Transforming growth factor beta (TGF-β) is activated by the CtBP2-p300-AP1 transcriptional complex in chronic renal failure

Abstract

Chronic renal failure (CRF), also known as chronic kidney disease (CKD), is a common renal disorder characterized by gradual kidney dysfunction. Molecular dissection reveals that transforming growth factor beta (TGF-β) plays a central role in the pathogenesis of CRF. However, the mechanism underlying TGF-β upregulation has not been demonstrated. Here, we verified that the elevated level of TGF-β was associated with the severity of CRF stages and the activation of TGF-β-mediated signaling in 120 renal biopsies from CRF patients. By analyzing the promoter region of the TGFB1 gene, we identified one AP-1 (activator protein 1) and four NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) binding sites. Knockdown of two AP-1 subunits (c-Jun and c-FOS) or blockage of AP-1 signaling with two inhibitors T-5224 and SR11302 could cause the downregulation of TGFB1, whereas knockdown of two NF-κB subunits (p65 and p50) or blockage of NF-κB signaling with two inhibitors TPCA1 and BOT-64 could not change the expression of TGFB1. Using mass spectrometry and coimmunoprecipitation analyses, we found that both c-Jun and c-FOS formed a complex with CtBP2 (C-terminal binding protein 2) and histone acetyltransferase p300. Our in vitro data demonstrated that induction of CtBP2 by recombinant IL-1β (interleukin-1 beta) led to the upregulation of TGFB1 and the activation of TGF-β downstream signaling, while knockdown of CtBP2 resulted in the reversed effects. Using chromatin immunoprecipitation assays, we revealed that the CtBP2-p300-AP1 complex specifically bound to the promoter of TGFB and that knockdown or blockage of CtBP2 significantly decreased the occupancies of the p300 and AP-1 subunits. Our results support a model in which the CtBP2-p300-AP1 transcriptional complex activates the expression of TGFB1, increasing its production and extracellular secretion. The secreted TGF-β binds to its receptors and initiates downstream signaling.

The extended effect of adsorbed damage-associated molecular patterns and Toll-like receptor 2 signaling on macrophage-material interactions

“…These results show that acute TLR2 inhibition of NF-κB and AP-1 transcription factor activity impacted both proinflammatory signaling (i.e., decreased MCP-1 and RANTES) and profibrotic signaling (i.e., decreased TGF-β1) in response to adsorbed-lysate on Teflon ™ AF at 72 h. This is consistent with the roles of NF-κB and AP-1, as they are known to regulate the expression of various proinflammatory cytokines, including MCP-1 and RANTES (Rovin et al, 1995;Kim et al, 2006;Liu et al, 2017). TGF-β1 expression is regulated, in part, by the AP-1 family and also has NF-κB binding sites in TGFB1 promoter region (Birchenall-Roberts et al, 1990;Zhou et al, 2020). A significant observation in this extended study was the TLR2-dependent induction of TGF-β1 expression, which was abolished by TLR2 inhibition.…”

Role of PCIF1‐mediated 5′‐cap N6‐methyladeonsine mRNA methylation in colorectal cancer and anti‐PD‐1 immunotherapy

“…FOS is a primary member of the AP‐1 family of transcription factors, is known to regulate transcription of TGF‐β (Pandey et al , 2012 ; Zhou et al , 2020 ), and TGFβ has a well‐characterized role in promoting CRC (Xu & Pasche, 2007 ). Given the known role of FOS in TGF‐β transcription, and the link between TGF‐β and CRC, we next asked whether FOS regulates TGF‐β expression in CRC, and if so, whether that occurs in a PCIF1‐dependent or ‐independent manners.…”

SoxE group transcription factor Sox8 promotes astrocytic differentiation of neural stem/precursor cells downstream of Nfia

“…Contrary to our expectation, an association between STAT3 and Sox8 was not detected (Figure 5A). Since bridging of distinct transcription factors via by transcriptional co‐activators such as p300 and CBP has been shown, 13,15,36 next we investigated the possibility that p300 mediates complex formation of Sox8 and STAT3 and found that this is the case. Sox8 interacted with p300 (Figure 5B), and interacted with STAT3 only in the presence of p300 (Figure 5C).…”