The Transcription Factor Myc Controls Metabolic Reprogramming upon T Lymphocyte Activation

Wang, Ruoning; Dillon, Christopher P.; Shi, Lewis Zhichang; Milasta, Sandra; Robert, Caroline; Finkelstein, David; McCormick, Laura L.; Fitzgerald, Patrick; Chi, Hongbo; Munger, Joshua; Green, Douglas R.

doi:10.1016/j.immuni.2011.09.021

Cited by 1,797 publications

(2,455 citation statements)

References 56 publications

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“…Consistent with the conflicting reports of the role of LGA in cancer, its expression can be upregulated both by the tumor suppressor p53 [62,118,119] and by the protooncoproteins c-Myc (reported in activated CD4 + T cells) and n-Myc [120,121].…”

supporting

confidence: 63%

A Tale of Two Glutaminases: Homologous Enzymes with Distinct Roles in Tumorigenesis

2017

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Many cancer cells exhibit an altered metabolic phenotype, in which glutamine consumption is upregulated relative to healthy cells. This metabolic reprogramming often depends upon mitochondrial glutaminase activity, which converts glutamine to glutamate, a key precursor for biosynthetic and bioenergetic processes. Two isozymes of glutaminase exist, a kidney-type (GLS) and a liver-type enzyme (GLS2 or LGA). While a majority of studies have focused on GLS, here we summarize key findings on both glutaminases, describing their structure and function, their roles in cancer and pharmacological approaches to inhibiting their activities.

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supporting

confidence: 63%

A Tale of Two Glutaminases: Homologous Enzymes with Distinct Roles in Tumorigenesis

2017

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“…Alterations in cell metabolism may indirectly influence OGT activity by affecting the availability of UDP-GlcNAc, which serves as the nucleotide sugar donor for OGT (26)(27)(28). After activation, T cells exhibit a dramatic increase in the consumption of glucose and glutamine (75). Both glucose and glutamine provide important precursors for the hexosamine biosynthesis pathway, which is responsible for the generation of UDP-GlcNAc.…”

Section: Discussionmentioning

confidence: 99%

“…3A, 3B). The transcription factor c-myc is clearly essential for increased O-GlcNAc levels in activated T cells (85), probably due, in part, to its role in driving expression of nutrient transporters (75). At the same time, OGT activity is critical for stabilizing c-myc expression (35,87).…”

Section: Discussionmentioning

confidence: 99%

Global Analysis of O-GlcNAc Glycoproteins in Activated Human T Cells

Lund

Elias

Davis

2016

The Journal of Immunology

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T cell activation in response to Ag is largely regulated by protein posttranslational modifications. Although phosphorylation has been extensively characterized in T cells, much less is known about the glycosylation of serine/threonine residues by O-linked N-acetylglucosamine (O-GlcNAc). Given that O-GlcNAc appears to regulate cell signaling pathways and protein activity similarly to phosphorylation, we performed a comprehensive analysis of O-GlcNAc during T cell activation to address the functional importance of this modification and to identify the modified proteins. Activation of T cells through the TCR resulted in a global elevation of O-GlcNAc levels and in the absence of O-GlcNAc, IL-2 production and proliferation were compromised. T cell activation also led to changes in the relative expression of O-GlcNAc transferase (OGT) isoforms and accumulation of OGT at the immunological synapse of murine T cells. Using a glycoproteomics approach, we identified >200 O-GlcNAc proteins in human T cells. Many of the identified proteins had a functional relationship to RNA metabolism, and consistent with a connection between O-GlcNAc and RNA, inhibition of OGT impaired nascent RNA synthesis upon T cell activation. Overall, our studies provide a global analysis of O-GlcNAc dynamics during T cell activation and the first characterization, to our knowledge, of the O-GlcNAc glycoproteome in human T cells.

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“…This idea is supported by data from Rag1 −/− × Myc V394D mice, which when stimulated with αCD3 antibodies were less efficient in producing DP cells than Rag1 −/− mice with a functional c-Myc protein that still binds to Miz-1. In addition, CD71 and CD98, key metabolic genes up-regulated at the DNto-DP transition and direct targets of c-Myc (33,34), are not upregulated on Rag1 −/− × Miz-1 ΔPOZ DN4 cells after mitogenic stimulation. Thus, we propose that, in contrast to the differentiation of DN3 cells to DN4, the DN4-to-DP transition represents a step requiring a functional c-Myc/Miz-1 complex.…”

Section: Cd19mentioning

confidence: 92%

Miz-1 regulates translation of Trp53 via ribosomal protein L22 in cells undergoing V(D)J recombination

Rashkovan

Vadnais

Ross

et al. 2014

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

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To be effective, the adaptive immune response requires a large repertoire of antigen receptors, which are generated through V(D)J recombination in lymphoid precursors. These precursors must be protected from DNA damage-induced cell death, however, because V(D)J recombination generates double-strand breaks and may activate p53. Here we show that the BTB/POZ domain protein Miz-1 restricts p53-dependent induction of apoptosis in both pro-B and DN3a pre-T cells that actively rearrange antigen receptor genes. Miz-1 exerts this function by directly activating the gene for ribosomal protein L22 (Rpl22), which binds to p53 mRNA and negatively regulates its translation. This mechanism limits p53 expression levels and thus contains its apoptosis-inducing functions in lymphocytes, precisely at differentiation stages in which V(D)J recombination occurs.T he development of T lymphocytes starts with early thymic progenitors (ETPs) that first enter the thymus after transiting through the bloodstream from the bone marrow. These progenitor cells differentiate through four CD4 − CD8 − double-negative stages of development (DN1-4) before becoming first CD4 + CD8 + double-positive (DP) cells and then either CD4 + or CD8 + single positive T cells. The four DN subsets are differentiated based on their expression of the cell surface markers CD44 and CD25. Cells at the DN3 stage (CD44 − CD25 + ) are fully committed to the T cell lineage and require signaling through cytokine receptors and Notch1 to survive (1). This DN3 population can be further subdivided into DN3a and DN3b based on their size and CD27 surface expression.Importantly, DN3a cells (FSC lo CD27 lo ) actively rearrange the genes encoding the T cell receptor β (TCRβ) chain through V(D)J recombination (1-3). Those DN3a cells that do not productively rearrange the TCRβ locus on both alleles are eliminated by apoptosis. In contrast, cells that productively rearrange their TCRβ chain genes are selected and become DN3b cells (FSC hi CD27 hi ), which express a pre-T cell receptor (pre-TCR), a heterodimer between the TCRβ chain and a pTα chain. DN3b cells grow in size, owing in part to increased metabolic activity (4), and give rise to the (CD44 − CD25 − ) DN4 subset, which in turn rapidly expands to produce CD4 + CD8 + DP cells.

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The Transcription Factor Myc Controls Metabolic Reprogramming upon T Lymphocyte Activation

Cited by 1,797 publications

References 56 publications

A Tale of Two Glutaminases: Homologous Enzymes with Distinct Roles in Tumorigenesis

A Tale of Two Glutaminases: Homologous Enzymes with Distinct Roles in Tumorigenesis

Global Analysis of O-GlcNAc Glycoproteins in Activated Human T Cells

Miz-1 regulates translation of Trp53 via ribosomal protein L22 in cells undergoing V(D)J recombination

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