Journal
CELLS
Volume 8, Issue 12, Pages -Publisher
MDPI
DOI: 10.3390/cells8121481
Keywords
invasion; JNK; cJun; TGF beta; AP-1; MAPK; signaling
Categories
Funding
- Swedish Cancer Society [2016/468, 2015/445]
- Swedish Research Council [2015-02757]
- European Research Council [787472]
- Netherlands Organisation for Scientific Research (NWO)
- Dutch Cancer Society (KWF)
- Cancer Genomics Centre Netherlands (CGC.NL)
- Swedish Research Council [2015-02757] Funding Source: Swedish Research Council
- European Research Council (ERC) [787472] Funding Source: European Research Council (ERC)
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Transforming growth factor-beta (TGF beta) has both tumor-suppressive and tumor-promoting effects in breast cancer. These functions are partly mediated through Smads, intracellular transcriptional effectors of TGF beta. 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 TGF beta 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 TGF beta 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.
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