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Metabolic regulation of cell growth and proliferation

Abstract

Cellular metabolism is at the foundation of all biological activities. The catabolic processes that support cellular bioenergetics and survival have been well studied. By contrast, how cells alter their metabolism to support anabolic biomass accumulation is less well understood. During the commitment to cell proliferation, extensive metabolic rewiring must occur in order for cells to acquire sufficient nutrients such as glucose, amino acids, lipids and nucleotides, which are necessary to support cell growth and to deal with the redox challenges that arise from the increased metabolic activity associated with anabolic processes. Defining the mechanisms of this metabolic adaptation for cell growth and proliferation is now a major focus of research. Understanding the principles that guide anabolic metabolism may ultimately enhance ways to treat diseases that involve deregulated cell growth and proliferation, such as cancer.

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Fig. 1: Glucose uptake and utilization.
Fig. 2: Amino acid sensing and acquisition.
Fig. 3: Fatty acid synthesis.
Fig. 4: Synthesis of pyrimidine and purine nucleotides.
Fig. 5: Metabolic interactions with the extracellular environment.
Fig. 6: Maintaining redox homeostasis in proliferating cells.

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Acknowledgements

The authors thank members of the Thompson laboratory for critical discussions during manuscript preparation. J.Z. is supported by the Leukemia and Lymphoma Society postdoctoral fellowship.

Reviewer information

Nature Reviews Molecular Cell Biology thanks N. Chandel, D. Sabatini, and other anonymous reviewer(s), for their contribution to the peer review of this work.

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The authors contributed equally to all aspects of the article.

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Correspondence to Craig B. Thompson.

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C.B.T. is a founder of Agios Pharmaceuticals and a member of its scientific advisory board. He is also a former member of the Board of Directors and stockholder of Merck and Charles River Laboratories. He has patents related to cellular metabolism.

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Supplementary information

Glossary

Non-essential amino acids

(NEAAs). Amino acids that can be synthesized endogenously and often participate in processes beyond protein translation, such as nucleotide synthesis.

Anaplerosis

The set of biochemical reactions that replenish the intermediates of metabolic pathways.

Minimal medium

Medium that contains the minimum nutrients possible for the growth of cells.

Positron-emission-tomography-based imaging

An imaging technique used clinically to observe metabolic processes for disease diagnosis or monitoring.

p70S6 kinase 1

(S6K1). A kinase downstream of the mTOR complex 1 signalling pathway, the activation of which can lead to increased protein synthesis.

eIF4E binding protein 1

(4EBP1). A protein translation repressor. Its activity is inhibited by phosphorylation mediated by mTOR complex 1 to increase protein synthesis.

Integrated stress response

A mechanism that usually suppresses general protein synthesis but promotes the expression of specific transcription factors to mediate cellular stress response.

Alternative open reading frames

Different open reading frames within a gene, the transcription of which can lead to different gene products that may assume different biological roles.

Cystine

The oxidized dimer form of the amino acid cysteine.

Endoplasmic reticulum (ER) stress

Cellular stress in the ER that often results from the accumulation of misfolded proteins or a failure to maintain the membrane integrity of the ER.

Lysophospholipids

Derivatives of phospholipids in which one of the two acyl chains is lost.

Sapienate

A fatty acid that is usually a component of the secretion from sebaceous glands in the skin. Sapienate can be synthesized from palmitate by desaturation.

Pentose phosphate pathway

A metabolic pathway parallel to glycolysis that involves the generation of various pentoses including ribose 5-phosphate that functions as a precursor for nucleotide synthesis.

One-carbon-unit cycle

A group of biochemical reactions that involve the transfer of the one-carbon groups between various molecules such as tetrahydrofolate, S-adenosylmethionine and vitamin B12.

Ubiquinone

A coenzyme that functions as an electron carrier in various biological processes, including the electron transport chain as part of aerobic cellular respiration.

Folate cycle

A group of biochemical reactions occurring in both the cytosolic and mitochondrial compartments that involve the metabolism of folate and its congeners. The folate cycle can provide critical metabolic intermediates for the biosynthesis of macromolecules such as nucleotides.

Antimetabolite

A chemical used in cancer treatment that often interferes with cellular nucleotide synthesis and DNA replication.

5-Fluorouracil

A medication used in cancer treatment primarily by targeting the thymidylate synthase to block thymidine synthesis.

Damage-associated molecular patterns

A group of biomolecules that are enriched upon non-infectious inflammatory responses such as during the process of wound healing.

Thioredoxin

A class of small proteins encoded by the TXN and TXN2 genes that mainly function as cellular antioxidants.

Cancer-associated fibroblasts

(CAFs). Cells derived from normal fibroblasts within the tumour microenvironment that promote cancer development.

Omentum

Layers of peritoneum that surround abdominal organs.

Malate–aspartate shuttle

A biochemical system that translocates electrons from the cytosol into the mitochondria for oxidative phosphorylation; the process involves the exchange of malate and aspartate between the two compartments.

Glutathione

A tripeptide of glutamate, cysteine and glycine that, together with glutathione-utilizing enzymes, functions to maintain cellular redox homeostasis and to detoxify electrophilic compounds such as reactive oxygen species.

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Zhu, J., Thompson, C.B. Metabolic regulation of cell growth and proliferation. Nat Rev Mol Cell Biol 20, 436–450 (2019). https://doi.org/10.1038/s41580-019-0123-5

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