title: Actin-myosin-based contraction is responsible for apoptotic nuclear disintegration.
abstract: Membrane blebbing during the apoptotic execution phase results from caspase-mediated cleavage and activation of ROCK I. Here, we show that ROCK activity, myosin light chain (MLC) phosphorylation, MLC ATPase activity, and an intact actin cytoskeleton, but not microtubular cytoskeleton, are required for disruption of nuclear integrity during apoptosis. Inhibition of ROCK or MLC ATPase activity, which protect apoptotic nuclear integrity, does not affect caspase-mediated degradation of nuclear proteins such as lamins A, B1, or C. The conditional activation of ROCK I was sufficient to tear apart nuclei in lamin A/C null fibroblasts, but not in wild-type fibroblasts. Thus, apoptotic nuclear disintegration requires actin-myosin contractile force and lamin proteolysis, making apoptosis analogous to, but distinct from, mitosis where nuclear disintegration results from microtubule-based forces and from lamin phosphorylation and depolymerization.
authors.affiliation: Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Croft
authors.forename: Mathew L
authors.initials: ML
authors.lastname: Coleman
authors.forename: Shuixing
authors.initials: S
authors.lastname: Li
authors.forename: David
authors.initials: D
authors.lastname: Robertson
authors.forename: Teresa
authors.initials: T
authors.lastname: Sullivan
authors.forename: Colin L
authors.initials: CL
authors.lastname: Stewart
authors.forename: Michael F
authors.initials: MF
authors.lastname: Olson
mesh_terms: D000199:Actins / Q000378:metabolism*; D000577:Amides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D003513:Cycloheximide / Q000494:pharmacology; D015638:Cytochalasin D / Q000494:pharmacology; D003598:Cytoskeletal Proteins; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000648:ultrastructure; D047908:Intracellular Signaling Peptides and Proteins; D034882:Lamins / Q000235:genetics / Q000378:metabolism*; D054461:Lim Kinases; D051379:Mice; D046529:Microscopy, Electron, Transmission; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D009154:Mutation / Q000502:physiology; D018994:Myosin Light Chains / Q000235:genetics / Q000378:metabolism; D043263:Myosin-Light-Chain Phosphatase / Q000378:metabolism; D009218:Myosins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D041681:NIH 3T3 Cells; D015739:Nocodazole / Q000494:pharmacology; D034881:Nuclear Lamina / Q000187:drug effects / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D054460:rho-Associated Kinases; D000099149:Ezrin
chemical_list: D000199:Actins; D000577:Amides; D061945:Caspase Inhibitors; D020169:Caspases; D003513:Cycloheximide; D015638:Cytochalasin D; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D034882:Lamins; D054461:Lim Kinases; D018994:Myosin Light Chains; D043263:Myosin-Light-Chain Phosphatase; D009218:Myosins; D015739:Nocodazole; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D054460:rho-Associated Kinases; D000099149:Ezrin; C108830:Y 27632; C515893:Limk1 protein, mouse