title: Overexpression of c-myc in pancreatic cancer caused by ectopic activation of NFATc1 and the Ca2+/calcineurin signaling pathway.
abstract: The nuclear factor of activated T cell (NFAT) proteins are a family of Ca2+/calcineurin-responsive transcription factors primarily recognized for their central roles in T lymphocyte activation and cardiac valve development. We demonstrate that NFATc1 is commonly overexpressed in pancreatic carcinomas and enhances the malignant potential of tumor cells through transcriptional activation of the c-myc oncogene. Activated NFATc1 directly binds to a specific element within the proximal c-myc promoter and upregulates c-myc transcription, ultimately resulting in increased cell proliferation and enhanced anchorage-independent growth. Conversely, c-myc transcription and anchorage-dependent and -independent cell growth is significantly attenuated by inhibition of Ca2+/calcineurin signaling or siRNA-mediated knock down of NFATc1 expression. Together, these results demonstrate that ectopic activation of NFATc1 and the Ca2+/calcineurin signaling pathway is an important mechanism of oncogenic c-myc activation in pancreatic cancer.
authors.affiliation: Translational Genome Research Group, Department of Internal Medicine I, University of Ulm, Ulm, Germany.
authors.forename: Malte
authors.initials: M
authors.lastname: Buchholz
authors.forename: Alexandra
authors.initials: A
authors.lastname: Schatz
authors.forename: Martin
authors.initials: M
authors.lastname: Wagner
authors.forename: Patrick
authors.initials: P
authors.lastname: Michl
authors.forename: Thomas
authors.initials: T
authors.lastname: Linhart
authors.forename: Guido
authors.initials: G
authors.lastname: Adler
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Gress
authors.forename: Volker
authors.initials: V
authors.lastname: Ellenrieder
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D019703:Calcineurin / Q000378:metabolism*; D020013:Calcium Signaling; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: C489427:MYC protein, human; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; D016271:Proto-Oncogene Proteins c-myc; D019703:Calcineurin