The translational repressor 4E-BP1 regulates RRM2 levels and functions as a tumor suppressor in Ewing sarcoma tumors

Kelli L Goss; Stacia L Koppenhafer; Torin Waters; William W Terry; Kuo-Kuang Wen; Meng Wu; Jason Ostergaard; Peter M Gordon; David J Gordon

doi:10.1038/s41388-020-01552-0

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The translational repressor 4E-BP1 regulates RRM2 levels and functions as a tumor suppressor in Ewing sarcoma tumors

Journal article

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Peer reviewed

The translational repressor 4E-BP1 regulates RRM2 levels and functions as a tumor suppressor in Ewing sarcoma tumors

Kelli L Goss, Stacia L Koppenhafer, Torin Waters, William W Terry, Kuo-Kuang Wen, Meng Wu, Jason Ostergaard, Peter M Gordon and David J Gordon

Oncogene, Vol.40(3), pp.564-577

01/2021

DOI: 10.1038/s41388-020-01552-0

PMCID: PMC7856031

PMID: 33191406

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https://www.ncbi.nlm.nih.gov/pmc/articles/7856031View

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Abstract

Ribonucleotide reductase (RNR), which is a heterodimeric tetramer composed of RRM1 and RRM2 subunits, is the rate-limiting enzyme in the synthesis of deoxyribonucleoside triphosphates (dNTPs) and essential for both DNA replication and the repair of DNA damage. The activity of RNR is coordinated with the cell cycle and regulated by fluctuations in the level of the RRM2 subunit. Multiple cancer types, including Ewing sarcoma tumors, are sensitive to inhibitors of RNR or a reduction in the levels of either the RRM1 or RRM2 subunits of RNR. Here, we show that the expression of the RRM2 protein is dependent on active protein synthesis and that 4E-BP1, a repressor of cap-dependent protein translation, specifically regulates the level of the RRM2 protein. Furthermore, inhibition of mTORC1/2, but not mTORC1, activates 4E-BP1, inhibits protein synthesis, and reduces the level of the RRM2 protein in multiple sarcoma cell lines. This effect of mTORC1/2 inhibitors on protein synthesis and RRM2 levels was rescued in cell lines with the CRISPR/Cas9-mediated knockout of 4E-BP1. In addition, the inducible expression of a mutant 4E-BP1 protein that cannot be phosphorylated by mTOR blocked protein synthesis and inhibited the growth of Ewing sarcoma cells in vitro and in vivo in a xenograft. Overall, these results provide insight into the multifaceted regulation of RRM2 protein levels and identify a regulatory link between protein translation and DNA replication.

Adaptor Proteins, Signal Transducing - genetics

Adaptor Proteins, Signal Transducing - metabolism

Cell Cycle Proteins - genetics

Cell Cycle Proteins - metabolism

Humans

Jurkat Cells

K562 Cells

Ribonucleoside Diphosphate Reductase - genetics

Ribonucleoside Diphosphate Reductase - metabolism

Sarcoma, Ewing - genetics

Sarcoma, Ewing - metabolism

Sarcoma, Ewing - pathology

Tumor Suppressor Proteins - genetics

Tumor Suppressor Proteins - metabolism

Details

Title: Subtitle: The translational repressor 4E-BP1 regulates RRM2 levels and functions as a tumor suppressor in Ewing sarcoma tumors
Creators: Kelli L Goss - University of Iowa
Stacia L Koppenhafer - University of Iowa
Torin Waters - University of Iowa
William W Terry - University of Iowa
Kuo-Kuang Wen - University of Iowa
Meng Wu - University of Iowa
Jason Ostergaard - University of Minnesota
Peter M Gordon - University of Minnesota
David J Gordon - University of Iowa
Resource Type: Journal article
Publication Details: Oncogene, Vol.40(3), pp.564-577
DOI: 10.1038/s41388-020-01552-0
PMID: 33191406
PMCID: PMC7856031
NLM abbreviation: Oncogene
ISSN: 0950-9232
eISSN: 1476-5594
Grant note: R50 CA243786 / NCI NIH HHS P30 CA016672 / NCI NIH HHS R37 CA217910 / NCI NIH HHS P30 CA086862 / NCI NIH HHS
Language: English
Date published: 01/2021
Academic Unit: Pharmacy; Stead Family Department of Pediatrics; Hematology/Oncology
Record Identifier: 9984353799802771

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