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| Hauptseite > Publikationsdatenbank > Binding of Par-4 to the actin cytoskeleton is essential for Par-4/Dlk-mediated apoptosis |
| Hauptseite > Publikationsdatenbank > Binding of Par-4 to the actin cytoskeleton is essential for Par-4/Dlk-mediated apoptosis |
| Journal Article | PreJuSER-45390 |
; ; ; ; ; ; ;
2005
Academic Press
Orlando, Fla.
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Please use a persistent id in citations: doi:10.1016/j.yexcr.2005.01.012
Abstract: Prostate apoptosis response-4 (Par-4) is a 38-kDa protein originally identified as a gene product upregulated in prostate cancer cells undergoing apoptosis. Cell death mediated by Par-4 and its interaction partner DAP like kinase (Dlk) is characterized by dramatic changes of the cytoskeleton. To uncover the role of the cytoskeleton in Par-4/Dlk-mediated apoptosis, we analyzed Par-4 for a direct association with cytoskeletal structures. Confocal fluorescence microscopy revealed that endogenous Par-4 is specifically associated with stress fibers in rat fibroblasts. In vitro cosedimentation analyses and in vivo FRET analyses showed that Par-4 directly binds to F-actin. Actin binding is mediated by the N-terminal 266 amino acids, but does not require the C-terminal region of Par-4 containing the leucine zipper and the death domain. Furthermore, the interaction of Par-4 with actin filaments leads to the formation of actin bundles in vitro and in vivo. In rat fibroblasts, this microfilament association is essential for the pro-apoptotic function of Par-4, since both disruption of the actin cytoskeleton by cytochalasin D treatment and overexpression of Par-4 constructs impaired in actin binding result in a significant decrease of apoptosis induction by Par-4 and Dlk. We propose a model, in which Par-4 recruits Dlk to stress fibers, leading to enhanced phosphorylation of the regulatory light chain of myosin II (MLC) and to the induction of apoptosis.
Keyword(s): Actin Cytoskeleton: chemistry (MeSH) ; Actin Cytoskeleton: metabolism (MeSH) ; Actins: analysis (MeSH) ; Actins: metabolism (MeSH) ; Animals (MeSH) ; Apoptosis: physiology (MeSH) ; Apoptosis Regulatory Proteins (MeSH) ; Calcium-Calmodulin-Dependent Protein Kinases (MeSH) ; Cardiac Myosins: metabolism (MeSH) ; Cell Line, Tumor (MeSH) ; Humans (MeSH) ; Intracellular Signaling Peptides and Proteins: analysis (MeSH) ; Intracellular Signaling Peptides and Proteins: genetics (MeSH) ; Intracellular Signaling Peptides and Proteins: metabolism (MeSH) ; MAP Kinase Kinase Kinases (MeSH) ; Male (MeSH) ; Mice (MeSH) ; Mutation: genetics (MeSH) ; Myosin Light Chains: metabolism (MeSH) ; Phosphorylation (MeSH) ; Protein-Serine-Threonine Kinases: metabolism (MeSH) ; Rats (MeSH) ; Up-Regulation (MeSH) ; Actins ; Apoptosis Regulatory Proteins ; Intracellular Signaling Peptides and Proteins ; Myosin Light Chains ; myosin light chain 2 ; prostate apoptosis response-4 protein ; Protein-Serine-Threonine Kinases ; death-associated protein kinase ; Calcium-Calmodulin-Dependent Protein Kinases ; MAP Kinase Kinase Kinases ; mitogen-activated protein kinase kinase kinase 12 ; Cardiac Myosins ; J ; actin (auto) ; cytoskeleton (auto) ; Par-4 (auto) ; Dlk (auto) ; apoptosis (auto)
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