Home About us Contact
|
Home About us Contact | ||
|
|
||
Crucial Regulator (crucial + regulator)
Selected AbstractsE-box protein E2-2 is a crucial regulator of plasmacytoid DC development,EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2008Eiji Esashi Abstract DC play central roles in priming both innate and adaptive immune responses. Multiple DC subsets have been identified on the basis of their phenotype and function. Plasmacytoid DC (pDC) are professional IFN-producing cells that play an essential role in anti-viral immunity. A series of recent studies demonstrates that the regulation of pDC development is different from other types of DC. In this issue of the European Journal of Immunology, new insight is provided into how human pDC development is regulated by various transcription factors, in particular by the Ets family protein Spi-B and E-box protein E2-2. [source] Obesity and metabolic syndrome in histone demethylase JHDM2a-deficient miceGENES TO CELLS, Issue 8 2009Takeshi Inagaki Histone H3 lysine 9 (H3K9) methylation is a crucial epigenetic mark of heterochromatin formation and transcriptional silencing. Recent studies demonstrated that most covalent histone lysine modifications are reversible and the jumonji C (JmjC)-domain-containing proteins have been shown to possess such demethylase activities. However, there is little information available on the biological roles of histone lysine demethylation in intact animal model systems. JHDM2A (JmjC-domain-containing histone demethylase 2A, also known as JMJD1A) catalyses removal of H3K9 mono- and dimethylation through iron and ,-ketoglutarate dependent oxidative reactions. Here, we demonstrate that JHDM2a also regulates metabolic genes related to energy homeostasis including anti-adipogenesis, regulation of fat storage, glucose transport and type 2 diabetes. Mice deficient in JHDM2a (JHDM2a,/,) develop adult onset obesity, hypertriglyceridemia, hypercholesterolemia, hyperinsulinemia and hyperleptinemia, which are hallmarks of metabolic syndrome. JHDM2a,/, mice furthermore exhibit fasted induced hypothermia indicating reduced energy expenditure and also have a higher respiratory quotient indicating less fat utilization for energy production. These observations may explain the obesity phenotype in these mice. Thus, H3K9 demethylase JHDM2a is a crucial regulator of genes involved in energy expenditure and fat storage, which suggests it is a previously unrecognized key regulator of obesity and metabolic syndrome. [source] EBAG9 is a tumor-promoting and prognostic factor for bladder cancerINTERNATIONAL JOURNAL OF CANCER, Issue 4 2009Jinpei Kumagai Abstract Upregulation of EBAG9 expression has been observed in several malignant tumors such as advanced breast and prostate cancers, indicating that EBAG9 may contribute to tumor proliferation. In the present study, we assess the role of EBAG9 in bladder cancer. We generated human bladder cancer EJ cells stably expressing FLAG-tagged EBAG9 (EJ-EBAG9) or empty vector (EJ-vector), and investigated whether EBAG9 overexpression modulates cell growth and migration in vitro as well as the in vivo tumor formation of EJ transfectants in xenograft models of BALB/c nude mice. EBAG9 overexpression promoted EJ cell migration, while the effect of EBAG9 to cultured cell growth was rather minimal. Tumorigenic experiments in nude mice showed that the size of EJ-EBAG9-derived tumors was significantly larger than EJ-vector-derived tumors. Loss-of-function study for EBAG9 using small interfering RNA (siRNA) in xenografts with parental EJ cells showed that the intra-tumoral injection of EBAG9 siRNA markedly reduced the EJ tumor formation compared with control siRNA. Furthermore, immunohistochemical study for EBAG9 expression was performed in 60 pathological bladder cancer specimens. Intense and diffuse cytoplasmic immunostaining was observed in 45% of the bladder cancer cases. Positive EBAG9 immunoreactivity was closely correlated with poor prognosis of the patients (p = 0.0001) and it was an independent prognostic predictor for disease-specific survival in multivariate analysis (p = 0.003). Our results indicate that EBAG9 would be a crucial regulator of tumor progression and a potential prognostic marker for bladder cancer. © 2008 Wiley-Liss, Inc. [source] Protein phosphatase 1, activity prevents oncogenic transformationMOLECULAR CARCINOGENESIS, Issue 9 2006Cathy W.Y. Liu Abstract Cyclin-dependent kinase 2 (Cdk2) phosphorylates Thr320 of protein phosphatase 1, (PP1,) in late G1, thereby inhibiting its activity. Phosphorylation-resistant PP1,T320A, acting as a constitutively active (CA) mutant, causes a late G1 arrest by preventing the phosphorylation and inactivation of the retinoblastoma protein (pRb). Both PP1,-mediated G1 arrest and PP1, phosphorylation in late G1 require the presence of pRb, indicating that PP1, is a crucial regulator of the pRb pathway, which is almost invariably mutated in human cancer. These findings prompted us to investigate whether PP1, interferes with oncogenic transformation. The ability of NIH 3T3 cells to form foci after transformation with ras/cyclin D1 was significantly inhibited by co-transfection with PP1,T320A, but not PP1,. Likewise, cells expressing PP1,T320A or PP1,T320A fused to green fluorescent protein (GFP) were unable to form colonies in soft agar, regardless of whether PP1, constructs were co-transfected with ras/cyclin D1 or transfected into stably transformed cells. Overexpressed wild-type (Wt) PP1, and GFP-PP1, were phosphorylated in Thr320, most likely explaining its lack of effect. Expression of GFP-PP1,T320A was associated with caspase-cleaved pRb in Western blots (WB) and morphological signs of cell death. These findings demonstrate that PP1, activity can override oncogenic signaling by causing cell-cycle arrest and/or apoptosis rather than restoring contact inhibition or anchorage dependence. © 2006 Wiley-Liss, Inc. [source] | ||||||||||