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Blood, Vol. 95 No. 4 (February 15), 2000:
pp. 1283-1292
Actin cytoskeletal function is spared, but apoptosis is
increased, in WAS patient hematopoietic cells
Ramesh Rengan,
Hans D. Ochs,
Leonard I. Sweet,
Michael L. Keil,
William T. Gunning,
Neil A. Lachant,
Laurence A. Boxer, and
Geneva M. Omann
From the Departments of Surgery, Biological Chemistry, and
Pediatrics and Communicable Diseases, University of Michigan Medical
School, Ann Arbor, MI; the Veterans Administration Medical Center, Ann
Arbor, MI; the Barbara Ann Karmanos Cancer Institute and Department of
Medicine, Wayne State University School of Medicine, Detroit, MI; the
Department of Pediatrics, University of Washington School of Medicine,
Seattle, WA; and the Department of Pathology, Medical College of Ohio,
Toledo, OH.
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.
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