title: Actin cytoskeletal function is spared, but apoptosis is increased, in WAS patient hematopoietic cells.
abstract: Mutations in the Wiskott-Aldrich syndrome protein (WASP) have been hypothesized to cause defective actin cytoskeletal function. This resultant dysfunction of the actin cytoskeleton has been implicated in the pathogenesis of Wiskott-Aldrich syndrome (WAS). In contrast, it was found that stimulated actin polymerization is kinetically normal in the hematopoietic lineages affected in WAS. It was also found that the actin cytoskeleton in WAS platelets is capable of producing the hallmark cytoarchitectural features associated with activation. Further analysis revealed accelerated cell death in WAS lymphocytes as evidenced by increased caspase-3 activity. This increased activity resulted in accelerated apoptosis of these cells. CD95 expression was also increased in these cells, suggesting an up-regulation in the FAS pathway in WAS lymphocytes. Additionally, inhibition of actin polymerization in lymphocytes using cytochalasin B did not accelerate apoptosis in these cells. This suggests that the accelerated apoptosis observed in WAS lymphocytes was not secondary to an underlying defect in actin polymerization caused by mutation of the WAS gene. These data indicate that WASP does not play a universal role in signaling actin polymerization, but does play a role in delaying cell death. Therefore, the principal consequence of mutations in the WAS gene is to accelerate lymphocyte apoptosis, potentially through up-regulation of the FAS-mediated cell death pathway. This accelerated apoptosis may ultimately give rise to the clinical manifestations observed in WAS. (Blood. 2000;95:1283-1292)
authors.affiliation: Departments of Surgery, Biological Chemistry, and Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: R
authors.initials: R
authors.lastname: Rengan
authors.forename: H D
authors.initials: HD
authors.lastname: Ochs
authors.forename: L I
authors.initials: LI
authors.lastname: Sweet
authors.forename: M L
authors.initials: ML
authors.lastname: Keil
authors.forename: W T
authors.initials: WT
authors.lastname: Gunning
authors.forename: N A
authors.initials: NA
authors.lastname: Lachant
authors.forename: L A
authors.initials: LA
authors.lastname: Boxer
authors.forename: G M
authors.initials: GM
authors.lastname: Omann
mesh_terms: D000199:Actins / Q000097:blood*; D000244:Adenosine Diphosphate / Q000494:pharmacology; D017209:Apoptosis; D001792:Blood Platelets / Q000166:cytology* / Q000187:drug effects / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D003571:Cytochalasin B / Q000494:pharmacology; D003599:Cytoskeleton / Q000502:physiology*; D015237:Dinoprost / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D007962:Leukocytes / Q000166:cytology* / Q000187:drug effects / Q000473:pathology; D008214:Lymphocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D020125:Mutation, Missense; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009336:Necrosis; D017354:Point Mutation; D011506:Proteins / Q000235:genetics; D012016:Reference Values; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013921:Thrombocytopenia / Q000097:blood / Q000235:genetics / Q000473:pathology; D014923:Wiskott-Aldrich Syndrome / Q000097:blood* / Q000235:genetics / Q000473:pathology; D051316:Wiskott-Aldrich Syndrome Protein; D019014:fas Receptor / Q000097:blood; D018909:src Homology Domains
chemical_list: D000199:Actins; D011506:Proteins; C495767:WAS protein, human; D051316:Wiskott-Aldrich Syndrome Protein; D019014:fas Receptor; D003571:Cytochalasin B; D009240:N-Formylmethionine Leucyl-Phenylalanine; D000244:Adenosine Diphosphate; D015237:Dinoprost; D013755:Tetradecanoylphorbol Acetate