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JNK-Dependent cJun ...
JNK-Dependent cJun Phosphorylation Mitigates TGF beta- and EGF-Induced Pre-Malignant Breast Cancer Cell Invasion by Suppressing AP-1-Mediated Transcriptional Responses
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- Sundqvist, Anders (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Institutionen för medicinsk biokemi och mikrobiologi
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- Voytyuk, Olexandr (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab
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- Hamdi, Mohamed (author)
- Leiden Univ, Med Ctr, Dept Cell & Chem Biol, POB 9600, NL-2300 RC Leiden, Netherlands;Leiden Univ, Med Ctr, Oncode Inst, POB 9600, NL-2300 RC Leiden, Netherlands;Amsterdam Univ Med Ctr, Dept Oncogen, NL-1105 AZ Amsterdam, Netherlands
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- Popeijus, Herman E. (author)
- Leiden Univ, Med Ctr, Dept Cell & Chem Biol, POB 9600, NL-2300 RC Leiden, Netherlands;Leiden Univ, Med Ctr, Oncode Inst, POB 9600, NL-2300 RC Leiden, Netherlands;Maastricht Univ, NUTRIM Sch Nutr & Translat Res Metab, Dept Nutr & Movement Sci, NL-6200 MD Maastricht, Netherlands
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- Bijlsma-van der Burgt, Corina (author)
- Leiden Univ, Med Ctr, Dept Cell & Chem Biol, POB 9600, NL-2300 RC Leiden, Netherlands;Leiden Univ, Med Ctr, Oncode Inst, POB 9600, NL-2300 RC Leiden, Netherlands
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- Janssen, Josephine (author)
- Leiden Univ, Med Ctr, Dept Cell & Chem Biol, POB 9600, NL-2300 RC Leiden, Netherlands;Leiden Univ, Med Ctr, Oncode Inst, POB 9600, NL-2300 RC Leiden, Netherlands
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- Martens, John W. M. (author)
- Erasmus Univ, Med Ctr, Dept Med Oncol, Erasmus MC Canc Inst, NL-3000 CA Rotterdam, Netherlands
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- Moustakas, Aristidis (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab
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- Heldin, Carl-Henrik, 1952- (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Institutionen för medicinsk biokemi och mikrobiologi
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- ten Dijke, Peter (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Institutionen för medicinsk biokemi och mikrobiologi,Leiden Univ, Med Ctr, Dept Cell & Chem Biol, POB 9600, NL-2300 RC Leiden, Netherlands;Leiden Univ, Med Ctr, Oncode Inst, POB 9600, NL-2300 RC Leiden, Netherlands
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- van Dam, Hans (author)
- Leiden Univ, Med Ctr, Dept Cell & Chem Biol, POB 9600, NL-2300 RC Leiden, Netherlands;Leiden Univ, Med Ctr, Oncode Inst, POB 9600, NL-2300 RC Leiden, Netherlands
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(creator_code:org_t)
- 2019-11-21
- 2019
- English.
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In: CELLS. - : MDPI. - 2073-4409. ; 8:12
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https://doi.org/10.3...
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https://uu.diva-port... (primary) (Raw object)
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Abstract
Subject headings
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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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- invasion
- JNK
- cJun
- TGF beta
- AP-1
- MAPK
- signaling
Publication and Content Type
- ref (subject category)
- art (subject category)
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Sundqvist, Ander ...
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Voytyuk, Olexand ...
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Hamdi, Mohamed
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Popeijus, Herman ...
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Bijlsma-van der ...
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Janssen, Josephi ...
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Martens, John W. ...
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Moustakas, Arist ...
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Heldin, Carl-Hen ...
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ten Dijke, Peter
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van Dam, Hans
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- MEDICAL AND HEALTH SCIENCES
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Uppsala University