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Open AccessArticle

JNK-Dependent cJun Phosphorylation Mitigates TGFβ- and EGF-Induced Pre-Malignant Breast Cancer Cell Invasion by Suppressing AP-1-Mediated Transcriptional Responses

Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Box 582, SE-751 23 Uppsala, Sweden
Department of Cell and Chemical Biology and Oncode Institute, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands
Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Present address: Department of Oncogenomics, Amsterdam University Medical Centers, 1105 AZ Amsterdam, The Netherlands.
Present address: Department of Nutrition and Movement Sciences, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University, 6200 MD Maastricht, The Netherlands.
Cells 2019, 8(12), 1481;
Received: 10 September 2019 / Revised: 12 November 2019 / Accepted: 18 November 2019 / Published: 21 November 2019
(This article belongs to the Special Issue TGF-beta/BMP Signaling Pathway)
Transforming growth factor-β (TGFβ) has both tumor-suppressive and tumor-promoting effects in breast cancer. These functions are partly mediated through Smads, intracellular transcriptional effectors of TGFβ. Smads form complexes with other DNA-binding transcription factors to elicit cell-type-dependent responses. Previously, we found that the collagen invasion and migration of pre-malignant breast cancer cells in response to TGFβ and epidermal growth factor (EGF) critically depend on multiple Jun and Fos components of the activator protein (AP)-1 transcription factor complex. Here we report that the same process is negatively regulated by Jun N-terminal kinase (JNK)-dependent cJun phosphorylation. This was demonstrated by analysis of phospho-deficient, phospho-mimicking, and dimer-specific cJun mutants, and experiments employing a mutant version of the phosphatase MKP1 that specifically inhibits JNK. Hyper-phosphorylation of cJun by JNK strongly inhibited its ability to induce several Jun/Fos-regulated genes and to promote migration and invasion. These results show that MEK-AP-1 and JNK-phospho-cJun exhibit distinct pro- and anti-invasive functions, respectively, through differential regulation of Smad- and AP-1-dependent TGFβ target genes. Our findings are of importance for personalized cancer therapy, such as for patients suffering from specific types of breast tumors with activated EGF receptor-Ras or inactivated JNK pathways. View Full-Text
Keywords: invasion; JNK; cJun; TGFβ; AP-1; MAPK; signaling invasion; JNK; cJun; TGFβ; AP-1; MAPK; signaling
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Sundqvist, A.; Voytyuk, O.; Hamdi, M.; Popeijus, H.E.; Bijlsma-van der Burgt, C.; Janssen, J.; Martens, J.W.; Moustakas, A.; Heldin, C.-H.; ten Dijke, P.; van Dam, H. JNK-Dependent cJun Phosphorylation Mitigates TGFβ- and EGF-Induced Pre-Malignant Breast Cancer Cell Invasion by Suppressing AP-1-Mediated Transcriptional Responses. Cells 2019, 8, 1481.

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