title: Regulation of S100A2 expression by TGF-β-induced MEK/ERK signalling and its role in cell migration/invasion.
abstract: S100A2, an EF hand calcium-binding protein, is a potential biomarker in several cancers and is also a TGF-β (transforming growth factor-β)-regulated gene in melanoma and lung cancer cells. However, the mechanism of S100A2 regulation by TGF-β and its significance in cancer progression remains largely unknown. In the present study we report the mechanism of S100A2 regulation by TGF-β and its possible role in TGF-β-mediated tumour promotion. Characterization of the S100A2 promoter revealed an AP-1 (activator protein-1) element at positions -1161 to -1151 as being the most critical factor for the TGF-β1 response. Chromatin immunoprecipitation and electrophoretic mobility-shift assays confirmed the functional binding of the AP-1 complex, predominantly JunB, to the S100A2 promoter in response to TGF-β1 in HaCaT keratinocytes. JunB overexpression markedly stimulated the S100A2 promoter which was blocked by the dominant-negative JunB and MEK1 [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase 1] inhibitor, PD98059. Intriguingly, despite the presence of a putative SMAD-binding element, S100A2 regulation by TGF-β1 was found to be SMAD3 independent. Interestingly, p53 protein and TGF-β1 show synergistic regulation of the S100A2 promoter. Finally, knockdown of S100A2 expression compromised TGF-β1-induced cell migration and invasion of Hep3B cells. Together our findings highlight an important link between the TGF-β1-induced MAPK and p53 signalling pathways in the regulation of S100A2 expression and pro-tumorigenic actions.
authors: Department of Molecular Reproduction Development and Genetics, Indian Institute of Science, Bangalore, 560012, India.
authors: Sarwat
authors: S
authors: Naz
authors: Prathibha
authors: P
authors: Ranganathan
authors: Priyanka
authors: P
authors: Bodapati
authors: Arun H
authors: AH
authors: Shastry
authors: Laxmi N
authors: LN
authors: Mishra
authors: Paturu
authors: P
authors: Kondaiah
mesh_terms: D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002630:Chemotactic Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D009418:S100 Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D002630:Chemotactic Factors; D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; D009418:S100 Proteins; C098997:S100A2 protein, human; C495901:TP53 protein, human; D018808:Transcription Factor AP-1; D053773:Transforming Growth Factor beta1; D016159:Tumor Suppressor Protein p53