Oncogenic Myc Induces Expression of Glutamine Synthetase through Promoter Demethylation

Bott, Alex J.; Peng, I‐Chen; Fan, Ying; Faubert, Brandon; Zhao, Lu; Li, Jinyu; Neidler, Sarah; Sun, Yu; Jaber, Nadia; Krokowski, Dawid; Lu, Wenyun; Pan, Jing; Powers, Scott; Rabinowitz, Joshua D.; Hatzoglou, Maria; Murphy, Daniel J.; Jones, Russell G.; Wu, Song; Girnun, Geoffrey D.; Zong, Wei‐Xing

doi:10.1016/j.cmet.2015.09.025

Cited by 191 publications

(183 citation statements)

References 33 publications

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“…Some tumors, however, also upregulate GS and glutamine synthesis (He et al, 2010; van der Vos et al, 2012). In a number of breast cancer and glioblastoma cell lines, increased GS activity and de novo synthesis of glutamine is essential for cell survival, growth, and proliferation under limited supply of exogenous glutamine (Bott et al, 2015; Tardito et al, 2015). In such cases, newly synthesized glutamine mainly contributes to the biosynthesis of nucleotides and asparagine, and to the transport of essential amino acids.…”

Section: Mitochondria Integrate Catabolism Anabolism and Signalingmentioning

confidence: 99%

Mitochondria and Cancer

2016

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Decades ago Otto Warburg observed that cancers ferment glucose in the presence of oxygen, suggesting that defects in mitochondrial respiration may be the underlying cause of cancer. We now know that the genetic events, which drive aberrant cancer cell proliferation, also alter biochemical metabolism including promoting aerobic glycolysis, but do not typically impair mitochondrial function. Mitochondria supply energy, provide building blocks for new cells, and control redox homeostasis, oncogenic signaling, innate immunity and apoptosis. Indeed, mitochondrial biogenesis and quality control are often upregulated in cancers. While some cancers have mutations in nuclear-encoded mitochondrial tricarboxylic acid (TCA) cycle enzymes that produce oncogenic metabolites, there is negative selection for pathogenic mitochondrial genome mutations. Eliminating mitochondrial DNA limits tumorigenesis and rare human tumors with mutant mitochondrial genomes are relatively benign. Thus, mitochondria play a central and multi-functional role in malignant tumor progression, and targeting mitochondria provides therapeutic opportunities.

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Section: Mitochondria Integrate Catabolism Anabolism and Signalingmentioning

confidence: 99%

Mitochondria and Cancer

2016

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“…The expression of pyruvate carboxylase, which can provide carbon to the TCA cycle through its conversion of pyruvate to oxaloacetate, represents a potential mechanism for glutaminase independence 120,175 . Glutamine synthetase (GLUL) expression may also predict glutamine independence and promote BPTES resistance 171,[176][177][178] .…”

Section: Therapymentioning

confidence: 99%

Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

Altman¹,

Stine²,

Dang³

2016

Nat Rev Cancer

222

108

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The resurgence of research in cancer metabolism has recently broadened interests beyond glucose and the Warburg Effect to other nutrients including glutamine. Because oncogenic alterations of metabolism render cancer cells addicted to nutrients, pathways involved in glycolysis or glutaminolysis could be exploited for therapeutic purposes. In this Review, we provide an updated overview of glutamine metabolism and its involvement in tumorigenesis in vitro and in vivo, and explore the recent potential applications of basic science discoveries in the clinical setting.

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“…As a result, some tumor cells require large amounts of exogenous glutamine to generate building blocks and energy for their growth and survival. In contrast, various tumor cell lines with high expression levels of GS enzyme can synthesize glutamine de novo and can grow and proliferate in the absence of exogenous glutamine (12)(13)(14).Befitting its critical role in nitrogen metabolism, GS activity is tightly regulated. Pioneering studies by Stadtman's group (15) and others demonstrated that bacterial GS is subject to complex feedback regulation by glutamine and downstream metabolites by reversible adenylylation and deadenylylation of a specific tyrosine residue, resulting in the inactivation of .…”

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p97/VCP promotes degradation of CRBN substrate glutamine synthetase and neosubstrates

Nguyen

Lu³

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Glutamine synthetase (GS) plays an essential role in metabolism by catalyzing the synthesis of glutamine from glutamate and ammonia. Our recent study showed that CRBN, a direct protein target for the teratogenic and antitumor activities of immunomodulatory drugs such as thalidomide, lenalidomide, and pomalidomide, recognizes an acetyl degron of GS, resulting in ubiquitylation and degradation of GS in response to glutamine. Here, we report that valosin-containing protein (VCP)/p97 promotes the degradation of ubiquitylated GS, resulting in its accumulation in cells with compromised p97 function. Notably, p97 is also required for the degradation of all four known CRBN neo-substrates [Ikaros family zinc finger proteins 1 (IKZF1) and 3 (IKZF3), casein kinase 1α (CK1α), and the translation termination factor GSPT1] whose ubiquitylation is induced by immunomodulatory drugs. Together, these data point to an unexpectedly intimate relationship between the E3 ubiquitin ligase CRL4 CRBN and p97 pathways.lutamine plays important roles in many cellular processes, including oxidative metabolism and ATP generation, biosynthesis of proteins, lipids, and nucleic acids, and cell growth and proliferation through the regulation of the mTOR signaling pathway, translation, and autophagy (1, 2). In mammals, it is the most abundant amino acid in plasma with a concentration of 0.5-0.9 mM (3), accounting for ∼20% of its free amino acid pool. Glutamine synthetase (GS) is the only enzyme that is capable of de novo synthesis of glutamine and also functions to detoxify glutamate and ammonia, depending on tissue localization. Skeletal muscles and lungs are major sites of glutamine synthesis, whereas cells of the gut and the immune system, such as lymphocytes and macrophages, consume large amounts of glutamine in plasma (4). GS protects neurons against excitotoxicity by converting glutamate into glutamine in brain, detoxifies ammonia in liver, and maintains physiologic pH in kidney (5). In an attempt to investigate the role of GS in development, He et al. generated GS-knockout mice and reported that GS is essential in early embryogenesis, because deletion of the murine GLUL gene causes lethality at the blastocyst stage (embryonic day 3.5) (6). Interestingly, mouse ES cells maintain pluripotency and proliferate when grown in the absence of exogenous glutamine (7). However, inhibition of GS with the small molecule methionine sulfoximine (MSO) is sufficient to block the proliferation of ES cells in glutamine-free medium (7). In humans, congenital systemic glutamine deficiency caused by homozygous GS mutations results in multiorgan failure and neonatal death (8).Recent studies highlight the importance of glutamine metabolism in metabolic reprogramming, because many tumor cells display "glutamine addiction" (9). Activation of oncogenes such as MYC, KRAS, and HIF1α and/or loss of tumor suppressor genes including p53 can directly mediate the reprogramming of glutamine metabolism by selectively activating their downstream signaling or metabolic pathway...

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Oncogenic Myc Induces Expression of Glutamine Synthetase through Promoter Demethylation

Cited by 191 publications

References 33 publications

Mitochondria and Cancer

Mitochondria and Cancer

Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

p97/VCP promotes degradation of CRBN substrate glutamine synthetase and neosubstrates

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