Reinterpreting polarity and cancer: The changing landscape from tumor suppression to tumor promotion

Cell polarity is a fundamental property used to generate asymmetry and structure in all cells. Cancer is associated with loss of cell and tissue structure. While observations made in model system such as Drosophila, identify polarity regulators as tumor suppressors that cause inappropriate cell division, studies in mammalian epithelia do not always support such a causative contribution. Our analysis of published cancer dataset shows that many polarity genes, including PARD6B, SCRIB, PRKCI, DLG1, DLG2, DLG5 and LLGL2, are frequently amplified in multiple cancers raising the possibility that mammalian epithelia may have evolved to use polarity proteins in multiple ways where they may have tumor promoting functions. In this review, we reinterpret the published results and propose a modified perspective for the role of polarity regulators in cancer biology. In addition to the traditional form of cell polarity, which is involved establishment of maintenance of normal cell structure and asymmetry, we propose that some mammalian polarity proteins also regulate subcellular polarity (intracellular asymmetry), which can improve cellular fitness to carry out functions such as proliferation, apoptosis, stress adaptation, stemness and organelle biology. Here, we define subcellular polarity and discuss evidence that supports a role for subcellular polarity in biology.     

Augmentation of RBP4/STRA6 signaling leads to insulin resistance and inflammation and the plausible therapeutic role of vildagliptin and metformin

A role of Retinol Binding Protein-4 (RBP4) in insulin resistance is widely studied. However, there is paucity of information on its receptor viz., Stimulated by Retinoic Acid-6 (STRA6) with insulin resistance. To address this, we investigated the regulation of RBP4/STRA6 expression in 3T3-L1 adipocytes exposed to glucolipotoxicity (GLT) and in visceral adipose tissue (VAT) from high fat diet (HFD) fed insulin-resistant rats. 3T3-L1 adipocytes were subjected to GLT and other experimental maneuvers with and without vildagliptin or metformin. Real-time PCR and western-blot experiments were performed to analyze RBP4, STRA6, PPARγ gene and protein expression. Adipored staining and glucose uptake assay were performed to evaluate lipid and glucose metabolism. Oral glucose tolerance test (OGTT) and Insulin Tolerance Test (ITT) were performed to determine the extent of insulin resistance in HFD fed male Wistar rats. Total serum RBP4 was measured by quantitative sandwich enzyme-linked immunosorbent assay kit. Adipocytes under GLT exhibited significantly increased RBP4/STRA6 expressions and decreased insulin sensitivity/glucose uptake. Vildagliptin and metformin not only restored the above but also decreased the expression of IL-6, NFκB, SOCS-3 along with lipid accumulation. Furthermore, HFD fed rats exhibited significantly increased serum levels of RBP4 along with VAT expression of RBP4, STRA6, PPARγ, IL-6. These molecules were significantly altered by the vildagliptin/ metformin treatment. We conclude that RBP4/STRA6 pathway is primarily involved in mediating inflammation and insulin resistance in adipocytes and visceral adipose tissues under glucolipotoxicity and in insulin resistant rats.

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Transposon Tn5 mutagenesis of Pseudomonas fluorescens to isolate mutants deficient in antibacterial activity

Abstract Pseudomonas fluorescens was subjected to insertion mutagenesis studies using the transposon Tn5-GM to generate mutants deficient in antibacterial activity minus mutants. The transposon located on the temperature-sensitive plasmid pCHR84 was conjugally transferred into the non-pathogenic pseudomonad using the triparental mating procedure. Random integration of Tn 5 -GM into the chromosome of P. fluorescens was achieved by heat ttreatment of the transformed cells at 42°C. Approximately 2% of transconjugants revealed an auxotrophic phenotype indicating efficient integration of the employed transposon into the chromosome of P. fluorescens . One transposon insertion mutant was obtained showing an antibacterial activity minus phenotype. This mutant (MM-7) was found to be defective in the production of an unidentified antibacterial compound against B. subtilis . These results introduce Tn 5 transposon mutagenesis as a new useful tool for the molecular analysis of P. fluorescens .     

Leakiness of genetic markers and susceptibility to post-plating mutagenesis inEscherichia coli

WhenEscherichia coli strain AB1157 is subjected to starvation for threonine or leucine on solid media, threonine-independent or leucine-independent colonies continue to emerge for several days after plating. This process is strongly streptomycin dependent. Under identical conditions arginine-independent colonies do not arise when arginine starvation is imposed. Since thethr1 andleuB6 alleles of AB1157 could be classified as ‘leaky’ while theargE3 allele cannot be so classified, there seems to be a correlation between leakiness of mutant genetic markers and post-plating mutagenesis which counters the effect of the mutations. Some of the threonine-independent variants acquired the ability to increase the leakiness of otherwise nonleaky markers such asargE3 and permit development of arginine independence in arecA-dependent,lexA-independent manner. I show that these variants harbour a mutation, tentatively namedadi (adaptation inducer), at around 72 min on the genetic map, and that theadi mutation increases the intrinsic leakiness of alacZ (ochre) mutation, perhaps by enhanced translational error. These observations are discussed in relation to the phenomenon of ‘adaptive’ mutagenesis, its possible mechanism, and its specificity.     

Nitrofurantoin-resistant mutants of Escherichia coli: isolation and mapping

Summary Mutants of Escherichia coli resistant to nitrofurantoin have been isolated. The mutations, designated nfnA and nfnB were introduced individually into a multiply auxotrophic E. coli F^– strain and mapped by conjugation and transduction. nfnA is located at 79.8 min and nfnB at 13.0 min on the E. coli chromosome.     

A new toxin isolated from Xanthomonas malvacearum which inhibits mitochondrial ATP--ADP translocase

The pathogenic effect of cotton blight disease is influenced by Xanthomonas malvacearum toxin. The toxin has been highly purified and the interaction between the toxin and the energy-generating system of mitochondria has been characterized. The results show that the toxin inhibits the ATP-ADP translocase system of the mitochondria.