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USP21 deubiquitinase elevates macropinocytosis to enable oncogenic KRAS bypass in pancreatic cancer
Activating mutations in KRAS (KRAS*) are present in nearly all pancreatic ductal adenocarcinoma (PDAC) cases and critical for tumor maintenance. By using an inducible KRAS* PDAC mouse model, we identified a deubiquitinase USP21-driven resistance mechanism to anti-KRAS* therapy. USP21 promotes KRAS*-...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494209/ https://www.ncbi.nlm.nih.gov/pubmed/34531315 http://dx.doi.org/10.1101/gad.348787.121 |
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author | Hou, Pingping Ma, Xingdi Yang, Zecheng Zhang, Qiang Wu, Chang-Jiun Li, Jun Tan, Lin Yao, Wantong Yan, Liang Zhou, Xin Kimmelman, Alec C. Lorenzi, Philip L. Zhang, Jianhua Jiang, Shan Spring, Denise Wang, Y. Alan DePinho, Ronald A. |
author_facet | Hou, Pingping Ma, Xingdi Yang, Zecheng Zhang, Qiang Wu, Chang-Jiun Li, Jun Tan, Lin Yao, Wantong Yan, Liang Zhou, Xin Kimmelman, Alec C. Lorenzi, Philip L. Zhang, Jianhua Jiang, Shan Spring, Denise Wang, Y. Alan DePinho, Ronald A. |
author_sort | Hou, Pingping |
collection | PubMed |
description | Activating mutations in KRAS (KRAS*) are present in nearly all pancreatic ductal adenocarcinoma (PDAC) cases and critical for tumor maintenance. By using an inducible KRAS* PDAC mouse model, we identified a deubiquitinase USP21-driven resistance mechanism to anti-KRAS* therapy. USP21 promotes KRAS*-independent tumor growth via its regulation of MARK3-induced macropinocytosis, which serves to maintain intracellular amino acid levels for anabolic growth. The USP21-mediated KRAS* bypass, coupled with the frequent amplification of USP21 in human PDAC tumors, encourages the assessment of USP21 as a novel drug target as well as a potential parameter that may affect responsiveness to emergent anti-KRAS* therapy. |
format | Online Article Text |
id | pubmed-8494209 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-84942092022-04-01 USP21 deubiquitinase elevates macropinocytosis to enable oncogenic KRAS bypass in pancreatic cancer Hou, Pingping Ma, Xingdi Yang, Zecheng Zhang, Qiang Wu, Chang-Jiun Li, Jun Tan, Lin Yao, Wantong Yan, Liang Zhou, Xin Kimmelman, Alec C. Lorenzi, Philip L. Zhang, Jianhua Jiang, Shan Spring, Denise Wang, Y. Alan DePinho, Ronald A. Genes Dev Research Communication Activating mutations in KRAS (KRAS*) are present in nearly all pancreatic ductal adenocarcinoma (PDAC) cases and critical for tumor maintenance. By using an inducible KRAS* PDAC mouse model, we identified a deubiquitinase USP21-driven resistance mechanism to anti-KRAS* therapy. USP21 promotes KRAS*-independent tumor growth via its regulation of MARK3-induced macropinocytosis, which serves to maintain intracellular amino acid levels for anabolic growth. The USP21-mediated KRAS* bypass, coupled with the frequent amplification of USP21 in human PDAC tumors, encourages the assessment of USP21 as a novel drug target as well as a potential parameter that may affect responsiveness to emergent anti-KRAS* therapy. Cold Spring Harbor Laboratory Press 2021-10-01 /pmc/articles/PMC8494209/ /pubmed/34531315 http://dx.doi.org/10.1101/gad.348787.121 Text en © 2021 Hou et al.; Published by Cold Spring Harbor Laboratory Press https://creativecommons.org/licenses/by-nc/4.0/This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) . |
spellingShingle | Research Communication Hou, Pingping Ma, Xingdi Yang, Zecheng Zhang, Qiang Wu, Chang-Jiun Li, Jun Tan, Lin Yao, Wantong Yan, Liang Zhou, Xin Kimmelman, Alec C. Lorenzi, Philip L. Zhang, Jianhua Jiang, Shan Spring, Denise Wang, Y. Alan DePinho, Ronald A. USP21 deubiquitinase elevates macropinocytosis to enable oncogenic KRAS bypass in pancreatic cancer |
title | USP21 deubiquitinase elevates macropinocytosis to enable oncogenic KRAS bypass in pancreatic cancer |
title_full | USP21 deubiquitinase elevates macropinocytosis to enable oncogenic KRAS bypass in pancreatic cancer |
title_fullStr | USP21 deubiquitinase elevates macropinocytosis to enable oncogenic KRAS bypass in pancreatic cancer |
title_full_unstemmed | USP21 deubiquitinase elevates macropinocytosis to enable oncogenic KRAS bypass in pancreatic cancer |
title_short | USP21 deubiquitinase elevates macropinocytosis to enable oncogenic KRAS bypass in pancreatic cancer |
title_sort | usp21 deubiquitinase elevates macropinocytosis to enable oncogenic kras bypass in pancreatic cancer |
topic | Research Communication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494209/ https://www.ncbi.nlm.nih.gov/pubmed/34531315 http://dx.doi.org/10.1101/gad.348787.121 |
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