Abstract
Serum deprivation induced in human lymphoblastoid Raji cells oxidative stress-associated apoptotic death and G0/G1 cell cycle arrest. Addition into culture medium of the immunomodulatory protein Seminal vesicle protein 4 (SV-IV) protected these cells against apoptosis but not against cycle arrest. The antiapoptotic activity was related to: (1) decrease of endocellular reactive Oxygen species (ROS) (2) increase of mRNAs encoding anti-oxidant enzymes (catalase, G6PD) and antiapoptotic proteins (survivin, cox-1, Hsp70, c-Fos); (3) decrease of mRNAs encoding proapoptotic proteins (c-myc, Bax, caspase-3, Apaf-1). The biochemical changes underlaying these effects were probably induced by a protein tyrosine kinase (PTK) activity triggered by the binding of SV-IV to its putative plasma membrane receptors. The ineffectiveness of SV-IV to abrogate the cycle arrest was accounted for by its downregulating effects on D1,3/E G1-cyclins and CdK2/4 gene expression, ppRb/pRb ratio, and intracellular ROS concentration. In conclusion, these experiments: (1) prove that SV-IV acts as a cell survival factor; (2) suggest the involvement of a PTK in SV-IV signaling; (3) point to cell cycle-linked enzyme inhibition as responsible for cycle arrest; (4) provide a model to dissect the cycle arrest and apoptosis induced by serum withdrawal; (5) imply a possible role of SV-IV in the survival of hemiallogenic implanting embryos.
MeSH terms
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Animals
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Antioxidants / metabolism*
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Antioxidants / pharmacology
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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Apoptosis* / drug effects
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Catalase / genetics
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Catalase / metabolism
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Cell Line, Tumor
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Cell Proliferation* / drug effects
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Culture Media, Serum-Free / metabolism
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Cyclin-Dependent Kinases / metabolism
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Cyclins / metabolism
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Cytotoxicity, Immunologic
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DNA Fragmentation
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Embryo Culture Techniques
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Embryo Implantation* / drug effects
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Embryonic Development
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G1 Phase* / drug effects
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Genomic Instability
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Glucosephosphate Dehydrogenase / genetics
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Glucosephosphate Dehydrogenase / metabolism
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Humans
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Killer Cells, Natural / immunology
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Killer Cells, Natural / metabolism
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Leukocytes, Mononuclear / drug effects
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Leukocytes, Mononuclear / enzymology
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Leukocytes, Mononuclear / immunology
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Leukocytes, Mononuclear / metabolism*
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Mice
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Mice, Inbred BALB C
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Oxidative Stress
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Phosphorylation
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Protein-Tyrosine Kinases / metabolism
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RNA, Messenger / metabolism
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Rats
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Rats, Wistar
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Reactive Oxygen Species / metabolism
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Resting Phase, Cell Cycle* / drug effects
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Retinoblastoma Protein / metabolism
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Seminal Vesicle Secretory Proteins / metabolism*
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Seminal Vesicle Secretory Proteins / pharmacology
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Serum / metabolism
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Signal Transduction
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Time Factors
Substances
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Antioxidants
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Apoptosis Regulatory Proteins
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Culture Media, Serum-Free
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Cyclins
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RNA, Messenger
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Reactive Oxygen Species
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Retinoblastoma Protein
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Seminal Vesicle Secretory Proteins
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Svs4 protein, rat
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Glucosephosphate Dehydrogenase
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Catalase
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Protein-Tyrosine Kinases
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Cyclin-Dependent Kinases