title: The DNA mismatch repair gene hMSH2 is a potent coactivator of oestrogen receptor alpha.
abstract: The DNA mismatch repair gene is a key regulator in the elimination of base-base mismatches and insertion/deletion loops (IDLs). Human MutS homologue 2 (hMSH2), originally identified as a human homologue of the bacterial MutS, is a tumour suppressor gene frequently mutated in hereditary non-polyposis colorectal cancer. Hereditary non-polyposis colorectal cancer is characterised by the early onset of colorectal cancer and the development of extracolonic cancers such as endometrial, ovarian, and urological cancers. Oestrogen receptor (ER) alpha and beta are members of a nuclear receptor (NR) superfamily. Ligand-dependent transcription of ER is regulated by the p160 steroid receptor coactivator family, the thyroid hormone receptor-associated proteins/the vitamin D receptor-interacting proteins (TRAP/DRIP) mediator complex, and the TATA box-binding protein (TBP)-free TBP associated factor complex (TFTC) type histone acetyltransferase complex. Here, we report the interaction between ER alpha/beta and hMSH2. Immunoprecipitation and glutathione-S-transferase pull-down assay revealed that ER alpha and hMSH2 interacted in a ligand-dependent manner, whereas ER beta and hMSH2 interacted in a ligand-independent manner. Oestrogen receptor alpha/beta bound to hMSH2 through the hMSH3/hMSH6 interaction domain of hMSH2. In a transient expression assay, hMSH2 potentiated the transactivation function of liganded ER alpha, but not that of ER beta. These results suggest that hMSH2 may play an important role as a putative coactivator in ER alpha dependent gene expression.
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan. owada-tky@umin.ac.jp
authors.forename: O
authors.initials: O
authors.lastname: Wada-Hiraike
authors.forename: T
authors.initials: T
authors.lastname: Yano
authors.forename: T
authors.initials: T
authors.lastname: Nei
authors.forename: Y
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: K
authors.initials: K
authors.lastname: Nagasaka
authors.forename: S
authors.initials: S
authors.lastname: Takizawa
authors.forename: H
authors.initials: H
authors.lastname: Oishi
authors.forename: T
authors.initials: T
authors.lastname: Arimoto
authors.forename: S
authors.initials: S
authors.lastname: Nakagawa
authors.forename: T
authors.initials: T
authors.lastname: Yasugi
authors.forename: S
authors.initials: S
authors.lastname: Kato
authors.forename: Y
authors.initials: Y
authors.lastname: Taketani
mesh_terms: D020137:Base Pair Mismatch / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics; D045744:Cell Line, Tumor; D002874:Chromosome Mapping; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000235:genetics*; D047629:Estrogen Receptor beta / Q000235:genetics; D005260:Female; D015870:Gene Expression; D016147:Genes, Tumor Suppressor; D006801:Humans; D051718:MutS Homolog 2 Protein; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D015533:Transcriptional Activation
chemical_list: D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein