N-Acetylglucosamine-inducible CaGAP1 encodes a general amino acid permease which co-ordinates external nitrogen source response and morphogenesis in Candida albicans

Candida albicans is able to grow in a variety of reversible morphological forms (yeast, pseudohyphal and hyphal) in response to various environmental signals, noteworthy among them being N-acetylglucosamine (GlcNAc). The gene CaGAP1, homologous to GAP1, which encodes the general amino acid permease from Saccharomyces cerevisiae, was isolated on the basis of its induction by GlcNAc through differential screening of a C. albicans genomic library. The gene could functionally complement an S. cerevisiae gap1 mutant by rendering it susceptible to the toxic amino acid analogue mimosine in minimal proline media. As in S. cerevisiae, mutation of the CaGAP1 gene had an effect on citrulline uptake in C. albicans. Northern analysis showed that GlcNAc-induced expression of CaGAP1 was further enhanced in synthetic minimal media supplemented with single amino acids (glutamate, proline and glutamine) or urea (without amino acids) but repressed in minimal ammonium media. Induction of CaGAP1 expression by GlcNAc was nullified in C. albicans deleted for the transcription factor CPH1 and the hyphal regulator RAS1, indicating the involvement of Cph1p-dependent Ras1p signalling in CaGAP1 expression. A homozygous mutant of this gene showed defective hyphal formation in solid hyphal-inducing media and exhibited less hyphal clumps when induced by GlcNAc. Alteration of morphology and short filamentation under nitrogen-starvation conditions in the heterozygous mutant suggested that CaGAP1 affects morphogenesis in a dose-dependent manner

Activation of Epithelial-Mesenchymal Transition and Altered β-Catenin Signaling in a Novel Indian Colorectal Carcinoma Cell Line

Colorectal cancer is the third major cause of cancer-related mortality worldwide. The upward trend in incidence and mortality rates, poor sensitivity to conventional therapies and a dearth of early diagnostic parameters pose a huge challenge in the management of colorectal cancer in India. Due to the high level of genetic diversity present in the Indian population, unraveling the genetic contributions toward pathogenesis is key for understanding the etiology of colorectal cancer and in reversing this trend. We have established a novel cell line, MBC02, from an Indian colorectal cancer patient and have carried out extensive molecular characterization to unravel the pathological alterations in this cell line. In-depth molecular analysis of MBC02 revealed suppression of E-cadherin expression, concomitant with overexpression of EMT related molecules, which manifested in the form of highly migratory and invasive cells. Loss of membrane-tethered E-cadherin released β-catenin from the adherens junction resulting in its cytoplasmic and nuclear accumulation and consequently, upregulation of c-Myc. MBC02 also showed dramatic transcriptional upregulation of β-catenin. Remarkably, we observed significantly elevated proteasome activity that perhaps co-evolved to compensate for the unnaturally high mRNA level of β-catenin to regulate the increased protein load. In addition, there was substantial misregulation of other clinically relevant signaling pathways that have clinical relevance in the pathogenesis of colorectal cancer. Our findings pave the way toward understanding the molecular differences that could define pathogenesis in cancers originating in the Indian population

Development of a facile antibody–drug conjugate platform for increased stability and homogeneity† †Electronic supplementary information (ESI) available: Synthetic schemes and characterization data, experimental procedures, Fig. S1 and S2. See DOI: 10.1039/c6sc05149a Click here for additional data file.

Despite the advances in the design of antibody–drug conjugates (ADCs), the search is still ongoing for novel approaches that lead to increased stability and homogeneity of the ADCs. We report, for the first time, an ADC platform technology using a platinum(ii)-based linker that can re-bridge the inter-chain cysteines in the antibody, post-reduction. The strong platinum–sulfur interaction improves the stability of the ADC when compared with a standard maleimide-linked ADC thereby reducing the linker–drug exchange with albumin significantly. Moreover, due to the precise conserved locations of cysteines, both homogeneity and site-specificity are simultaneously achieved. Additionally, we demonstrate that our ADCs exhibit increased anticancer efficacy in vitro and in vivo. The Pt-based ADCs can emerge as a simple and exciting proposition to address the limitations of the current ADC linker technologies

Analyzing the adoption of enterprise resource planning systems in Indian organizations:a process framework

This paper is based on an empirical study of ERP implementation exercises in Indian organizations. The results show that the ERP implementation process is composed of successive phases, in each of which a specific number of modules of the software are implemented. Each phase has distinct stages, which address specific activities within the phase and describe different aspects of the implementation process. Differences of the model with existing models have been identified, and opportunities for generalizing it to other similar societies have been analyzed

Adoption of enterprise resource planning software by organizations in India:a managerial framework

Enterprise Resource Planning (ERP) systems are designed to integrate various functions and processes, and are used by organizations as the first-level transaction processing systems in their information architecture. Although many studies have been conducted and reported on ERP implementation cases in the developed countries, there is not much literature on the experiences of companies in Asia and other parts of the developing world. These organizations confront issues that are significantly different from those faced by companies in the developed world, because of differences in the sophistication of IT use, and cultural and social contexts. This chapter describes a three-stage model for analyzing the deployment of ERP in developing countries, based on an empirical study of ERP implementation exercises in Indian organizations. Each stage describes a specific aspect of the implementation process. The specific characteristics of each stage and their implications for managers have also been discussed

IQGAP1 Is a Scaffold for Mitogen-Activated Protein Kinase Signaling

IQGAP1 modulates many cellular functions such as cell-cell adhesion, transcription, cytoskeletal architecture, and selected signaling pathways. We previously documented that IQGAP1 binds extracellular signal-regulated kinase (ERK) 2 and regulates growth factor-stimulated ERK activity. Here we show that MEK, the molecule immediately upstream of ERK in the Ras/mitogen-activated protein (MAP) kinase signaling cascade, also interacts directly with IQGAP1. Both MEK1 and MEK2 bound IQGAP1 in vitro and coimmunoprecipitated with IQGAP1. The addition of ERK2 enhanced by fourfold the in vitro interaction of MEK2 with IQGAP1 without altering binding of MEK1. Similarly, ERK1 promoted MEK binding to IQGAP1, but either MEK protein altered the association between IQGAP1 and ERK. Epidermal growth factor (EGF) differentially regulated binding, enhancing MEK1 interaction while reducing MEK2 binding to IQGAP1. In addition, both knockdown and overexpression of IQGAP1 reduced EGF-stimulated activation of MEK and ERK. Analyses with selective IQGAP1 mutant constructs indicated that MEK binding is crucial for IQGAP1 to modulate EGF activation of ERK. Our data strongly suggest that IQGAP1 functions as a molecular scaffold in the Ras/MAP kinase pathway