Abstract
Recent studies have suggested that MAP kinase phosphatase 1 (MKP-1) is overexpressed in prostate cancer. To evaluate the role of MKP-1 in regulating cell death and tumor growth in prostate cancer, MKP-1 was conditionally overexpressed in the human prostate cancer cell line DU145. Overexpression of MKP-1 in DU145 cells blocked activation of stress-activated protein kinase (SAPK/JNK). MKP-1 overexpression in DU-145 cells was also found to inhibit Fas ligand (FasL)-induced apoptosis, as well as block the activation of caspases by Fas engagement. In addition, MKP-1 blocked the activation of apoptosis by transfected MEKK-1 and ASK-1, presumably through its inhibition of the SAPK/JNK family of enzymes. MKP-1 blocked the ability of FasL to induce loss of mitochondrial transmembrane potential (delta Psi(m)), suggesting that MKP-1 acts upstream of mitochondrial pro-apoptotic events induced by FasL and that the SAPK/JNK pathway may form the signaling link between Fas receptor and mitochondrial dysfunction. Thus, MKP-1 overexpression in prostate cancer may play a role in promoting prostate carcinogenesis by inhibiting FasL-induced cell death.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Apoptosis*
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Caspases / metabolism
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Cell Cycle Proteins*
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Dual Specificity Phosphatase 1
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Enzyme Activation
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Fas Ligand Protein
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Humans
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Immediate-Early Proteins / genetics
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Immediate-Early Proteins / metabolism*
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MAP Kinase Kinase Kinase 1*
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MAP Kinase Kinase Kinase 5
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MAP Kinase Kinase Kinases / metabolism
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Male
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Membrane Glycoproteins / metabolism*
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Membrane Potentials
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Metallothionein / genetics
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Mitochondria / metabolism*
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Mitogen-Activated Protein Kinase 10
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Mitogen-Activated Protein Kinases / metabolism
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Phosphoprotein Phosphatases*
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Promoter Regions, Genetic
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Prostatic Neoplasms / metabolism*
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Prostatic Neoplasms / pathology
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Protein Phosphatase 1
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Protein Serine-Threonine Kinases*
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Protein Tyrosine Phosphatases / genetics
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Protein Tyrosine Phosphatases / metabolism*
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Protein-Tyrosine Kinases / metabolism
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Tumor Cells, Cultured
Substances
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Cell Cycle Proteins
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FASLG protein, human
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Fas Ligand Protein
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Immediate-Early Proteins
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Membrane Glycoproteins
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Recombinant Proteins
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Metallothionein
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Mitogen-Activated Protein Kinase 10
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Protein-Tyrosine Kinases
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Protein Serine-Threonine Kinases
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinase 1
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MAP Kinase Kinase Kinase 5
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MAP Kinase Kinase Kinases
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MAP3K1 protein, human
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MAP3K5 protein, human
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Phosphoprotein Phosphatases
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Protein Phosphatase 1
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DUSP1 protein, human
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Dual Specificity Phosphatase 1
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Protein Tyrosine Phosphatases
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Caspases