title: Histone methyltransferase protein SETD2 interacts with p53 and selectively regulates its downstream genes.
abstract: SETD2 (SET domain containing protein 2) is a histone H3K36 trimethyltransferase protein that associates with hyperphosphorylated RNA polymerase II and involves in transcriptional elongation. However, whether and how SETD2 is implicated in the specific regulation of gene transcription remains unknown. Here we show that SETD2 could interact with p53 and selectively regulate the transcription factor activity of p53. The interaction was dependent of C-terminal region of SETD2, which contains the SET and WW domains, and the N-terminal transactivation domain (residues 1-45) of p53. Overexpression of SETD2 upregulated the expression levels of a subset of p53 targets including puma, noxa, p53AIP1, fas, p21, tsp1, huntingtin, but downregulated that of hdm2. In contrast, it had no significant effect on those of 14-3-3sigma, gadd45 and pig3. Consistently, knockdown of endogenous SETD2 expression by RNA interference resulted in converse effects as expected. In p53-deficient H1299 cells, SETD2 lost the ability to regulate these gene expression except hdm2, indicating the dependence of p53. Furthermore, we demonstrated that SETD2 downregulated hdm2 expression by targeting its P2 promoter and then enhanced p53 protein stability. Collectively, these findings suggest that the histone methyltransferase SETD2 could selectively regulate the transcription of subset genes via cooperation with the transcription factor p53.
authors.affiliation: Beijing Proteomics Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Xie
authors.forename: Chunyan
authors.initials: C
authors.lastname: Tian
authors.forename: Liguo
authors.initials: L
authors.lastname: An
authors.forename: Jing
authors.initials: J
authors.lastname: Nie
authors.forename: Kefeng
authors.initials: K
authors.lastname: Lu
authors.forename: Guichun
authors.initials: G
authors.lastname: Xing
authors.forename: Lingqiang
authors.initials: L
authors.lastname: Zhang
authors.forename: Fuchu
authors.initials: F
authors.lastname: He
mesh_terms: D002460:Cell Line; D015536:Down-Regulation; D005786:Gene Expression Regulation; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D011485:Protein Binding; D025941:Protein Interaction Mapping; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D013816:Thermodynamics; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D011495:Histone-Lysine N-Methyltransferase; C521636:SETD2 protein, human; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2