Deregulated NFATc1 activity transforms murine fibroblasts via an autocrine growth factor-mediated Stat3-dependent pathway.
The nuclear factor of activated T cells (NFAT) family of transcription factors has recently been implicated with a role in tumorigenesis. Forced expression of a constitutively active NFATc1 mutant (caNFATc1) has been shown to transform immortalized murine fibroblasts in vitro, while constitutive activation of the NFAT-signaling pathway has been found in a number of human cancers, where it has been shown to contribute towards various aspects of the tumor phenotype. Here we have investigated the molecular mechanisms underlying the oncogenic potential of deregulated NFAT activity. We now show that ectopic expression of caNFATc1 in murine 3T3-L1 fibroblasts induces the secretion of an autocrine factor(s) that is sufficient to promote the transformed phenotype. We further demonstrate that this NFATc1-induced autocrine factor(s) specifically induces the tyrosine phosphorylation of the Stat3 transcription factor via a JAK kinase-dependent pathway. Interestingly, this effect of sustained NFAT signaling on the autocrine growth factor-mediated activation of Stat3 is not restricted to murine fibroblasts, but is also observed in the PANC-1 and MCF10A human cell lines. Most importantly, we find that the shRNA-mediated depletion of endogenous Stat3 significantly attenuates the ability of caNFATc1 to transform 3T3-L1 fibroblasts. Taken together, our results afford significant new insights into the molecular mechanisms underlying the oncogenic potential of deregulated NFATc1 activity by demonstrating that constitutive NFATc1 activity transforms cells via an autocrine factor-mediated pathway that is critically dependent upon the activity of the Stat3 transcription factor.
Lagunas
Lucio
L
Department of Pharmacology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois 60153, USA.
Clipstone
Neil A
NA
D041721:3T3-L1 Cells; D000818:Animals; D019898:Autocrine Communication; D002454:Cell Differentiation; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
D036341:Intercellular Signaling Peptides and Proteins; D050778:NFATC Transcription Factors; D050796:STAT3 Transcription Factor