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

Xuefeng Wu, Weizhou Zhang, Joan Font-Burgada, Trenis Palmer, Alexander S. Hamil, Subhra K. Biswas, Michael Poidinger, Nicholas Borcherding, Qing Xie, Lesley G. Ellies, Nikki K. Lytle, Li Wha Wu, Raymond G. Fox, Jing Yang, Steven F. Dowdy, Tannishtha Reya, Michael Karin

研究成果: Article同行評審

61 引文 斯高帕斯(Scopus)

摘要

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 TGFâ-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.

原文English
頁(從 - 到)13870-13875
頁數6
期刊Proceedings of the National Academy of Sciences of the United States of America
111
發行號38
DOIs
出版狀態Published - 2014 九月 23

All Science Journal Classification (ASJC) codes

  • General

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