Disrupting the Myc-Tfeb circuit confers vulnerabilities targeting amino acid homeostasis and provokes metabolic anergy
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ABSTRACT:
PROVIDER: PRJNA643255 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12120529_1.fastq.gz | Fastqsanger.gz | |||
| SRR12120529_2.fastq.gz | Fastqsanger.gz | |||
| SRR12120530_1.fastq.gz | Fastqsanger.gz | |||
| SRR12120530_2.fastq.gz | Fastqsanger.gz | |||
| SRR12120531_1.fastq.gz | Fastqsanger.gz |
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Project description:Metabolic reprogramming sustains cancer cell anabolism, and MYC oncoproteins control many aspects of this response. Normal cells adapt to nutrient-limiting conditions by activating autophagy, which is required for amino acid (AA) homeostasis. Surprisingly, here we report the autophagy-lysosomal pathway is suppressed by Myc in normal B cells, in premalignant and neoplastic B cells of Eµ-Myc transgenic mice, and in MYC-driven human Burkitt lymphoma. Myc suppresses autophagy by antagonizing expression and function of TFEB, a master regulator of autophagy/lysosome genes. Notably, compensatory mechanisms that sustain AA pools in MYC-expressing B cells include marked increases in AA transport and coordinate induction of the proteasome. Finally, reactivation of the autophagy-lysosomal pathway by constitutively active TFEB disables the malignant state, by perturbing mitochondrial functions and disrupting proteasome activity, amino acid transport, and disrupts amino acid and nucleotide metabolism, leading to growth arrest and apoptosis. This scenario provides therapeutic opportunities that disable MYC-driven tumorigenesis, including AA restriction and treatment with proteasome inhibitors.
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Project description:MYC family oncoproteins are regulators of metabolic reprogramming that sustains cancer cell anabolism. Normal cells adapt to nutrient-limiting conditions by activating autophagy, which is required for amino acid (AA) homeostasis. Here we report that the autophagy pathway is suppressed by Myc in normal B cells, in premalignant and neoplastic B cells of Eμ-Myc transgenic mice, and in human MYC-driven Burkitt lymphoma. Myc suppresses autophagy by antagonizing the expression and function of transcription factor EB (TFEB), a master regulator of autophagy. Mechanisms that sustained AA pools in MYC-expressing B cells include coordinated induction of the proteasome and increases in AA transport. Reactivation of the autophagy-lysosomal pathway by TFEB disabled the malignant state by disrupting mitochondrial functions, proteasome activity, AA transport, and AA and nucleotide metabolism, leading to metabolic anergy, growth arrest, and apoptosis. This phenotype provides therapeutic opportunities to disable MYC-driven malignancies, including AA restriction and treatment with proteasome inhibitors.SignificanceMYC suppresses TFEB and autophagy and controls amino acid homeostasis by upregulating amino acid transport and the proteasome, and reactivation of TFEB disables the metabolism of MYC-driven tumors.
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Project description:T cell receptor(TCR) engagement in the absence of costimulation leads to a state of T cell tolerance known as anergy. Anergy induction requires new protein synthesis since it is inhibited by cycloheximide. In this experiment, we tried to figure out kinetic properties of the gene expression in anergy induction phase and the subsequent anergy maintenance phase.
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