期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 285, 期 35, 页码 27241-27250出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110.100438
关键词
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资金
- Deutsche Forschungsgemeinschaft (DFG) [SFB-TR17, KFO 210]
- German Cancer Research Foundation (Deutsche Krebshilfe) [70-3022-El I]
- Division of Oncology Research, Mayo Clinic Cancer Center, Miles and Shirley Fiterman Center for Digestive Disease [CA136526]
- Carole and Bob Daly AACR-PANCAN Career Development Award for Pancreatic Cancer Research, Mayo Clinic Pancreatic SPORE [P50 CA102701]
- NIDDK [P30DK084567]
- Leukemia and Lymphoma Society Translational Research Program
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.
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