| Functional PAK-2 knockout and replacement with a caspase cleavage-deficient mutant in mice reveals differential requirements of full-length PAK-2 and caspase-activated PAK-2p34. | |
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MedLine Citation:
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PMID: 21499899 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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. |
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Authors:
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Jerry W Marlin; Yu-Wen E Chang; Margaret Ober; Amy Handy; Wenhao Xu; Rolf Jakobi |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-4-17 |
Journal Detail:
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Title: Mammalian genome : official journal of the International Mammalian Genome Society Volume: - ISSN: 1432-1777 ISO Abbreviation: - Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-4-18 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9100916 Medline TA: Mamm Genome Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Biochemistry, Kansas City University of Medicine and Biosciences, 1750 Independence Avenue, Kansas City, MO, 64106, USA. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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