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

Abstract

Transforming growth factor b (TGF-b) is a pluripotent cytokine that regulates cell growth and differentiation in a cell type-dependent fashion. TGF-b 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-b can also activate MAPK cascades. Here, we show that TGF-b 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-bdependent 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-b 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-b1 involves ERK1/2 and potentially an interplay between MAPK pathways, thereby opening the possibility for finely tuned transcriptional regulation.

Bone Morphogenetic Protein 2 Mediates Dentin Sialophosphoprotein Expression and Odontoblast Differentiation via NF-Y Signaling

“…However, these authors have not addressed whether mutant NF-YA at the serine residues affects intracellular distribution of this protein (74,75). Recently, Alabert et al (56) have observed that TGF-␤ induced NF-YA and NF-YB nuclear accumulation in NIH3T3 fibroblasts and MDCK epithelial cells via the ERK1/2 cascade. NF-YC was also described to undergo nuclear relocalization during the cell cycle (76).…”

“…MAPK is also involved in response to BMP2 and regulates BSP and osteocalcin gene expressions in dental follicle and periodontal ligament cells (36). In addition, other transcription factors are known to be targeted by TGF-␤/BMPs signaling (56). Therefore, we focused on testing whether BMP2 regulates DSPP expression at transcriptional levels.…”

“…Recently, NF-Y has been reported to be a regulatory protein that is responsive to several molecular stimulations (55)(56)(57). Caretti et al (55) showed that serum up-regulated NF-Y recruitment into promoters of several cell cycle genes in NIH3T3 cells and activated their gene expressions.…”

Gene Expression Signature of Human Cancer Cell Lines Treated with the Ras Inhibitor Salirasib (S-Farnesylthiosalicylic Acid)

“…4. Ample evidence indeed exists for the critical role of active Ras and its downstream effectors in regulation of the cyclin-dependent kinase 4 (CDK4)-cyclin D1/RB/E2F1 pathway (32) and of NF-Y activation (21,33). In addition, we and others have shown that, concomitantly with FTS inhibition of Ras, the levels of cyclin D1 are decreased and the activity and expression of E2F are down-regulated in various human tumor cell lines, including U87 glioblastoma cells, neuroblastoma LAN1 cells, melanoma, and LNCaP and PC3 prostate cells (3,6).…”

Transforming Growth Factor-β3 Increases the Invasiveness of Endometrial Carcinoma Cells through Phosphatidylinositol 3-Kinase-dependent Up-regulation of X-linked Inhibitor of Apoptosis and Protein Kinase C-dependent Induction of Matrix Metalloproteinase-9

“…Activated T␤RII serine/threonine kinase receptor recruits, phosphorylates, and activates T␤RI; Smad2 and Smad3 directly interact with and become phosphorylated by activated T␤RI and subsequently associate with Smad4 to form heterodimeric complexes that translocate to the nucleus, where they can trigger downstream transcriptional responses (4). TGF-␤ can also trigger ERK activation (5), again leading to modulation of cellular transcriptional activity.…”