors.initials: JC
authors.lastname: Lee
authors.forename: Shin Won
authors.initials: SW
authors.lastname: Ha
authors.forename: So Young
authors.initials: SY
authors.lastname: Bang
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Park
authors.forename: Sang Ah
authors.initials: SA
authors.lastname: Yi
authors.forename: Min Gyu
authors.initials: MG
authors.lastname: Lee
authors.forename: Dae Sung
authors.initials: DS
authors.lastname: Kim
authors.forename: Ki Hong
authors.initials: KH
authors.lastname: Nam
authors.forename: Ji Hee
authors.initials: JH
authors.lastname: Yoo
authors.forename: So Hee
authors.initials: SH
authors.lastname: Kwon
authors.forename: Jeung-Whan
authors.initials: JW
authors.lastname: Han
mesh_terms: D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D009154:Mutation; D011401:Promoter Regions, Genetic; D026601:Protein D-Aspartate-L-Isoaspartate Methyltransferase / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D047628:Estrogen Receptor alpha; C051838:TFF1 protein, human; D015534:Trans-Activators; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; D026601:Protein D-Aspartate-L-Isoaspartate Methyltransferase