Argininosuccinic aciduria: from a monogenic to a complex disorder

Erez, Ayelet

doi:10.1038/gim.2012.166

Cited by 34 publications

(31 citation statements)

References 47 publications

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“…Upregulated ASS1 not only promotes Arg biosynthesis to relieve Arg-auxotrophic pressure, but also feedbacks to downregulate c-Myc and Axl expression. This feedback mechanism provides a self-guarding mechanism for ASS1 homeostasis control because elevated expression of ASS1 may result in over-production of argininosuccinate, which is cytotoxic 10 . Furthermore, the self-regulatory mechanism of ASS1 may be an integral part of metabolic flux in urea cycle regulation.…”

Section: Discussionmentioning

confidence: 99%

Gas6/Axl is the sensor of arginine-auxotrophic response in targeted chemotherapy with arginine-depleting agents

et al. 2015

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Many human malignancies lack de novo biosynthesis of arginine (Arg) because the key enzyme argininosuccinate synthetase 1 (ASS1) is silenced. These tumors acquire ectopic Arg for survival, and depleting this source by Arg-depleting recombinant enzyme ADI-PEG20 results in cell death. Mechanisms underlying Arg auxotrophy in these tumors and how they respond to Arg-auxotrophic stress are poorly understood. Here, we report that an immediate early event of Arg-auxotrophic response involves ROS-mediated secretion of Gas6 which interacts with its receptor Axl and activates the downstream Ras/PI3K/Akt growth signal leading to accumulation of c-Myc by protein stabilization. Arg-auxotrophic challenge also transcriptionally upregulates c-Myc expression which feedbacks to enhance Axl expression. c-Myc is a positive regulator of ASS1, but elevated ASS1 feedbacks to suppress c-Myc and Axl. Our results revealed multiple inter-regulatory pathways in Arg-auxotrophic response consisting of Axl, c-Myc, ASS1 that regulate Arg homeostasis and ADI-PEG20 sensitivity. These pathways provide potential targets for improving the efficacy of treating Arg-auxotrophic tumors using Arg deprivation strategies.

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Section: Discussionmentioning

confidence: 99%

Gas6/Axl is the sensor of arginine-auxotrophic response in targeted chemotherapy with arginine-depleting agents

et al. 2015

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“…5). These functions result from participation of these enzymes in protein complexes, altered localization of the enzymes to different subcellular compartments and noncanonical functions, some of which are independent of the catalytic function 86 . Increased expression of these noncanonical functions implies that a complete understanding of IEM pathophysiology will require thinking beyond the metabolic network.…”

Section: Non-metabolic Roles Of Enzymesmentioning

confidence: 99%

Metabolic dysregulation in monogenic disorders and cancer — finding method in madness

Erez

DeBerardinis

2015

Nat Rev Cancer

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Cancer is a prime example of a disease process in which carcinogenic and metabolic changes are intertwined to promote cell survival and growth. One approach to unravel this complex relationship is by studying rare, monogenic disorders caused by mutations in genes encoding metabolic enzymes or regulators. There are hundreds of these diseases, most of which manifest in childhood and are collectively termed 'inborn errors of metabolism' (IEMs). Several IEMs demonstrate the consequences of chronic, systemic loss of a particular metabolic activity that can result in malignancy. In this Opinion article, we present a conceptual categorization of IEMs associated with cancer and discuss how assessment of these rare diseases might inform us about the biological foundations of common types of cancer and opportunities for cancer diagnosis and therapy.

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“…The ornithine circle (also known as the urea cycle) is related to TCA cycle through the synthesis and catabolism of argininosuccinate. Ornithine is transformed to argininosuccinate, which is then cleaved to form arginine and fumarate by argininosuccinase in the ornithine circle, after which fumarate enters the TCA cycle [22]. l-Ornithine hydrochloride may be used as a carbon source during 168-240 h as a result of low levels of residual sugar.…”

Section: Metabolic Regulation Based On Compound Transformation Mechanmentioning

confidence: 99%

Designing novel glucose/ornithine replenishment strategies by biosynthetic and bioprocess analysis to improve fibrinolytic FGFC1 production by the marine fungus Stachybotrys longispora

Wang

et al. 2015

Process Biochemistry

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Argininosuccinic aciduria: from a monogenic to a complex disorder

Abstract: Genetics in medicine | Volume 15 | Number 4 |

Cited by 34 publications

References 47 publications

Gas6/Axl is the sensor of arginine-auxotrophic response in targeted chemotherapy with arginine-depleting agents

Gas6/Axl is the sensor of arginine-auxotrophic response in targeted chemotherapy with arginine-depleting agents

Metabolic dysregulation in monogenic disorders and cancer — finding method in madness

Designing novel glucose/ornithine replenishment strategies by biosynthetic and bioprocess analysis to improve fibrinolytic FGFC1 production by the marine fungus Stachybotrys longispora

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