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  • 1
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    Impaired Viability, Platelet Survival, Morphology and Function in Mice Lacking Filamin A. (2006)
    American Society of Hematology
    Details
    Publication Date: 2006-11-16
    Description: Platelet filamin A (FlnA), encoded by the FLNA gene on the X-chromosome, cross-links actin filaments, links them to the GPIbα subunit of the von Willebrand factor (vWf) receptor in the plasma membrane, and serves as a scaffold for signaling proteins. Mice lacking FlnA were generated. FlnA deficiency is embryonic lethal in hemizygous males due to pericardial and visceral hemorrhage. Heterozygous females are born, but experience premature mortality. The distribution of FlnA-expressing hematopoietic cells in FlnA+/− females was investigated by intracellular flow cytometry. About half of all hematopoietic cells investigated express FlnA, including bone marrow megakaryocytes, suggesting a random X-chromosome inactivation in these cells. However, about 90% of all blood platelets express FlnA. Mice lacking platelet FlnA were further generated by breeding FlnA loxP females with GATA-1 Cre males. FlnA loxP/+ GATA-1 Cre female offspring outnumber FlnA loxP/y GATA-1 Cre males by a ratio of 7:1. FlnA loxP/y GATA-1 Cre males have about 25% of normal blood platelet counts and their platelets are large, lack a normal actin cytoskeleton, and have decreased GPIbα expression, which has an altered distribution by electron microscopy. FlnA-null platelets are cleared rapidly from the circulation when transfused into GATA-1 Cre recipients and have severely impaired functional and signaling responses downstream of the collagen receptor GPVI, i.e. α-granule secretion, integrin αIibβ3 activation and protein tyrosine phosphorylation. Surprisingly, thrombin-mediated GPIbα down-regulation and botrocetin-mediated vWf binding are minimally affected in FlnA-null platelets. The data show the critical nature of FlnA for platelet survival, morphology and function.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology
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  • 2
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    Failure of gelsolin overexpression to regulate lymphocyte apoptosis (2000)
    American Society of Hematology
    Details
    Publication Date: 2000-06-01
    Description: The actin regulatory protein gelsolin cleaves actin filaments in a calcium- and polyphosphoinositide-dependent manner. Gelsolin has recently been described as a novel substrate of the cysteinyl protease caspase-3, an effector protease activated during apoptosis. Cleavage by caspase-3 generates an amino-terminal fragment of gelsolin that can sever actin filaments independently of calcium regulation. The disruption of the actin cytoskeleton by cleaved gelsolin is hypothesized to mediate many of the downstream morphological changes associated with apoptosis. In contrast, overexpression of full-length gelsolin has also been reported to inhibit apoptotic cell death upstream of the activation of caspase-3, suggesting that gelsolin may also act prior to commitment to cell death. The authors previously observed that actin stabilization by the cell permeant agent jasplakinolide enhanced cell death upon interleukin (IL)-2 or IL-3 withdrawal from growth-factor–dependent lymphocyte cell lines, and hypothesized that actin polymerization could alter the activity of gelsolin, thus enhancing apoptosis. Here the authors show that constitutive overexpression of gelsolin did not, however, inhibit or dramatically enhance apoptotic cell death upon growth-factor withdrawal, nor did it modify sensitivity to jasplakinolide. In contrast to previous reports, overexpression of gelsolin in Jurkat T cells did not prevent or delay apoptosis induced by Fas ligation or ceramide treatment. Overexpressed gelsolin protein was cleaved during apoptosis, as seen previously in this and other cell types. In these model systems, therefore, the level of gelsolin expression was not a rate-limiting determinant in commitment to or time to the morphological changes of apoptosis.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology
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  • 3
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    Failure of gelsolin overexpression to regulate lymphocyte apoptosis (2000)
    American Society of Hematology
    Details
    Publication Date: 2000-06-01
    Description: The actin regulatory protein gelsolin cleaves actin filaments in a calcium- and polyphosphoinositide-dependent manner. Gelsolin has recently been described as a novel substrate of the cysteinyl protease caspase-3, an effector protease activated during apoptosis. Cleavage by caspase-3 generates an amino-terminal fragment of gelsolin that can sever actin filaments independently of calcium regulation. The disruption of the actin cytoskeleton by cleaved gelsolin is hypothesized to mediate many of the downstream morphological changes associated with apoptosis. In contrast, overexpression of full-length gelsolin has also been reported to inhibit apoptotic cell death upstream of the activation of caspase-3, suggesting that gelsolin may also act prior to commitment to cell death. The authors previously observed that actin stabilization by the cell permeant agent jasplakinolide enhanced cell death upon interleukin (IL)-2 or IL-3 withdrawal from growth-factor–dependent lymphocyte cell lines, and hypothesized that actin polymerization could alter the activity of gelsolin, thus enhancing apoptosis. Here the authors show that constitutive overexpression of gelsolin did not, however, inhibit or dramatically enhance apoptotic cell death upon growth-factor withdrawal, nor did it modify sensitivity to jasplakinolide. In contrast to previous reports, overexpression of gelsolin in Jurkat T cells did not prevent or delay apoptosis induced by Fas ligation or ceramide treatment. Overexpressed gelsolin protein was cleaved during apoptosis, as seen previously in this and other cell types. In these model systems, therefore, the level of gelsolin expression was not a rate-limiting determinant in commitment to or time to the morphological changes of apoptosis.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology
    Location Call Number Expected Availability
    BibTip Others were also interested in ...
    PAPER CURRENT
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