TWIST1 associates with NF-κB subunit RELA via carboxyl-terminal WR domain to promote cell autonomous invasion through IL8 production

BMC Biology

Research Article

Zheng Liu¹  Steven Flanagan²  Carlotta A Glackin²  Gina Lowe²  Maricela Covarrubias³  Yu-Huey Lin⁴  Yuan Han Teh⁴  Karen S Aboody⁵  Stephen E Kendall⁶  James Finlay⁷  Shan Li⁷  Raquel Raices⁸  Simi Dhillon⁹  Victoria Leigh^1,10 

[1] Department of Molecular Medicine, Beckman Research Institute of the City of Hope, 91010, Duarte, CA, USA;Division of Neurosciences, Beckman Research Institute of the City of Hope, 91010, Duarte, CA, USA;Division of Neurosciences, Beckman Research Institute of the City of Hope, 91010, Duarte, CA, USA;Affymetrix, 95051, Santa Clara, CA, USA;Division of Neurosciences, Beckman Research Institute of the City of Hope, 91010, Duarte, CA, USA;Department of Biological Sciences, California State Polytechnic Institute, 91768, Pomona, CA, USA;Division of Neurosciences, Beckman Research Institute of the City of Hope, 91010, Duarte, CA, USA;Department of Neurosurgery, Beckman Research Institute of the City of Hope, 91010, Duarte, CA, USA;Division of Neurosciences, Beckman Research Institute of the City of Hope, 91010, Duarte, CA, USA;GeneTex, 92606, Irvine, CA, USA;Division of Neurosciences, Beckman Research Institute of the City of Hope, 91010, Duarte, CA, USA;Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope, 91010, Duarte, CA, USA;Division of Neurosciences, Beckman Research Institute of the City of Hope, 91010, Duarte, CA, USA;StemCell Technologies Inc., V5Z 1B3, Vancouver, BC, Canada;Division of Neurosciences, Beckman Research Institute of the City of Hope, 91010, Duarte, CA, USA;University of California Berkeley, 94720, Berkeley, CA, USA;Division of Neurosciences, Beckman Research Institute of the City of Hope, 91010, Duarte, CA, USA;Western University of Health Sciences, 91766, Pomona, CA, USA;

关键词: TWIST1;    WR domain;    RELA;    NF-κB;    IL8;   

DOI  :  10.1186/1741-7007-10-73

 received in 2012-02-10, accepted in 2012-08-14,  发布年份 2012

来源: Springer

【 摘 要 】

BackgroundMetastasis is the primary cause of death for cancer patients. TWIST1, an evolutionarily conserved basic helix-loop-helix (bHLH) transcription factor, is a strong promoter of metastatic spread and its expression is elevated in many advanced human carcinomas. However, the molecular events triggered by TWIST1 to motivate dissemination of cancer cells are largely unknown.ResultsHere we show that TWIST1 induces the production of interleukin 8 (IL8), which activates matrix metalloproteinases and promotes invasion of breast epithelial and cancer cells. In this novel mechanism, TWIST1-mediated IL8 transcription is induced through the TWIST1 carboxy-terminal WR (Trp-Arg) domain instead of the classic DNA binding bHLH domain. Co-immunoprecipitation analyses revealed that the WR domain mediates the formation of a protein complex comprised of TWIST1 and the nuclear factor-kappaB (NF-κB) subunit RELA (p65/NF-κB3), which synergistically activates the transcriptional activity of NF-κB. This activation leads to increased DNA binding affinity of RELA to the IL8 promoter and thus induces the expression of the cytokine. Blockage of IL8 signaling by IL8 neutralizing antibodies or receptor inhibition reduced the invasiveness of both breast epithelial and cancer cells, indicating that TWIST1 induces autonomous cell invasion by establishing an IL8 antocrine loop.ConclusionsOur data demonstrate that the TWIST1 WR domain plays a critical role in TWIST1-induced IL8 expression through interactions with and activation of NF-κB. The produced IL8 signals through an autocrine loop and promotes extracellular matrix degradation to enable cell invasion across the basement membrane.

【 授权许可】

Unknown   
© Li et al; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.