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.
Regulation of S100A2 expression by TGF-β-induced MEK/ERK signalling and its role in cell migration/invasion
Sarwat Naz, Prathibha Ranganathan, Priyanka Bodapati, Arun H. Shastry, Laxmi N. Mishra, Paturu Kondaiah; Regulation of S100A2 expression by TGF-β-induced MEK/ERK signalling and its role in cell migration/invasion. Biochem J 1 October 2012; 447 (1): 81–91. doi: https://doi.org/10.1042/BJ20120014
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