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JAM-A Acts via C/EB...
JAM-A Acts via C/EBP-alpha to Promote Claudin-5 Expression and Enhance Endothelial Barrier Function
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- Kakogiannos, Nikolaos (författare)
- FIRC Inst Mol Oncol, Milan, Italy.
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- Ferrari, Laura (författare)
- FIRC Inst Mol Oncol, Milan, Italy.
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- Giampietro, Costanza (författare)
- EMPA, Swiss Fed Lab Mat Sci & Technol, Expt Continuum Mech, Dubendorf, Switzerland.
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- Scalise, Anna Agata (författare)
- FIRC Inst Mol Oncol, Milan, Italy.
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- Maderna, Claudio (författare)
- FIRC Inst Mol Oncol, Milan, Italy.
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- Rava, Micol (författare)
- European Inst Oncol IRCSS, Expt Oncol, Milan, Italy.
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- Taddei, Andrea (författare)
- Benevolent AI, London, England.
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- Lampugnani, Maria Grazia (författare)
- FIRC Inst Mol Oncol, Milan, Italy.;Mario Negri Inst Pharmacol Res, Milan, Italy.
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- Pisati, Federica (författare)
- Cogentech SRI Benefit Corp, Milan, Italy.
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- Malinverno, Matteo (författare)
- FIRC Inst Mol Oncol, Milan, Italy.
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- Martini, Emanuele (författare)
- FIRC Inst Mol Oncol, Milan, Italy.
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- Costa, Ilaria (författare)
- FIRC Inst Mol Oncol, Milan, Italy.
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- Lupia, Michela (författare)
- European Inst Oncol IRCSS, Unit Gynaecol Oncol Res, Milan, Italy.
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- Cavallaro, Ugo (författare)
- European Inst Oncol IRCSS, Unit Gynaecol Oncol Res, Milan, Italy.
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- Beznoussenko, Galina, V (författare)
- FIRC Inst Mol Oncol, Milan, Italy.
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- Mironov, Alexander A. (författare)
- FIRC Inst Mol Oncol, Milan, Italy.
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- Fernandes, Bethania (författare)
- Humanitas Clin & Res Ctr, Pathol Unit, Milan, Italy.
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- Rudini, Noemi (författare)
- Humanitas Clin & Res Ctr, Pathol Unit, Milan, Italy.
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- Dejana, Elisabetta (författare)
- Uppsala universitet,Vaskulärbiologi,FIRC Inst Mol Oncol, Milan, Italy.;Univ Milan, Sch Med, Oncol & Haemato Oncol, Milan, Italy.
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- Giannotta, Monica (författare)
- FIRC Inst Mol Oncol, Milan, Italy.
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FIRC Inst Mol Oncol, Milan, Italy EMPA, Swiss Fed Lab Mat Sci & Technol, Expt Continuum Mech, Dubendorf, Switzerland. (creator_code:org_t)
- Lippincott Williams & Wilkins, 2020
- 2020
- Engelska.
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Ingår i: Circulation Research. - : Lippincott Williams & Wilkins. - 0009-7330 .- 1524-4571. ; 127:8, s. 1056-1073
- Relaterad länk:
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Rationale: Intercellular tight junctions are crucial for correct regulation of the endothelial barrier. Their composition and integrity are affected in pathological contexts, such as inflammation and tumor growth. JAM-A (junctional adhesion molecule A) is a transmembrane component of tight junctions with a role in maintenance of endothelial barrier function, although how this is accomplished remains elusive.Objective: We aimed to understand the molecular mechanisms through which JAM-A expression regulates tight junction organization to control endothelial permeability, with potential implications under pathological conditions.Methods and Results: Genetic deletion of JAM-A in mice significantly increased vascular permeability. This was associated with significantly decreased expression of claudin-5 in the vasculature of various tissues, including brain and lung. We observed that C/EBP-α (CCAAT/enhancer-binding protein-α) can act as a transcription factor to trigger the expression of claudin-5 downstream of JAM-A, to thus enhance vascular barrier function. Accordingly, gain-of-function for C/EBP-α increased claudin-5 expression and decreased endothelial permeability, as measured by the passage of fluorescein isothiocyanate (FITC)-dextran through endothelial monolayers. Conversely, C/EBP-α loss-of-function showed the opposite effects of decreased claudin-5 levels and increased endothelial permeability. Mechanistically, JAM-A promoted C/EBP-α expression through suppression of β-catenin transcriptional activity, and also through activation of EPAC (exchange protein directly activated by cAMP). C/EBP-α then directly binds the promoter of claudin-5 to thereby promote its transcription. Finally, JAM-A–C/EBP-α–mediated regulation of claudin-5 was lost in blood vessels from tissue biopsies from patients with glioblastoma and ovarian cancer.Conclusions: We describe here a novel role for the transcription factor C/EBP-α that is positively modulated by JAM-A, a component of tight junctions that acts through EPAC to up-regulate the expression of claudin-5, to thus decrease endothelial permeability. Overall, these data unravel a regulatory molecular pathway through which tight junctions limit vascular permeability. This will help in the identification of further therapeutic targets for diseases associated with endothelial barrier dysfunction.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Kardiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cardiac and Cardiovascular Systems (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Hematologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Hematology (hsv//eng)
Nyckelord
- claudin-5
- endothelium
- junctional adhesion molecule A
- tight junctions
- vascular permeability
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- Av författaren/redakt...
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Kakogiannos, Nik ...
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Ferrari, Laura
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Giampietro, Cost ...
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Scalise, Anna Ag ...
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Maderna, Claudio
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Rava, Micol
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visa fler...
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Taddei, Andrea
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Lampugnani, Mari ...
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Pisati, Federica
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Malinverno, Matt ...
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Martini, Emanuel ...
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Costa, Ilaria
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Lupia, Michela
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Cavallaro, Ugo
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Beznoussenko, Ga ...
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Mironov, Alexand ...
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Fernandes, Betha ...
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Rudini, Noemi
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Dejana, Elisabet ...
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Giannotta, Monic ...
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Medicinska och f ...
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och Cell och molekyl ...
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Kardiologi
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Hematologi
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Circulation Rese ...
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Uppsala universitet