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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

1
Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Box 582, SE-751 23 Uppsala, Sweden
2
Department of Cell and Chemical Biology and Oncode Institute, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands
3
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; https://doi.org/10.3390/cells8121481
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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