Overexpression of c-myc in pancreatic cancer caused by ectopic activation of NFATc1 and the Ca2+/calcineurin signaling pathway.
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.
Buchholz
Malte
M
Translational Genome Research Group, Department of Internal Medicine I, University of Ulm, Ulm, Germany.
Schatz
Alexandra
A
Wagner
Martin
M
Michl
Patrick
P
Linhart
Thomas
T
Adler
Guido
G
Gress
Thomas M
TM
Ellenrieder
Volker
V
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
C489427:MYC protein, human; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; D016271:Proto-Oncogene Proteins c-myc; D019703:Calcineurin