Aberrant activation of stress-response pathways leads to TNF-alpha oversecretion in Fanconi anemia
| Autor: | Frederic Subra, Filippo Rosselli, Gaëtane Macé-Aimé, Delphine Briot |
|---|---|
| Přispěvatelé: | Observatoire de Paris - Site de Paris (OP), Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Génomes et cancer (GC (FRE2939)), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie et de Pharmacologie Appliquée (LBPA), École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
MAPK/ERK pathway
medicine.medical_treatment Immunology MESH: NF-kappa B [SDV.CAN]Life Sciences [q-bio]/Cancer Matrix metalloproteinase Biology Transfection MESH: Actins Biochemistry MESH: Mitogen-Activated Protein Kinase Kinases 03 medical and health sciences 0302 clinical medicine Fanconi anemia MESH: Reverse Transcriptase Polymerase Chain Reaction MESH: RNA Small Interfering medicine Humans RNA Small Interfering Luciferases 030304 developmental biology Mitogen-Activated Protein Kinase Kinases 0303 health sciences MESH: Humans Reverse Transcriptase Polymerase Chain Reaction Tumor Necrosis Factor-alpha MESH: Transfection NF-kappa B Bone marrow failure Cell Biology Hematology medicine.disease Actins 3. Good health MESH: Hela Cells Leukemia MESH: Fanconi Anemia Fanconi Anemia Cytokine 030220 oncology & carcinogenesis MESH: Tumor Necrosis Factor-alpha Cancer research Tumor necrosis factor alpha MESH: Luciferases HeLa Cells |
| Zdroj: | Blood Blood, American Society of Hematology, 2008, 111 (4), pp.1913-23. ⟨10.1182/blood-2007-07-099218⟩ |
| ISSN: | 0006-4971 1528-0020 |
| Popis: | Fanconi anemia (FA), an inherited syndrome that associates bone marrow failure, cancer predisposition, and genetic instability, is characterized by an overproduction of the myelosuppressive cytokine TNF-alpha through unknown mechanisms. We demonstrate here that FANC pathway loss-of-function results in the aberrant activation of 2 major stress-signaling pathways: NF-kappaB and MAPKs. These responses are independent on TNF-alpha expression. On the contrary, inhibition of the MAPK pathways normalizes TNF-alpha oversecretion in FA. Moreover, our data show that the overexpression of the matrix metalloproteinase MMP-7 is the key event directly responsible for the high rate of TNF-alpha shedding and release from the cytoplasmic membrane in FA. TNF-alpha overproduction is, indeed, normalized by MMP-7 inhibition. Finally, MAPK inhibition impacts on MMP-7 overexpression. Evidence is provided of the existence of a linear pathway in which FANC mutations activate MAPK signaling that induces MMP-7 overexpression leading, in fine, to TNF-alpha oversecretion. TNF-alpha may, in turn, sustain or amplify both MAPKs and NF-kappaB activation. Aberrant expression or activity of NF-kappaB and/or MAPKs has been already involved in bone marrow failure and leukemia, and their inhibition offered clinical benefit for patients. In conclusion, our data provide a strong rationale for new clinical trials on FA patients. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|