Enigma Prevents Cbl-c-Mediated Ubiquitination and Degradation of RETMEN2A

The Cbl proteins (Cbl, Cbl-b, and Cbl-c) are a highly conserved family of RING finger ubiquitin ligases (E3s) that function as negative regulators of tyrosine kinases in a wide variety of signal transduction pathways. In this study, we identify a new Cbl-c interacting protein, Enigma (PDLIM7). This interaction is specific to Cbl-c as Enigma fails to bind either of its closely related homologues, Cbl and Cbl-b. The binding between Enigma and Cbl-c is mediated through the LIM domains of Enigma as removal of all three LIM domains abrogates this interaction, while only LIM1 is sufficient for binding. Here we show that Cbl-c binds wild-type and MEN2A isoforms of the receptor tyrosine kinase, RET, and that Cbl-c enhances ubiquitination and degradation of activated RET. Enigma blocks Cbl-c-mediated RETMEN2A ubiquitination and degradation. Cbl-c decreased downstream ERK activation by RETMEN2A and co-expression of Enigma blocked the Cbl-c-mediated decrease in ERK activation. Enigma showed no detectable effect on Cbl-c-mediated ubiquitination of activated EGFR suggesting that this effect is specific to RET. Through mapping studies, we show that Cbl-c and Enigma bind RETMEN2A at different residues. However, binding of Enigma to RETMENA prevents Cbl-c recruitment to RETMEN2A. Consistent with these biochemical data, exploratory analyses of breast cancer patients with high expression of RET suggest that high expression of Cbl-c correlates with a good outcome, and high expression of Enigma correlates with a poor outcome. Together, these data demonstrate that Cbl-c can ubiquitinate and downregulate RETMEN2A and implicate Enigma as a positive regulator of RETMEN2A through blocking of Cbl-mediated ubiquitination and degradation.     

Somaclonal variation in soybean plants regenerated from tissue culture

Callus cultures of soybean (Glycine max (L.) Merr.) genotypes PI 88788, PI 438489B, and cultivar Bedford were initiated in vitro from seedling explants consisting of the cotyledonary node plus epicotyl from germinated mature seed. Plants were regenerated from these callus cultures and subsequently evaluated for qualitative variation in three to four subsequent generations. Variant phenotypes observed that have not been previously reported from tissue culture include lanceolate leaves, leaf variegation (chimeral variegated plants), pod variegation on otherwise normal plants, and change in growth habit from indeterminate to determinate. The lanceolate leaf, chimeral variegated plant, and change from indeterminate to determinate growth habit characters were inherited through at least three generations (R₀-R₂), and segregation occurred in each generation. Pod variegation was inherited through the two generations tested thus far and segregation occurred in each generation. No variation was observed in control plants derived from normal seed. Variants appeared more frequently in regenerants from PI 88788 and PI 438489B than from Bedford. These results confirm and extend the finding that certain tissue culture techniques may be used to induce novel plant formation from somatic tissue of soybean.Missouri Agricultural Experiment Station, University of Missouri, Columbia, Missouri, USAMention of tradenames does not constitute a guarantee or warranty of the product by University of Missouri or USDA-ARS and does not imply their approval to the exclusion of other products.     

Synergistic interaction between particular X-chromosome deletions andSex-lethal causes female lethality inDrosophila melanogaster

We studied the effect on female viability oftrans-heterozygous combinations of X-chromosome deficiencies andSxl ^f1, a null allele ofSex-lethal. Twentyfive deficiencies, which together covered 80% of the X chromosome, were tested. Seven of thesetrans-hcterozygous combinations caused significant levels of female lethality. Two of the seven interacting deficiencies include the previously known sex determination genessans fills andsisterless-a. Four of the remaining uncover X-chromosomal regions that were not hitherto known to contain sex determination genes. These newly identified regions are defined by deficienciesDf(1)RA2 (7D10; 8A4-5),DJ(1)KA14 (7F1-2; 8C6),Df(1)C52 (8E; 9C-D) andDf(1)NI9 (17A1; 18A2). These four deficiencies were characterized further to determine whether it was the maternal or zygotic dosage that was primarily responsible for the observed lethality of female embryos,daughterless andextra macrochaetae, two known regulators ofSxl, influence the interaction of these deficiencies withSxl.     

Neurotoxic mechanisms of triclosan: The antimicrobial agent emerging as a toxicant

Several scientific studies have suggested a link between increased exposure to pollutants and a rise in the number of neurodegenerative disorders of unknown origin. Notably, triclosan (an antimicrobial agent) is used in concentrations ranging from 0.3% to 1% in various consumer products. Recent studies have also highlighted triclosan as an emerging toxic pollutant due to its increasing global use. However, a definitive link is missing to associate the rising use of triclosan and the growing number of neurodegenerative disorders or neurotoxicity. In this article, we present systematic scientific evidence which are otherwise scattered to suggest that triclosan can indeed induce neurotoxic effects, especially in vertebrate organisms including humans. Mechanistically, triclosan affected important developmental and differentiation genes, structural genes, genes for signaling receptors and genes for neurotransmitter controlling enzymes. Triclosan-induced oxidative stress impacting cellular proteins and homeostasis which triggers apoptosis. Though the scientific evidence collated in this article unequivocally indicates that triclosan can cause neurotoxicity, further epidemiological studies may be needed to confirm the effects on humans.     

Origin and radiation of the house mouse: clues from nuclear genes

Although quite a lot is known about the genetic structure of the polytypic species Mus musculus at the periphery of its range, the centre of origin and dispersion of the species remains unknown. To investigate the amount of genetic subdivision that occurs in the central parts of its range, we analysed the genetic variation in four new samples of mice coming from Iran, Pakistan, northern and southern India using 35 autosomal protein loci and restriction fragment length polymorphisms of three genes of the Vβ gene complex of the immune system. The variation was then compared with that found in the subspecies occupying the peripheral regions of the species range. The two samples from the northern part of the Indian subcontinent were shown to be more heterozygous than the samples from any of the other regions. They also contain the majority of the alleles that exist in the differentiated subspecies at the periphery of the species range. A neighbour-joining analysis on Nei's genetic distances and a factorial analysis of correspondences on the allelic composition of each sample both place the Pakistani and Indian populations in a phylogenetically and genetically central position compared to the peripheral subspecies. These results suggest that the populations in this geographically central area have retained most of the ancestral polymorphisms, which in turn indicates that the Indian subcontinent is probably the cradle of the species. The nature of the genetic relationships between the various populations throughout the species range and the possibility that they form an incipient ring species are also discussed. Our results are in agreement with the classical model of geographic differentiation where genetic divergence in allopatry is considered to be the prime cause of subspecies formation that may eventually lead to partial reproductive isolation on secondary contact.     

Effect of Soil Temperature and pH on Resistance of Soybean to Heterodera glycines

Soybean cyst nematode (SCN), Heterodera glycines Ichinohe, is a major pest of soybean, Glycine max L. Merr. Soybean cultivars resistant to SCN are commonly grown in nematode-infested fields. The objective of this study was to examine the stability of SCN resistance in soybean genotypes at different soil temperatures and pH levels. Reactions of five SCN-resistant genotypes, Peking, Plant Introduction (PI) 88788, Custer, Bedford, and Forrest, to SCN races 3, 5, and 14 were studied at 20, 26, and 32 C, and at soil pH''s 5.5, 6.5, and 7.5. Soybean cultivar Essex was included as a susceptible check. Temperature, SCN race, soybean genotype, and their interactions significantly affected SCN reproduction. The effect of temperature on reproduction was quadratic with the three races producing significantly greater numbers of cysts at 26 C; however, reproduction on resistant genotypes remained at a low level. Higher numbers of females matured at the soil pH levels of 6.5 and 7.5 than at pH 5.5. Across the ranges of temperature and soil pH studied, resistance to SCN in the soybean genotypes remained stable.     

Movement and distribution pattern of the residues of granular insecticides in tropical soil and okra plants

Summary The increased downward mobility of phorate, quinalphos and carbofuran residues was detected in soil with increase in depth of soil column whereas aldicarb was found to remain localised mainly in 0–7.5 cm and 7.5–15.0 cm layers. Persistence of organophosphate insecticides was higher as compared to carbamates in all the soil layers. Residues of all the four insecticides got distributed in all parts of okra plant through uptake but accumulated in higher amounts in fruits only. Contribution No. 312/83 from I.I.H.R. Bangalore (India)     

Pharmacological characterization of lower esophageal sphincter relaxation induced by swallowing, vagal efferent nerve stimulation, and esophageal distention.

To characterize the neural pathways involved in lower esophageal sphincter relaxation, intraluminal pressures from the lower esophageal sphincter of the opossum were monitored during swallowing, vagal efferent nerve stimulation, and intraluminal balloon distention in the presence and absence of pharmacologic antagonism of putative neurotransmitters. The combination of atropine, hexamethonium, and 5-methoxydimethyltryptamine, which is known to block ganglionic transmission in the vagal inhibitory pathway to the lower esophageal sphincter, significantly antagonized LES relaxation induced by both swallowing and vagal stimulation, but did not affect the LES relaxation induced by balloon distention. Administration of the nitric oxide synthase inhibitor N omega nitro-L-arginine methyl ester, on the other hand, markedly inhibited LES relaxation induced by vagal stimulation, swallowing, and balloon distention, and this effect was reversed by administration of the nitric oxide synthase substrate L-arginine. These studies indicate that the distension-induced intramural pathway mediating LES relaxation does not involve ganglionic transmission similar to that of the vagal inhibitory pathway to the LES. However, the LES relaxation induced by all forms of stimuli appears to depend on nitric oxide as a final mediator.