Here we show a novel pathway of transcriptional regulation of a DNA-binding transcription factor by coupled interaction and modification (e.g., acetylation) through the DNA-binding domain (DBD). The oncogenic regulator SET was isolated by affinity purification of factors interacting with the DBD of the cardiovascular transcription factor KLF5. SET negatively regulated KLF5 DNA binding, transactivation, and cellproliferative activities. Down-regulation of the negative regulator SET was seen in response to KLF5-mediated gene activation. The coactivator/acetylase p300, on the other hand, interacted with and acetylated KLF5 DBD, and activated its transcription. Interestingly, SET inhibited KLF5 acetylation, and a nonacetylated mutant of KLF5 showed reduced transcriptional activation and cell growth complementary to the actions of SET. These findings suggest a new pathway for regulation of a DNA-binding transcription factor on the DBD through interaction and coupled acetylation by two opposing regulatory factors of a coactivator/acetylase and a negative cofactor harboring activity to inhibit acetylation.The Sp/KLF (for Sp1-and Krüppel-like factor) family of zinc finger transcription factors has received recent attention due to important roles in developmental, differentiation, and oncogenic processes, among others (2, 3,35). It is comprised of over 15 mammalian family members which have in common three similar C 2 H 2 -type zinc fingers at the carboxyl terminus which comprises the DNA-binding domain (DBD). Sp/KLF family members include the founding ubiquitous factor Sp1 (9), the erythroid differentiation factor EKLF/KLF1 (27), and the tumor suppressor gene KLF6/GBF/Zf9/COPEB, which we and others identified as a cellular factor possibly involved in human immunodeficiency virus type 1 transcription (18,32,44). It was recently shown by gene knockout studies that the proto-oncogene KLF5/BTEB2/IKLF (40, 42) is important for cardiovascular remodeling in response to stress (41). Contrary to initial expectations that this family of factors would likely have redundant functions, they in fact have important individual biological functions. However, the underlying mechanisms governing their specific functions and regulation are poorly understood.We have studied the regulatory mechanisms of action of Sp/KLF family members in the past and have shown differential regulation through interaction and acetylation on the DBD by the coactivator/acetylase p300 (45). Acetylation is an important nuclear regulatory signal which regulates transcriptional processes with biological implications, including regulation of development, differentiation, and oncogenesis (5, 10, 31), which closely resembles the roles of Sp/KLF family members. We therefore thought that the Sp/KLF factors may be differently regulated by acetylation and showed that the coactivator/acetylase p300, but not the MYST-type acetylase Tip60, specifically interacts and acetylates Sp1 but not KLF6 through the zinc finger DBD and that DNA binding inhibits this interaction and ace...

To determine the possible associations of medical status and physical fitness with periodontal disease, a cross-sectional study was conducted. The subjects were 517 males and 113 females aged 23 to 83 years who participated in a multiphasic health test at the Aichi Prefectural Center of Health Care, Japan, from 1992 to 1997. Their periodontal status was assessed by means of the CPITN scoring system. To assess the strength of associations between the examined factors and the score, odds ratios were computed using ordinal logistic models. Conventional risk factors such as old age, smoking habits, and higher fasting plasma glucose and simplified debris index increased the risk of periodontal disease. Hypertension, hematuria, leucocytosis or thrombocytosis, positive C-reactive protein and higher serum alkaline phosphatase were positively associated with the score, whereas higher serum high-density lipoprotein cholesterol was related to a lower risk. Poor physical fitness affecting aerobic capacity, foot balance and reaction was associated with a higher CPITN score. These associations were independent of the conventional risk factors. Although these new potential risk factors should be further investigated for their causal relationship, our findings suggested a close relationship of oral health to medical status and physical fitness.

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Aim: Endothelial cell (EC) dysfunction contributes to insulin resistance in diabetes and is characterized by reduced nitric oxide (NO) release, increased nitroxidative stress and enhanced inflammation. The purpose of this study was to test the effect of improved postprandial glucose control on EC function in insulin-resistant rats as compared to fasting glucose (FG) changes. Methods: Obese Zucker rats were treated with 10 mg/kg/day saxagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, for 4 or 8 weeks and compared to lean rats. NO and peroxynitrite (ONOO ) release from aortic and glomerular ECs was measured ex vivo using amperometric approaches and correlated with FG, postprandial glucose, insulin, soluble CD40 (sCD40) and L-citrulline levels. Results: Saxagliptin treatment improved NO production and reduced ONOO release prior to any observed changes in FG levels. In untreated obese animals, NO release from aortic and glomerular ECs decreased by 22% and 31%, respectively, while ONOO release increased by 26% and 40%. Saxagliptin increased aortic and glomerular NO release by 18% and 31%, respectively, with comparable reductions in ONOO levels; the NO/ONOO ratio, an indicator of NO synthase coupling, increased by 40%. Improved glycemic control was further associated with a reduction in sCD40 levels by more than ten-fold (from 300 206 to 22 22 pg/mL, p 0.001). Conclusion: These findings indicate that enhanced glycemic control with DPP4 inhibition improved NO release and reduced inflammation in a manner not predicted by FG changes alone. J Atheroscler Thromb, 2011; 18:774-783.