Abstract
For many years, a connection between circadian clocks and cancer has been postulated. Here we describe an unexpected function for the circadian repressor CRY2 as a component of an FBXL3-containing E3 ligase that recruits T58-phosphorylated c-MYC for ubiquitylation. c-MYC is a critical regulator of cell proliferation; T58 is central in a phosphodegron long recognized as a hotspot for mutation in cancer. This site is also targeted by FBXW7, although the full machinery responsible for its turnover has remained obscure. CRY1 cannot substitute for CRY2 in promoting c-MYC degradation. Their unique functions may explain prior conflicting reports that have fueled uncertainty about the relationship between clocks and cancer. We demonstrate that c-MYC is a target of CRY2-dependent protein turnover, suggesting a molecular mechanism for circadian control of cell growth and a new paradigm for circadian protein degradation.
Keywords:
CRY2; FBXL3; MYC; circadian clock; circadian rhythm; cryptochrome; ubiquitin.
Copyright © 2016 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carrier Proteins / chemistry
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Cell Transformation, Neoplastic / genetics*
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Cell Transformation, Neoplastic / metabolism
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Cell Transformation, Neoplastic / pathology
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Circadian Clocks / genetics*
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Circadian Rhythm / genetics
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Cryptochromes / chemistry
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Cryptochromes / genetics*
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Cryptochromes / metabolism
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Cullin Proteins / chemistry
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Cullin Proteins / genetics
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Cullin Proteins / metabolism
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F-Box Proteins / chemistry
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F-Box Proteins / genetics*
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F-Box Proteins / metabolism
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Fibroblasts
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Gene Expression Regulation, Neoplastic*
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HEK293 Cells
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Humans
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Lymphoma / genetics*
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Lymphoma / metabolism
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Lymphoma / mortality
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Lymphoma / pathology
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Mice
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Mice, Knockout
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Models, Molecular
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Protein Stability
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Protein Structure, Secondary
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Proteolysis
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Proto-Oncogene Proteins c-myc / chemistry
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Proto-Oncogene Proteins c-myc / genetics*
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Proto-Oncogene Proteins c-myc / metabolism
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S-Phase Kinase-Associated Proteins / chemistry
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S-Phase Kinase-Associated Proteins / genetics
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S-Phase Kinase-Associated Proteins / metabolism
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Signal Transduction
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Survival Analysis
Substances
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Carrier Proteins
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Cry2 protein, mouse
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Cryptochromes
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Cullin 1
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Cullin Proteins
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F-Box Proteins
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Fbxl3 protein, mouse
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Myc protein, mouse
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Proto-Oncogene Proteins c-myc
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RBX1 protein, mouse
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S-Phase Kinase-Associated Proteins