Reciprocal negative regulation between the tumor suppressor protein p53 and B cell CLL/lymphoma 6 (BCL6) via control of caspase-1 expression.

Even in the face of physiological DNA damage or expression of the tumor suppressor protein p53, B cell CLL/lymphoma 6 (BCL6) increases proliferation and antagonizes apoptotic responses in B cells. BCL6 represses TP53 transcription and also appears to inactivate p53 at the protein level, and additional findings have suggested negative mutual regulation between BCL6 and p53. Here, using Bcl6-/- knockout mice, HEK293A and HCT116 p53-/- cells, and site-directed mutagenesis, we found that BCL6 interacts with p53 and thereby inhibits acetylation of Lys-132 in p53 by E1A-binding protein p300 (p300), a modification that normally occurs upon DNA damage-induced cellular stress and whose abrogation by BCL6 diminished transcriptional activation of p53 target genes, including that encoding caspase-1. Conversely, we also found that BCL6 protein is degraded via p53-induced, caspase-mediated proteolytic cleavage, and the formation of a BCL6-p53-caspase-1 complex. Our results suggest that p53 may block oncogenic transformation by decreasing BCL6 stability via caspase-1 up-regulation, whereas aberrant BCL6 expression inactivates transactivation of p53 target genes, either by inhibiting p53 acetylation by p300 or repressing TP53 gene transcription. These findings have implications for B cell development and lymphomagenesis.

Prevalence of Dyslipidemia in Tibetan Monks from Gansu Province, Northwest China.

Tibetan monks have a special way of life and food habits, however, little is known about their dyslipidemia. This study aimed to investigate the prevalence of dyslipidemia and risk factors of this population. A cross-sectional study of dyslipidemia was conducted in 876 Tibetan monks and 912 local residents in the same area. All subjects underwent interviews and physical examinations. The total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) of the subjects were analyzed. Compared to local residents, the overall prevalence of dyslipidemia in monks was 29.5%, which was significantly lower (p<0.05). It was increased with higher age and BMI, but reduced with higher educational level (p<0.05). The typical forms of dyslipidemia in monks were elevated TG and low HDL-C, while it was lower HDL-C in residents (p<0.05). Our study demonstrated that monks in Gannan Tibetan autonomous district had a lower prevalence of dyslipidemia. It suggested that the relatively healthy lifestyle and food habits of monks were mainly responsible of the lower prevalence of dyslipidemia.

Derepression of matrix metalloproteinase gene transcription and an emphysema-like phenotype in transcription factor Zbtb7c knockout mouse lungs.

Dysregulated matrix metalloproteinase (MMP) gene expression is a major cause of the degradation of lung tissue that is integral to emphysema pathogenesis. Cigarette smoking (CS) increases MMP gene expression, a major contributor to emphysema development. We previously reported that Zbtb7c is a transcriptional repressor of several Mmp genes (Mmps-8, -10, -13, and -16). Here, we show that Zbtb7c knockout mice have mild emphysema-like phenotypes, including alveolar wall destruction, enlarged alveoli, and upregulated Mmp genes. Alveolar size and Mmp gene expression in Zbtb7c-/- mouse lungs are increased more severely upon exposure to CS, compared to those of Zbtb7c+/+ mouse lungs. These observations suggest that Zbtb7c degradation or absence may contribute to the pathogenesis of emphysema.

Zbtb7c is a critical gluconeogenic transcription factor that induces glucose-6-phosphatase and phosphoenylpyruvate carboxykinase 1 genes expression during mice fasting.

Gluconeogenesis is essential for blood glucose homeostasis during fasting and is regulated by various enzymes, which are encoded by gluconeogenic genes. Those genes are controlled by various transcription factors. Zinc finger and BTB domain-containing 7c (Zbtb7c, also called Kr-pok) is a BTB-POZ family transcription factor with proto-oncogenic activity. Previous findings have indicated that Zbtb7c is involved in the regulation of fatty acid biosynthesis, suggesting an involvement also in primary metabolism. We found here that fasting induced Zbtb7c expression in the mouse liver and in primary liver hepatocytes. We also observed that Zbtb7c-knockout mice have decreased blood glucose levels, so we investigated whether Zbtb7c plays a role in gluconeogenesis. Indeed, differential gene expression analysis of Zbtb7c-knockout versus wild type mouse livers showed downregulated transcription of gluconeogenic genes encoding the glucose 6-phosphatase catalytic subunit (G6pc) and phosphoenolpyruvate carboxykinase 1 (Pck1), while Zbtb7c expression upregulated these two genes, under fasting conditions. Mechanistically, we found that when complexed with histone deacetylase 3 (Hdac3), Zbtb7c binds insulin response elements (IREs) within the G6pc and Pck1 promoters. Moreover, complexed Zbtb7c deacetylated forkhead box O1 (Foxo1), thereby increasing Foxo1 binding to the G6pc and Pck1 IREs, resulting in their transcriptional activation. These results demonstrate Zbtb7c to be a crucial metabolic regulator of blood glucose homeostasis, during mammalian fasting.

HIC2, a new transcription activator of SIRT1.

The protein deacetylase SIRT1 is crucial to numerous physiological processes, such as aging, metabolism, and autoimmunity, and is repressed by various transcription factors, including HIC1. Conversely, we found that HIC2, which is highly homologous to HIC1, is a transcriptional activator of SIRT1 due to opposite activity of the intermediate domains of the two homologs. Importantly, this relationship between HIC2 and SIRT1 could be important for cardiac development, where both proteins are implicated. Here, we assessed whether ectopic expression of HIC2, and subsequent upregulation of SIRT1, might decrease apoptosis in H9c2 cardiomyocytes under simulated ischemia/reperfusion (I/R) injury conditions. Our results demonstrate that unlike its structural homolog HIC1, HIC2 is a pivotal transcriptional activator of SIRT1 and, consequently, may protect the heart from I/R injury.

Is plasma neutrophil gelatinase-associated lipocalin a predictive biomarker for acute kidney injury in sepsis patients? A systematic review and meta-analysis.

PURPOSE: Neutrophil gelatinase-associated lipocalin (NGAL) is a useful biomarker for early diagnosis of acute kidney injury (AKI). However, the diagnostic value of NGAL for predicting AKI in sepsis patients is unclear. METHODS: MEDLINE, EMBASE, and Cochrane Library databases were searched to identify research publications. RESULTS: Twelve studies from 9 countries including a total of 1582 patients, of whom 315 (19.9%) developed AKI, were included in the study; plasma NGAL levels were significantly higher in adult sepsis patients with AKI than in those without AKI (mean difference, 274.65; 95% confidence interval [CI], 106.16-443.15; I(2) = 94%). Urine NGAL levels were not significantly different. The diagnostic odds ratio of plasma NGAL for predicting AKI in sepsis patients was 6.64 (95% CI, 3.80-11.58). The diagnostic accuracy of plasma NGAL was 0.881 (95% CI, 0.819-0.923) for sensitivity, 0.474 (95% CI, 0.367-0.582) for specificity, 0.216 (95% CI, 0.177-0.261) for positive predictive value and 0.965 (95% CI, 0.945-0.977) for negative predictive value. CONCLUSION: Plasma NGAL has a high sensitivity and a high negative predictive value for detection of AKI in adult sepsis patients. However, its low specificity and low positive predictive value could limit its clinical utility. The usefulness of urine NGAL was not revealed in this study.

Incidence and natural course of inflammatory bowel disease in Korea, 2006-2012: a nationwide population-based study.

BACKGROUND: Although a rising trend in the incidence of inflammatory bowel disease (IBD) in Asia has been recognized, national-level, population-based studies are lacking. In this study, we investigate the epidemiological features and natural course of IBD in Korea, including incidence, bowel resection rates, survival, and cause of death. METHODS: We analyzed the Rare Intractable Disease registration and Health Insurance Review and Assessment Services claims database, which include information on every patients with IBD diagnosed through uniform criteria from 2006 to 2012. Twenty-seven thousand four hundred nineteen patients with IBD newly diagnosed from 2006 to 2012 were traced to bowel resection, survival, and cause of death. RESULTS: During study period, mean annual incidence for ulcerative colitis was 4.6 per 10 and for Crohn's disease (CD) was 3.2 per 10. Bowel resection rates at 1 and 5 years for patients with ulcerative colitis were 0.8% and 2.1%, respectively, and for patients with CD were 5.0% and 9.1%, respectively. Survival of patients with CD was lower than that of the general population, whereas patients with ulcerative colitis had similar survival. In patients with CD, mortality for colon cancer, lung cancer, and gastrointestinal disease was significantly increased compared with general population. CONCLUSIONS: Incidence of IBD found in our study is the highest in East Asia. Lower bowel resection rates and higher survival compared to those of Western nations suggest that the natural course of IBD may be different between East Asia and the West.