Journal article
Ubiquitin-conjugating enzyme Ubc13 controls breast cancer metastasis through a TAK1-p38 MAP kinase cascade
Proceedings of the National Academy of Sciences - PNAS, Vol.111(38), pp.13870-13875
09/23/2014
DOI: 10.1073/pnas.1414358111
PMCID: PMC4183333
PMID: 25189770
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.
Details
- Title: Subtitle
- Ubiquitin-conjugating enzyme Ubc13 controls breast cancer metastasis through a TAK1-p38 MAP kinase cascade
- Creators
- Xuefeng Wu - University of California, San DiegoWeizhou Zhang - University of Iowa, Radiation OncologyJoan Font-Burgada - Laboratory of Gene Regulation and Signal Transduction and Departments of Pharmacology, Pathology, andTrenis Palmer - Departments of PharmacologyAlexander S Hamil - Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093Subhra K Biswas - Singapore Immunology Network, Agency for Science, Technology and Research (ASTAR), Singapore 138648Michael Poidinger - Singapore Immunology Network, Agency for Science, Technology and Research (ASTAR), Singapore 138648; Department of Biological Sciences, National University of Singapore, Singapore 117543Nicholas Borcherding - University of Iowa, DermatologyQing Xie - Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242Lesley G Ellies - Pathology, andNikki K Lytle - Departments of Pharmacology, Sanford Consortium for Regenerative Medicine, La Jolla, CA 92093; andLi-Wha WuRaymond G Fox - Departments of Pharmacology, Sanford Consortium for Regenerative Medicine, La Jolla, CA 92093; andJing Yang - Departments of PharmacologySteven F Dowdy - Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093Tannishtha Reya - Departments of Pharmacology, Sanford Consortium for Regenerative Medicine, La Jolla, CA 92093; andMichael Karin - Laboratory of Gene Regulation and Signal Transduction and Departments of Pharmacology, Pathology, and karinoffice@ucsd.edu
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.111(38), pp.13870-13875
- DOI
- 10.1073/pnas.1414358111
- PMID
- 25189770
- PMCID
- PMC4183333
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Grant note
- CA163798 / NCI NIH HHS R01 CA163798 / NCI NIH HHS T32 GM007752-36 / NIGMS NIH HHS AI043477 / NIAID NIH HHS DP1 CA174422 / NCI NIH HHS R01 AI043477 / NIAID NIH HHS 1R01CA168689 / NCI NIH HHS P30 CA023100 / NCI NIH HHS DP1 OD006430 / NIH HHS R01 CA168689 / NCI NIH HHS DP1CA174422 / NCI NIH HHS T32 CA009523 / NCI NIH HHS T32 GM007752 / NIGMS NIH HHS T32 CA009523-29 / NCI NIH HHS 3R01CA168689-02W1 / NCI NIH HHS
- Language
- English
- Date published
- 09/23/2014
- Academic Unit
- Dermatology; Radiation Oncology
- Record Identifier
- 9984213858002771
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