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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*-...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2021
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.
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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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