Sequential activation of NFAT and c-Myc transcription factors mediates the TGF-beta switch from a suppressor to a promoter of cancer cell proliferation.
Transforming growth factor beta (TGF-beta) has a dual role in carcinogenesis, acting as a growth inhibitor in early tumor stages and a promoter of cell proliferation in advanced diseases. Although this cellular phenomenon is well established, the underlying molecular mechanisms remain elusive. Here, we report that sequential induction of NFAT and c-Myc transcription factors is sufficient and required for the TGF-beta switch from a cell cycle inhibitor to a growth promoter pathway in cancer cells. Mechanistically, TGF-beta induces in a calcineurin-dependent manner the expression and activation of NFAT factors, which then translocate into the nucleus to promote c-Myc expression. In response to TGF-beta, activated NFAT factors bind to and displace Smad3 repressor complexes from the previously identified TGF-beta inhibitory element (TIE) to transactivate the c-Myc promoter. c-Myc in turn stimulates cell cycle progression and growth through up-regulation of D-type cyclins. Most importantly, NFAT knockdown not only prevents c-Myc activation and cell proliferation, but also partially restores TGF-beta-induced cell cycle arrest and growth suppression. Taken together, this study provides the first evidence for a Smad-independent master regulatory pathway in TGF-beta-promoted cell growth that is defined by sequential transcriptional activation of NFAT and c-Myc factors.
Signal Transduction and Transcription Laboratory, Department of Gastroenterology and Endocrinology, Philipps-University of Marburg, 35043 Marburg, Germany.
Garima
G
Singh
Signal Transduction and Transcription Laboratory, Department of Gastroenterology and Endocrinology, Philipps-University of Marburg, 35043 Marburg, Germany.
Shiv K
SK
Singh
Signal Transduction and Transcription Laboratory, Department of Gastroenterology and Endocrinology, Philipps-University of Marburg, 35043 Marburg, Germany.
Alexander
A
König
Signal Transduction and Transcription Laboratory, Department of Gastroenterology and Endocrinology, Philipps-University of Marburg, 35043 Marburg, Germany.
Kristina
K
Reutlinger
Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota 55905.
Monica D
MD
Nye
Institute for Molecular Biology and Tumor Research, Philipps-University of Marburg, 35032 Marburg, Germany.
Tillman
T
Adhikary
Department of Physiological Chemistry II, Theodor Boveri Institute, University of Würzburg, 97074 Würzburg, Germany.
Martin
M
Eilers
Signal Transduction and Transcription Laboratory, Department of Gastroenterology and Endocrinology, Philipps-University of Marburg, 35043 Marburg, Germany.
Thomas M
TM
Gress
Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota 55905. Electronic address: fernandezzapico.martin@mayo.edu.
Martin E
ME
Fernandez-Zapico
Signal Transduction and Transcription Laboratory, Department of Gastroenterology and Endocrinology, Philipps-University of Marburg, 35043 Marburg, Germany. Electronic address: ellenrie@med.uni-marburg.de.
Volker
V
Ellenrieder
D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology
C489427:MYC protein, human; D050778:NFATC Transcription Factors; D016271:Proto-Oncogene Proteins c-myc; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D019703:Calcineurin