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Mamm Genome ; 22(5-6): 306-17, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21499899

ABSTRACT

p21-Activated protein kinase 2 (PAK-2) has both anti- and pro-apoptotic functions depending on its mechanism of activation. Activation of full-length PAK-2 by the monomeric GTPases Cdc42 or Rac stimulates cell survival, whereas caspase activation of PAK-2 to the PAK-2p34 fragment is involved in the apoptotic response. In this study we use functional knockout of PAK-2 and gene replacement with the caspase cleavage-deficient PAK-2D212N mutant to differentiate the biological functions of full-length PAK-2 and caspase-activated PAK-2p34. Knockout of PAK-2 results in embryonic lethality at early stages before organ development, whereas replacement with the caspase cleavage-deficient PAK-2D212N results in viable and healthy mice, indicating that early embryonic lethality is caused by deficiency of full-length PAK-2 rather than lack of caspase activation to the PAK-2p34 fragment. However, deficiency of caspase activation of PAK-2 decreased spontaneous cell death of primary mouse embryonic fibroblasts and increased cell growth at high cell density. In contrast, stress-induced cell death by treatment with the anti-cancer drug cisplatin was not reduced by deficiency of caspase activation of PAK-2, but switched from an apoptotic to a nonapoptotic, caspase-independent mechanism. Homozygous PAK-2D212N primary mouse embryonic fibroblasts that lack the ability to generate the proapoptotic PAK-2p34 show less activation of the effector caspase 3, 6, and 7, indicating that caspase activation of PAK-2 amplifies the apoptotic response through a positive feedback loop resulting in more activation of effector caspases.


Subject(s)
Apoptosis/genetics , CARD Signaling Adaptor Proteins/genetics , Peptide Fragments/metabolism , p21-Activated Kinases/genetics , p21-Activated Kinases/metabolism , Animals , Blotting, Southern , Blotting, Western , CARD Signaling Adaptor Proteins/metabolism , Caspases, Effector/metabolism , Cisplatin , DNA Primers/genetics , Feedback, Physiological , Fibroblasts , Genetic Vectors , Mice , Mice, Knockout , Mutation, Missense/genetics , Peptide Fragments/genetics , Polymerase Chain Reaction
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