TNFalpha inhibits skeletal myogenesis through a PW1-dependent pathway by recruitment of caspase pathways
Open Access
- 15 February 2002
- journal article
- research article
- Published by Springer Nature in The EMBO Journal
- Vol. 21 (4) , 631-642
- https://doi.org/10.1093/emboj/21.4.631
Abstract
Cachexia is associated with poor prognosis in patients with chronic disease. Tumor necrosis factor‐alpha (TNFα) plays a pivotal role in mediating cachexia and has been demonstrated to inhibit skeletal muscle differentiation in vitro . It has been proposed that TNFα‐mediated activation of NFκB leads to down regulation of MyoD, however the mechanisms underlying TNFα effects on skeletal muscle remain poorly understood. We report here a novel pathway by which TNFα inhibits muscle differentiation through activation of caspases in the absence of apoptosis. TNFα‐mediated caspase activation and block of differentiation are dependent upon the expression of PW1, but occur independently of NFκB activation. PW1 has been implicated previously in p53‐mediated cell death and can induce bax translocation to the mitochondria. We show that bax‐deficient myoblasts do not activate caspases and differentiate in the presence of TNFα, highlighting a role for bax‐dependent caspase activation in mediating TNFα effects. Taken together, our data reveal that TNFα inhibits myogenesis by recruiting components of apoptotic pathways through PW1.Keywords
This publication has 52 references indexed in Scilit:
- Siah ubiquitin ligase is structurally related to TRAF and modulates TNF-α signalingNature Structural & Molecular Biology, 2001
- Tumor Necrosis Factor-α Regulates the Expression of Inducible Costimulator Receptor Ligand on CD34+ Progenitor Cells during Differentiation into Antigen Presenting CellsJournal of Biological Chemistry, 2001
- Proapoptotic BAX and BAK: A Requisite Gateway to Mitochondrial Dysfunction and DeathScience, 2001
- Loss of skeletal muscle in cancer: biochemical mechanismsFrontiers in Bioscience-Landmark, 2001
- Activation of the NF-κB pathway by Caspase 8 and its homologsOncogene, 2000
- Procaspase 3/p21 complex formation to resist Fas-mediated cell death is initiated as a result of the phosphorylation of p21 by protein kinase ACell Death & Differentiation, 2000
- Insulin-like Growth Factor-II, Phosphatidylinositol 3-Kinase, Nuclear Factor-κB and Inducible Nitric-oxide Synthase Define a Common Myogenic Signaling PathwayJournal of Biological Chemistry, 1999
- MyoD Is Indispensable for Muscle-specific Alternative Splicing in Mouse Mitochondrial ATP Synthase γ-Subunit Pre-mRNAPublished by Elsevier ,1998
- Early Lethality, Functional NF-κB Activation, and Increased Sensitivity to TNF-Induced Cell Death in TRAF2-Deficient MiceImmunity, 1997
- Comparison of three actin-coding sequences in the mouse; Evolutionary relationships between the actin genes of warm-blooded vertebratesJournal of Molecular Evolution, 1986