scholarly journals deltex, a locus interacting with the neurogenic genes, Notch, Delta and mastermind in Drosophila melanogaster.

Genetics ◽  
1990 ◽  
Vol 126 (3) ◽  
pp. 665-677 ◽  
Author(s):  
T Xu ◽  
S Artavanis-Tsakonas
Keyword(s):  
Drosophila Melanogaster ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Transmembrane Protein ◽  
Wild Type ◽  
Linked Gene ◽  
Neurogenic Genes ◽  
Allele Specific ◽  
Epidermal Growth ◽  
Notch Locus

Abstract The Notch locus of Drosophila melanogaster, which codes for a transmembrane protein sharing homology with the mammalian epidermal growth factor, is one of a small number of zygotically acting genes, the so called neurogenic loci, which are necessary for the correct segregation of neural from epidermal lineages during embryogenesis. In an attempt to identify genes whose products may interact with that of Notch, we designed a genetic screen aimed at identifying suppressors of certain Notch mutations which are known to affect the extracellular epidermal growth factor homologous domain of Notch. Mutations in two neurogenic loci were identified as suppressors: Delta, whose product was recently shown to interact with Notch and mastermind. In addition, a third, X-linked gene was shown capable of acting as a suppressor. We show that this gene is the deltex locus, characterize the phenotype of deltex mutations, and demonstrate both a maternal and zygotic action of the locus. All deltex alleles behave as recessive viables affecting wing, ocellar and eye morphology. There are allele specific interactions between deltex and various Notch alleles; for example, deltex mutants with a reduced dosage of wild-type Notch die as pupae. deltex also interacts with Delta and mastermind in a fashion that is formally analogous to its interaction with Notch. These results emphasize the special relationship between Notch, Delta and mastermind suggested by previous work and indicate that deltex is likely to play an important role in the same genetic circuitry within which these three neurogenic loci operate.

scholarly journals Agonistic anti-CD148 monoclonal antibody attenuates diabetic nephropathy in mice

2020 ◽  
Vol 318 (3) ◽  
pp. F647-F659 ◽  
Author(s):  
Keiko Takahashi ◽  
Rachel H. Kim ◽  
Lejla Pasic ◽  
Lilly He ◽  
Shinya Nagasaka ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Diabetic Nephropathy ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Transmembrane Protein ◽  
Growth Factor Receptor ◽  
Diabetic Mice ◽  
Wild Type ◽  
Renal Vasculature ◽  
Epidermal Growth

CD148 is a transmembrane protein tyrosine phosphatase (PTP) that is expressed in the renal vasculature, including the glomerulus. Previous studies have shown that CD148 plays a role in the negative regulation of growth factor signals (including epidermal growth factor and vascular endothelial growth factor), suppressing cell proliferation and transformation. However, the role of CD148 in kidney disease remains unknown. Here, we generated an agonistic anti-CD148 antibody and evaluated its effects in murine diabetic nephropathy (DN). Monoclonal antibodies (mAbs) against the mouse CD148 ectodomain sequence were generated by immunizing CD148 knockout (CD148KO) mice. The mAbs that increased CD148 activity were selected by biological (proliferation) and biochemical (PTP activity) assays. The mAb (18E1) that showed strong agonistic activity was injected (10 mg/kg ip) in streptozotocin-induced wild-type and CD148KO diabetic mice for 6 wk, and the renal phenotype was then assessed. The effects of 18E1 mAb in podocyte growth factor signals were also assessed in culture. Compared with control IgG, 18E1 mAb significantly decreased albuminuria and mesangial expansion without altering hyperglycemia and blood pressure in wild-type diabetic mice. Immunohistochemical evaluation showed that 18E1 mAb significantly prevented the reduction of podocyte number and nephrin expression and decreased glomerular fibronectin expression and renal macrophage infiltration. The 18E1 mAb showed no effects in CD148KO diabetic mice. Furthermore, we demonstrated that 18E1 mAb reduces podocyte epidermal growth factor receptor signals in culture and in diabetic mice. These findings suggest that agonistic anti-CD148 mAb attenuates DN in mice, in part by reducing epidermal growth factor receptor signals in podocytes. This antibody may be used for the treatment of early DN.

scholarly journals Interaction of Hairless, Delta, Enhancer of split and Notch genes of Drosophila melanogaster as expressed in adult morphology

1989 ◽  
Vol 54 (1) ◽  
pp. 23-26 ◽  
Author(s):  
Mariitta Siren ◽  
Petter Portin
Keyword(s):  
Drosophila Melanogaster ◽  
Related Gene ◽  
Wild Type ◽  
Adult Morphology ◽  
Neurogenic Genes ◽  
Large Intron ◽  
Allele Specific ◽  
Notch Locus ◽  
Comparison Of The Results ◽  
Enhancer Of Split

SummaryThe interaction of three neurogenic loci viz. Delta, Enhancer of split and Notch, and a related gene, Hairless, of Drosophila melanogaster was investigated at the adult morphology level by measuring the effects of the mutations of the three other genes on the expression of the recessive lethal antimorphic Abruptex mutations of the Notch locus. The Abruptex mutations were also coupled in cis or trans with facet-glossy or split mutations of the Notch locus. In some of the experiments, the genotype of the fly was homozygous for either facet-glossy or split mutation or their wild type alleles but heterozygous for the Abruptex. Facet-glossy is located in a large intron of the locus, whereas split is located in the same exon as Abruptex. In all compounds studied, Delta suppressed the expression of Abruptex while Hairless and Enhancer of split enhanced it. The interactions of the four genes studied were allele specific, suggesting an interaction at the protein level. The comparison of the results presented in this study on the interaction of the neurogenic genes with other results on the same subject suggests that the interactions are similar in embryonic and imaginal development.

scholarly journals Chemotherapy versus erlotinib as second-line treatment in patients with advanced non-small cell lung cancer and wild-type epidermal growth factor receptor: an individual patient data (IPD) analysis

ESMO Open ◽  
2018 ◽  
Vol 3 (6) ◽  
pp. e000327
Author(s):  
Marina Chiara Garassino ◽  
Tomoya Kawaguchi ◽  
Vanesa Gregorc ◽  
Eliana Rulli ◽  
Masahiko Ando ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Individual Patient Data ◽  
Growth Factor Receptor ◽  
Line Treatment ◽  
Second Line ◽  
Wild Type ◽  
Mean Survival Time ◽  
Epidermal Growth

The efficacy of second-line treatment in patients with epidermal growth factor receptor (EGFR) wild-type tumours is still debatable. We assessed the efficacy of a standard second-line chemotherapy compared with erlotinib in an individual patient data approach for meta-analysis. The primary endpoint was overall survival (OS), and secondary endpoint was progression-free survival (PFS). Both were compared by log-rank test. The ‘restricted mean survival time’ (RMST) was estimated in each study and the difference in mean survival time up to the last available time point was calculated. The Cox proportional hazards model was used on survival analyses to provide HRs, to adjust for confounding variables and to test possible interaction with selected factors. Three randomised trials comparing chemotherapy versus erlotinib were analysed, including 587 randomised patients. Overall, 74% of patients included in the original trials were considered. 464 deaths and 570 progressions or deaths were observed. Compared with erlotinib, chemotherapy was associated to a decreased risk of progression (29%; HR: 0.71, 95% CI: 0.60 to 0.84, p< 0.0001;) but with no statistical significant reduction in OS (HR: 0.89, 95% CI: 0.74 to 1.06; p<0.20). No heterogeneity was found in both analyses. Patients treated with chemotherapy gained an absolute 1.5 and 1.6 months, respectively, in PFS and lifetime (RMST 95% CI: PFS 0.49 to 2.44; OS 95% CI: −1.04 to 4.25). These results showed that patients without a constitutively activated EGFR had better PFS with chemotherapy rather than with erlotinib while no statistical difference was observed in OS.

scholarly journals Localization of Phospholipase D1 to Caveolin-enriched Membrane via Palmitoylation: Implications for Epidermal Growth Factor Signaling

2002 ◽  
Vol 13 (11) ◽  
pp. 3976-3988 ◽  
Author(s):  
Jung Min Han ◽  
Yong Kim ◽  
Jun Sung Lee ◽  
Chang Sup Lee ◽  
Byoung Dae Lee ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Egf Receptor ◽  
Point Mutations ◽  
Dominant Negative ◽  
Growth Factor Signaling ◽  
Wild Type ◽  
Caveolin 1 ◽  
Epidermal Growth ◽  
Egf Signaling

Phospholipase D (PLD) has been suggested to mediate epidermal growth factor (EGF) signaling. However, the molecular mechanism of EGF-induced PLD activation has not yet been elucidated. We investigated the importance of the phosphorylation and compartmentalization of PLD1 in EGF signaling. EGF treatment of COS-7 cells transiently expressing PLD1 stimulated PLD1 activity and induced PLD1 phosphorylation. The EGF-induced phosphorylation of threonine147 was completely blocked and the activity of PLD1 attenuated by point mutations (S2A/T147A/S561A) of PLD1 phosphorylation sites. The expression of a dominant negative PKCα mutant by adenovirus-mediated gene transfer greatly inhibited the phosphorylation and activation of PLD1 induced by EGF in PLD1-transfected COS-7 cells. EGF-induced PLD1 phosphorylation occurred primarily in the caveolin-enriched membrane (CEM) fraction, and the kinetics of PLD1 phosphorylation in the CEM were strongly correlated with PLD1 phosphorylation in the total membrane. Interestingly, EGF-induced PLD1 phosphorylation and activation and the coimmunoprecipitation of PLD1 with caveolin-1 and the EGF receptor in the CEM were significantly attenuated in the palmitoylation-deficient C240S/C241S mutant, which did not localize to the CEM. Immunocytochemical analysis revealed that wild-type PLD1 colocalized with caveolin-1 and the EGF receptor and that phosphorylated PLD1 was localized exclusively in the plasma membrane, although some PLD1 was also detected in vesicular structures. Transfection of wild-type PLD1 but not of C240S/C241S mutant increased EGF-induced raf-1 translocation to the CEM and ERK phosphorylation. This study shows, for the first time, that EGF-induced PLD1 phosphorylation and activation occur in the CEM and that the correct localization of PLD1 to the CEM via palmitoylation is critical for EGF signaling.

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