Actin cytoskeletal function is spared, but apoptosis is increased, in WAS patient hematopoietic cells

Citation
R. Rengan et al., Actin cytoskeletal function is spared, but apoptosis is increased, in WAS patient hematopoietic cells, BLOOD, 95(4), 2000, pp. 1283-1292
Citations number
50
Categorie Soggetti
Hematology,"Cardiovascular & Hematology Research
Journal title
BLOOD
ISSN journal
00064971 → ACNP
Volume
95
Issue
4
Year of publication
2000
Pages
1283 - 1292
Database
ISI
SICI code
0006-4971(20000215)95:4<1283:ACFISB>2.0.ZU;2-F
Abstract
Mutations in the Wiskott-Aldrich syndrome protein (WASP) have been hypothes ized to cause defective actin cytoskeletal function. This resultant dysfunc tion of the actin cytoskeleton has been implicated in the pathogenesis of W iskott-Aldrich syndrome (WAS). In contrast, it was found that stimulated ac tin polymerization is kinetically normal in the hematopoietic lineages affe cted 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 l ymphocytes as evidenced by increased caspase-3 activity. This increased act ivity resulted in accelerated apoptosis of these cells. CD95 expression was also increased in these cells, suggesting an up-regulation in the FAS path way in WAS lymphocytes, Additionally, inhibition of actin polymerization in lymphocytes using cytochalasin B did not accelerate apoptosis in these cel ls, This suggests that the accelerated apoptosis observed in WAS lymphocyte s 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 d elaying cell death. Therefore, the principal consequence of mutations in th e WAS gene is to accelerate lymphocyte apoptosis, potentially through upreg ulation of the FAS-mediated cell death pathway. This accelerated apoptosis may ultimately give rise to the clinical manifestations observed in WAS. (C ) 2000 by The American Society of Hematology.