Naz, Sarwat and Ranganathan, Prathibha and Bodapati, Priyanka and Shastry, Arun H and Mishra, Laxmi N and Kondaiah, Paturu (2012) Regulation of S100A2 expression by TGF-beta-induced MEK/ERK signalling and its role in cell migration/invasion. In: BIOCHEMICAL JOURNAL, 447 (Part 1). pp. 81-91.
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S100A2, an EF hand calcium-binding protein, is a potential biomarker in several cancers and is also a TGF-beta (transforming growth factor-beta)-regulated gene in melanoma and lung cancer cells. However, the mechanism of S100A2 regulation by TGF-beta and its significance in cancer progression remains largely unknown. In the present study we report the mechanism of S100A2 regulation by TGF-beta and its possible role in TGF-beta-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-beta 1 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-beta 1 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-beta 1 was found to be SMAD3 independent. Interestingly, p53 protein and TGF-beta 1 show synergistic regulation of the S100A2 promoter. Finally, knockdown of S100A2 expression compromised TGF-beta 1-induced cell migration and invasion of Hep3B cells. Together our findings highlight an important link between the TGF-beta 1-induced MAPK and p53 signalling pathways in the regulation of S100A2 expression and pro-tumorigenic actions.
|Item Type:||Journal Article|
|Additional Information:||Copyright for this article belongs to PORTLAND PRESS LTD, ENGLAND.|
|Keywords:||activator protein-1 (AP-1);HaCaT cell;Hep3B cell;p53 protein;S100 protein;SMAD-binding element|
|Department/Centre:||Division of Biological Sciences > Molecular Reproduction, Development & Genetics (formed by the merger of DBGL and CRBME)|
|Depositing User:||Francis Jayakanth|
|Date Deposited:||06 Dec 2012 09:54|
|Last Modified:||06 Dec 2012 09:54|
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