Sequential activation of NFAT and c-Myc transcription factors mediates the TGF-β switch from a suppressor to a promoter of cancer cell proliferation

Garima Singh, Shiv K. Singh, Alexander König, Kristina Reutlinger, Monica D. Nye, Tillman Adhikary, Martin Eilers, Thomas M. Gress, Martin E Fernandez-Zapico, Volker Ellenrieder

Research output: Contribution to journalArticle

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Abstract

Transforming growth factor β(TGF-β) 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, wereport that sequential induction of NFAT and c-Myc transcription factors is sufficient and required for the TGF-β switch from a cell cycle inhibitor to a growth promoter pathway in cancer cells. Mechanistically, TGF-β 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-β, activated NFAT factors bind to and displace Smad3 repressor complexes from the previously identified TGF-βinhibitory 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-β-induced cell cycle arrest and growth suppression. Taken together, this study provides the first evidence for a Smad-independent master regulatory pathway in TGF-β-promoted cell growth that is defined by sequential transcriptional activation of NFAT and c-Myc factors.

Original languageEnglish (US)
Pages (from-to)27241-27250
Number of pages10
JournalJournal of Biological Chemistry
Volume285
Issue number35
DOIs
StatePublished - Aug 27 2010

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Cell proliferation
Transforming Growth Factors
Transcription Factors
Chemical activation
Switches
Cell Proliferation
Cells
Neoplasms
Growth
Cell Cycle
Cyclin D
Growth Inhibitors
Calcineurin
Cell growth
Cell Cycle Checkpoints
Transcriptional Activation
Tumors
Carcinogenesis
Up-Regulation

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Sequential activation of NFAT and c-Myc transcription factors mediates the TGF-β switch from a suppressor to a promoter of cancer cell proliferation. / Singh, Garima; Singh, Shiv K.; König, Alexander; Reutlinger, Kristina; Nye, Monica D.; Adhikary, Tillman; Eilers, Martin; Gress, Thomas M.; Fernandez-Zapico, Martin E; Ellenrieder, Volker.

In: Journal of Biological Chemistry, Vol. 285, No. 35, 27.08.2010, p. 27241-27250.

Research output: Contribution to journalArticle

Singh, Garima ; Singh, Shiv K. ; König, Alexander ; Reutlinger, Kristina ; Nye, Monica D. ; Adhikary, Tillman ; Eilers, Martin ; Gress, Thomas M. ; Fernandez-Zapico, Martin E ; Ellenrieder, Volker. / Sequential activation of NFAT and c-Myc transcription factors mediates the TGF-β switch from a suppressor to a promoter of cancer cell proliferation. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 35. pp. 27241-27250.
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