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Critical Players (critical + player)
Selected AbstractsNuclear factor-,B contributes to interleukin-4- and interferon-dependent polymeric immunoglobulin receptor expression in human intestinal epithelial cellsIMMUNOLOGY, Issue 1 2004Laynez W. Ackermann Summary Polymeric immunoglobulins (pIgs) that are present at mucosal surfaces play key roles in both the innate and adaptive immune responses. These pIgs are delivered to the mucosal surface via transcytosis across the epithelium, a process mediated by the polymeric immunoglobulin receptor (pIgR). Previous studies demonstrate that expression of the pIgR is regulated by multiple immunomodulatory factors including interleukin-4 (IL-4) and interferon-, (IFN-,). In studies using human intestinal epithelial cells (HT29), multiple inhibitors of the transcription factor nuclear factor-,B (NF-,B), including a dominant negative I,B,-serine mutant, inhibited both IL-4- and IFN-dependent increases in pIgR expression. Under identical conditions, NF-,B inhibitors had no effect on cytokine-dependent increases in expression of the transcription factor interferon regulatory factor-1. Over-expression of the I,B,-serine mutant also inhibited reporter gene expression in response to IL-4, TNF-,, IL-1,, and in some cases IFN-, using constructs with sequences from the pIgR promoter. Reduced levels of pIgR were observed even when inhibitors were added ,24 hr after cytokines suggesting that prolonged activation of NF-,B is required. Finally, reporter gene studies with NF-,B enhancer elements indicated that IFN-, alone and IL-4 in combination with other cytokines activated NF-,B in HT29 cells. Together, these studies provide additional insight into the signalling pathways that contribute to expression of the pIgR, a critical player in mucosal immunity. [source] Shepherding AKT and androgen receptor by Ack1 tyrosine kinaseJOURNAL OF CELLULAR PHYSIOLOGY, Issue 2 2010Kiran Mahajan Ack1 (also known as ACK, TNK2, or activated Cdc42 kinase) is a structurally unique non-receptor tyrosine kinase that is expressed in diverse cell types. It integrates signals from plethora of ligand-activated receptor tyrosine kinases (RTKs), for example, MERTK, EGFR, HER2, PDGFR and insulin receptor to initiate intracellular signaling cascades. Ack1 transduces extracellular signals to cytosolic and nuclear effectors such as the protein kinase AKT/PKB and androgen receptor (AR), to promote cell survival and growth. While tyrosine phosphorylation of AR at Tyr267 regulates androgen-independent recruitment of AR to the androgen-responsive enhancers and transcription of AR target genes to drive prostate cancer progression, phosphorylation of an evolutionarily conserved Tyrosine 176 in the kinase domain of AKT is essential for mitotic progression and positively correlates with breast cancer progression. In contrast to AR and AKT, Ack1-mediated phosphorylation of the tumor suppressor Wwox at Tyr287 lead to rapid Wwox polyubiquitination followed by degradation. Thus, by its ability to promote tumor growth by negatively regulating tumor suppressor such as Wwox and positively regulating pro-survival factors such as AKT and AR, Ack1 is emerging as a critical player in cancer biology. In this review, we discuss recent advances in understanding the physiological functions of Ack1 signaling in normal cells and the consequences of its hyperactivation in various cancers. J. Cell. Physiol. 224: 327,333, 2010. © 2010 Wiley-Liss, Inc. [source] Identification of novel genes expressed during mouse tooth development by microarray gene expression analysisDEVELOPMENTAL DYNAMICS, Issue 8 2007Trevor J. Pemberton Abstract To identify genes heretofore undiscovered as critical players in the biogenesis of teeth, we have used microarray gene expression analysis of the developing mouse molar tooth (DMT) between postnatal day (P) 1 and P10 to identify genes differentially expressed when compared with 16 control tissues. Of the top 100 genes exhibiting increased expression in the DMT, 29 were found to have been previously associated with tooth development. Differential expression of the remaining 71 genes not previously associated with tooth development was confirmed by quantitative reverse transcription-polymerase chain reaction analysis. Further analysis of seven of the latter genes by mRNA in situ hybridization found that five were specific to the developing tooth in the craniofacial region (Rspo4, Papln, Amtn, Gja1, Maf). Of the remaining two, one was found to be more widely expressed (Sp7) and the other was found to be specific to the nasal serous gland, which is close to, but distinct from, the developing tooth (Vrm). Developmental Dynamics 236:2245,2257, 2007. © 2007 Wiley-Liss, Inc. [source] Mixed lineage leukemia histone methylases play critical roles in estrogen-mediated regulation of HOXC13FEBS JOURNAL, Issue 24 2009Khairul I. Ansari HOXC13, a homeobox-containing gene, is involved in hair development and human leukemia. The regulatory mechanism that drives HOXC13 expression is mostly unknown. Our studies have demonstrated that HOXC13 is transcriptionally activated by the steroid hormone estrogen (17,-estradiol; E2). The HOXC13 promoter contains several estrogen-response elements (EREs), including ERE1 and ERE2, which are close to the transcription start site, and are associated with E2-mediated activation of HOXC13. Knockdown of the estrogen receptors (ERs) ER, and ER, suppressed E2-mediated activation of HOXC13. Similarly, knockdown of mixed lineage leukemia histone methylase (MLL)3 suppressed E2-induced activation of HOXC13. MLLs (MLL1,MLL4) were bound to the HOXC13 promoter in an E2-dependent manner. Knockdown of either ER, or ER, affected the E2-dependent binding of MLLs (MLL1,MLL4) into HOXC13 EREs, suggesting critical roles of ERs in recruiting MLLs in the HOXC13 promoter. Overall, our studies have demonstrated that HOXC13 is transcriptionally regulated by E2 and MLLs, which, in coordination with ER, and ER,, play critical roles in this process. Although MLLs are known to regulate HOX genes, the roles of MLLs in hormone-mediated regulation of HOX genes are unknown. Herein, we have demonstrated that MLLs are critical players in E2-dependent regulation of the HOX gene. [source] Prisoners' Adjustment, Correctional Officers, and Context: The Foreground and Background of Punishment in Late ModernityLAW & SOCIETY REVIEW, Issue 2 2008Mike Vuolo Past research indicates that front-line criminal justice workers are the critical players in determining whether innovations in penal policy are realized. Recent attempts to understand the diversity in the application of the penal harm movement have, however, sidestepped the primary audience of these policies, the population of convicted offenders. This article uses data from two prisons to examine the effects of correctional officers on women prisoners' adjustment to prison life. Using regression models and interview data, we find that correctional officer behavior has a profound impact on women's ability to adjust to prison, and this effect is largely independent of the prisoners' characteristics and the institutions in which they are housed. On a theoretical level, the findings speak to recent calls to examine the background and foreground of penal culture. On a practical level, they highlight the need to understand the environments from which women are emerging, not just the communities into which they are released. [source] ,-Catenin dysregulation in cancer: interactions with E-cadherin and beyond,THE JOURNAL OF PATHOLOGY, Issue 2 2010Qun Lu Abstract Stable E-cadherin-based adherens junctions are pivotal in maintaining epithelial tissue integrity and are the major barrier for epithelial cancer metastasis. Proteins of the p120ctn subfamily have emerged recently as critical players for supporting this stability. The identification of the unique juxtamembrane domain (JMD) in E-cadherin that binds directly to ,-catenin/NPRAP/neurojungin (CTNND2) and p120ctn (CTNND1) provides a common motif for their interactions. Recently, crystallographic resolution of the JMD of p120ctn further highlighted possibilities of intervening between interactions of p120ctn subfamily proteins and E-cadherin for designing anti-cancer therapeutics. For most epithelial cancers, studies have demonstrated a reduction of p120ctn expression or alteration of its subcellular distribution. On the other hand, ,-catenin, a primarily neural-enriched protein in the brain of healthy individuals, is up-regulated in all cancer types that have been studied to date. Two research articles in the September 2010 issue of The Journal of Pathology increase our understanding of the involvement of these proteins in lung cancer. One reports the identification of rare p120ctn (CTNND1) gene amplification in lung cancer. One mechanism by which ,-catenin and p120ctn may play a role in carcinogenesis is their competitive binding to E-cadherin through the JMD. The other presents the first vigorous characterization of ,-catenin overexpression in lung cancer. Unexpectedly, the authors observed that ,-catenin promotes malignant phenotypes of non-small cell lung cancer by non-competitive binding to E-cadherin with p120ctn in the cytoplasm. Looking towards the future, the understanding of ,-catenin and p120ctn with and beyond their localization at the cell,cell junction should provide further insight into their roles in cancer pathogenesis. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Invited Commentary for Castillo et al. Gene amplification of the transcription factor DP1 and CTNND1 in human lung cancer, Journal of Pathology, 2010; 222: 89,98. And for Zhang et al. ,-Catenin promotes malignant phenotype of non-small cell lung cancer by non-competative binding to E-cadherin with p120ctn in cytoplasm. Journal of Pathology, 2010; 222: 76,88. [source] Protein Kinase C Activators as Synaptogenic and Memory TherapeuticsARCHIV DER PHARMAZIE, Issue 12 2009Miao-Kun Sun Abstract The last decade has witnessed a rapid progress in understanding of the molecular cascades that may underlie memory and memory disorders. Among the critical players, activity of protein kinase C (PKC) isoforms is essential for many types of learning and memory and their dysfunction, and is critical in memory disorders. PKC inhibition and functional deficits lead to an impairment of various types of learning and memory, consistent with the observations that neurotoxic amyloid inhibits PKC activity and that transgenic animal models with PKC, deficit exhibit impaired capacity in cognition. In addition, PKC isozymes play a regulatory role in amyloid production and accumulation. Restoration of the impaired PKC signal pathway pharmacologically results in an enhanced memory capacity and synaptic remodeling / repair and synaptogenesis, and, therefore, represents a potentially important strategy for the treatment of memory disorders, including Alzheimer's dementia. The PKC activators, especially those that are isozyme-specific, are a new class of drug candidates that may be developed as future memory therapeutics. [source] | ||||||||||||||||