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Longchamp, Alban,Mirabella, Teodelinda,Arduini, Alessandro,MacArthur, Michael R.,Das, Abhirup,Treviñ,o-Villarreal, J. Humberto,Hine, Christopher,Ben-Sahra, Issam,Knudsen, Nelson H.,Brace, Lear E Elsevier 2018 Cell Vol.173 No.1
<P><B>Summary</B></P> <P>Angiogenesis, the formation of new blood vessels by endothelial cells (ECs), is an adaptive response to oxygen/nutrient deprivation orchestrated by vascular endothelial growth factor (VEGF) upon ischemia or exercise. Hypoxia is the best-understood trigger of VEGF expression via the transcription factor HIF1α. Nutrient deprivation is inseparable from hypoxia during ischemia, yet its role in angiogenesis is poorly characterized. Here, we identified sulfur amino acid restriction as a proangiogenic trigger, promoting increased VEGF expression, migration and sprouting in ECs <I>in vitro</I>, and increased capillary density in mouse skeletal muscle <I>in vivo</I> via the GCN2/ATF4 amino acid starvation response pathway independent of hypoxia or HIF1α. We also identified a requirement for cystathionine-γ-lyase in VEGF-dependent angiogenesis via increased hydrogen sulfide (H<SUB>2</SUB>S) production. H<SUB>2</SUB>S mediated its proangiogenic effects in part by inhibiting mitochondrial electron transport and oxidative phosphorylation, resulting in increased glucose uptake and glycolytic ATP production.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Sulfur amino acid (SAA) restriction triggers angiogenesis independent of hypoxia or HIF1α </LI> <LI> GCN2/ATF4 pathway regulates VEGF and CGL expression upon SAA restriction in ECs </LI> <LI> CGL is required for skeletal muscle angiogenesis activated by diet or exercise </LI> <LI> H<SUB>2</SUB>S triggers glucose uptake, glycolysis, and PPP concomitant with OXPHOS inhibition in ECs </LI> </UL> </P> <P><B>Graphical Abstract</B></P> <P>[DISPLAY OMISSION]</P>
Park, Duck Hwan,Mirabella, Rossana,Bronstein, Philip A.,Preston, Gail M.,Haring, Michel A.,Lim, Chun Keun,Collmer, Alan,Schuurink, Robert C. Blackwell Publishing Ltd 2010 The Plant journal Vol.64 No.2
<P>Summary</P><P><I>Pseudomonas syringae</I> pv. <I>tomato</I> DC3000 is a bacterial pathogen of Arabidopsis and tomato that grows in the apoplast. The non-protein amino acid &ggr;-amino butyric acid (GABA) is produced by Arabidopsis and tomato and is the most abundant amino acid in the apoplastic fluid of tomato. The DC3000 genome harbors three genes annotated as <I>gabT</I> GABA transaminases. A DC3000 mutant lacking all three <I>gabT</I> genes was constructed and found to be unable to utilize GABA as a sole carbon and nitrogen source. In complete minimal media supplemented with GABA, the mutant grew less well than wild-type DC3000 and showed strongly reduced expression of <I>hrpL</I> and <I>avrPto</I>, which encode an alternative sigma factor and effector, respectively, associated with the type III secretion system. The growth of the <I>gabT</I> triple mutant was weakly reduced in Arabidopsis ecotype <I>Landberg erecta</I> (L<I>er</I>) and strongly reduced in the L<I>er pop2-1</I> GABA transaminase-deficient mutant that accumulates higher levels of GABA. Much of the ability to grow on GABA-amended minimal media or in Arabidopsis <I>pop2-1</I> leaves could be restored to the <I>gabT</I> triple mutant by expression <I>in trans</I> of just <I>gabT2.</I> The ability of DC3000 to elicit the hypersensitive response (HR) in tobacco leaves is dependent upon deployment of the type III secretion system, and the <I>gabT</I> triple mutant was less able than wild-type DC3000 to elicit this HR when bacteria were infiltrated along with GABA at levels of 1 m<SMALL>M</SMALL> or more. GABA may have multiple effects on <I>P. syringae</I>–plant interactions, with elevated levels increasing disease resistance.</P>
Lim, Chae-Seok,Kang, Xi,Mirabella, Vincent,Zhang, Huaye,Bu, Qian,Araki, Yoichi,Hoang, Elizabeth T.,Wang, Shiqiang,Shen, Ying,Choi, Sukwoo,Kaang, Bong-Kiun,Chang, Qiang,Pang, Zhiping P.,Huganir, Richar Cold Spring Harbor Laboratory Press 2017 Genes & development Vol.31 No.6
<P>Rapid advances in genetics are linking mutations on genes to diseases at an exponential rate, yet characterizing the gene mutation-cell behavior relationships essential for precision medicine remains a daunting task. More than 350 mutations on small GTPase BRaf are associated with various tumors, and similar to 40 mutations are associated with the neurodevelopmental disorder cardio-facio-cutaneous syndrome (CFC). Wedeveloped a fast cost-effective lentivirus-based rapid gene replacement method to interrogate the physiopathology of BRaf and similar to 50 disease-linked BRaf mutants, including all CFC-linked mutants. Analysis of simultaneous multiple patch-clamp recordings from 6068 pairs of rat neurons with validation in additional mouse and human neurons and multiple learning tests from 1486 rats identified BRaf as the key missing signaling effector in the common synaptic NMDA-R-CaMKII-SynGap-Ras-BRaf-MEK-ERK transduction cascade. Moreover, the analysis creates the original big data unveiling three general features of BRaf signaling. This study establishes the first efficient procedure that permits large-scale functional analysis of human disease-linked mutations essential for precision medicine.</P>