Cell type-dependent control of NF-Y activity by TGF-β

Transforming growth factor b (TGF-beta) is a pluripotent cytokine that regulates cell growth and differentiation in a cell type-dependent fashion. TGF-beta exerts its effects through the activation of several signaling pathways. One involves membrane proximal events that lead to nuclear translocation of members of the Smad family of transcriptional regulators. TGF-beta can also activate MAPK cascades. Here, we show that TGF-beta induces nuclear translocation of the NF-YA subunit of the transcription factor NF-Y by a process that requires activation of the ERK cascade. This results in increased binding of endogenous NF-Y to chromatin and TGF-beta-dependent transcriptional regulation of the NF-Y target gene cyclin A2. Interestingly, the kinetics of NF-YA relocalization differs between epithelial cells and fibroblasts. NIH3T3 fibroblasts show an elevated basal level of phosphorylated p38 and delayed nuclear accumulation of NF-YA after TGF-beta treatment. In contrast, MDCK cells show low basal p38 activation, higher basal ERK phosphorylation and more rapid localization of NF-YA after induction. Thus, NF-Y activation by TGF-beta 1 involves ERK1/2 and potentially an interplay between MAPK pathways, thereby opening the possibility for finely tuned transcriptional regulation.