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PMID: 25189770 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Ubiquitin-conjugating enzyme Ubc13 controls breast cancer metastasis through a TAK1-p38 MAP kinase cascade.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 111 ·No. 38 ·2014-09-23 ·Pages 13870-5

Wu X, Zhang W, Font-Burgada J, Palmer T, Hamil AS, Biswas SK, Poidinger M, Borcherding N, Xie Q, Ellies LG, Lytle NK, Wu LW, Fox RG, Yang J, Dowdy SF, Reya T, Karin M

Abstract

Metastatic spread is the leading cause of cancer mortality. Breast cancer (BCa) metastatic recurrence can happen years after removal of the primary tumor. Here we show that Ubc13, an E2 enzyme that catalyzes K63-linked protein polyubiquitination, is largely dispensable for primary mammary tumor growth but is required for metastatic spread and lung colonization by BCa cells. Loss of Ubc13 inhibited BCa growth and survival only at metastatic sites. Ubc13 was dispensable for transforming growth factor β (TGFβ)-induced SMAD activation but was required for activation of non-SMAD signaling via TGFβ-activating kinase 1 (TAK1) and p38, whose activity controls expression of numerous metastasis promoting genes. p38 activation restored metastatic activity to Ubc13-deficient cells, and its pharmacological inhibition attenuated BCa metastasis in mice, suggesting it is a therapeutic option for metastatic BCa.

Keywords
pre-clinical studies ubiquitination-mediated signaling
MeSH Terms
Animals Breast Neoplasms/enzymology,genetics,pathology Cell Line, Tumor Female Heterografts Humans MAP Kinase Kinase Kinases/genetics,metabolism MAP Kinase Signaling System Mice Mice, Inbred NOD Mice, SCID Neoplasm Metastasis Neoplasm Proteins/genetics,metabolism Neoplasm Transplantation Ubiquitin-Conjugating Enzymes/genetics,metabolism p38 Mitogen-Activated Protein Kinases/genetics,metabolism
Chemicals
Neoplasm Proteins UBE2N protein, human Ubiquitin-Conjugating Enzymes p38 Mitogen-Activated Protein Kinases MAP Kinase Kinase Kinases MAP kinase kinase kinase 7
Authors & Affiliations
17 authors, click to expand affiliations / ORCID
Wu Xuefeng
Laboratory of Gene Regulation and Signal Transduction and Departments of Pharmacology, Pathology, and.
Zhang Weizhou
Laboratory of Gene Regulation and Signal Transduction and Departments of Pharmacology, Pathology, and Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242;
Font-Burgada Joan
Laboratory of Gene Regulation and Signal Transduction and Departments of Pharmacology, Pathology, and.
Palmer Trenis
Departments of Pharmacology.
Hamil Alexander S
Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093;
Biswas Subhra K
Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore 138648;
Poidinger Michael
Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore 138648; Department of Biological Sciences, National University of Singapore, Singapore 117543;
Borcherding Nicholas
Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242;
Xie Qing
Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242;
Ellies Lesley G
Pathology, and.
Lytle Nikki K
Departments of Pharmacology, Sanford Consortium for Regenerative Medicine, La Jolla, CA 92093; and.
Wu Li-Wha
Laboratory of Gene Regulation and Signal Transduction and Departments of Pharmacology, Pathology, and Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.
Fox Raymond G
Departments of Pharmacology, Sanford Consortium for Regenerative Medicine, La Jolla, CA 92093; and.
Yang Jing
Departments of Pharmacology.
Dowdy Steven F
Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093;
Reya Tannishtha
Departments of Pharmacology, Sanford Consortium for Regenerative Medicine, La Jolla, CA 92093; and.
Karin Michael
Laboratory of Gene Regulation and Signal Transduction and Departments of Pharmacology, Pathology, and karinoffice@ucsd.edu.
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.1414358111
Email
karinoffice@ucsd.edu
Published
2014-09-23
Epub
2014-00-04
Pages
13870-5
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC4183333
Subset
IM
Grants
NCI NIH HHS · R01 CA168689 · United States
NCI NIH HHS · 1R01CA168689 · United States
NCI NIH HHS · CA163798 · United States
NCI NIH HHS · DP1CA174422 · United States
NCI NIH HHS · DP1 CA174422 · United States
NCI NIH HHS · T32 CA009523 · United States
NIGMS NIH HHS · T32 GM007752-36 · United States
NIAID NIH HHS · AI043477 · United States
NCI NIH HHS · 3R01CA168689-02W1 · United States
NIH HHS · DP1 OD006430 · United States
NCI NIH HHS · T32 CA009523-29 · United States
NCI NIH HHS · P30 CA023100 · United States
NIGMS NIH HHS · T32 GM007752 · United States
NCI NIH HHS · R01 CA163798 · United States
NIAID NIH HHS · R01 AI043477 · United States
Databases
GEO
GSE55649
External Links
PubMed source DOI: 10.1073/pnas.1414358111 PMC Full Text View journal details
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