Abstract
Complement system activation plays an important role in both innate and acquired immunity. Activation of the complement and the subsequent formation of C5b-9 channels (the membrane attack complex) on the cell membranes lead to cell death. However, when the number of channels assembled on the surface of nucleated cells is limited, sublytic C5b-9 can induce cell cycle progression by activating signal transduction pathways and transcription factors and inhibiting apoptosis. This induction by C5b-9 is dependent upon the activation of the phosphatidylinositol 3-kinase/Akt/FOXO1 and ERK1 pathways in a Gi protein-dependent manner. C5b-9 induces sequential activation of CDK4 and CDK2, enabling the G1/S-phase transition and cellular proliferation. In addition, it induces RGC-32, a novel gene that plays a role in cell cycle activation by interacting with Akt and the cyclin B1-CDC2 complex. C5b-9 also inhibits apoptosis by inducing the phosphorylation of Bad and blocking the activation of FLIP, caspase-8, and Bid cleavage. Thus, sublytic C5b-9 plays an important role in cell activation, proliferation, and differentiation, thereby contributing to the maintenance of cell and tissue homeostasis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
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Review
MeSH terms
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Animals
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Apoptosis / immunology*
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BH3 Interacting Domain Death Agonist Protein / immunology
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BH3 Interacting Domain Death Agonist Protein / metabolism
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CDC2 Protein Kinase
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Caspase 8 / immunology
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Caspase 8 / metabolism
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Cell Cycle Proteins / immunology
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Cell Cycle Proteins / metabolism
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Cell Membrane / immunology*
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Cell Membrane / metabolism
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Complement Membrane Attack Complex / immunology*
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Complement Membrane Attack Complex / metabolism
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Cyclin B / immunology
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Cyclin B / metabolism
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Cyclin-Dependent Kinase 2 / immunology
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Cyclin-Dependent Kinase 2 / metabolism
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Cyclin-Dependent Kinase 4 / genetics
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Cyclin-Dependent Kinase 4 / metabolism
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Cyclin-Dependent Kinases
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Forkhead Box Protein O1
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Forkhead Transcription Factors / immunology
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Forkhead Transcription Factors / metabolism
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G1 Phase / immunology
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Humans
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MAP Kinase Signaling System / immunology*
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Mitogen-Activated Protein Kinase 3 / immunology
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Mitogen-Activated Protein Kinase 3 / metabolism
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Muscle Proteins / immunology
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Muscle Proteins / metabolism
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Nerve Tissue Proteins / immunology
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Nerve Tissue Proteins / metabolism
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Phosphatidylinositol 3-Kinases / immunology
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation / immunology
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Proto-Oncogene Proteins c-akt / immunology
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Proto-Oncogene Proteins c-akt / metabolism
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S Phase / immunology
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bcl-Associated Death Protein / immunology
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bcl-Associated Death Protein / metabolism
Substances
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BAD protein, human
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BH3 Interacting Domain Death Agonist Protein
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BID protein, human
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Cell Cycle Proteins
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Complement Membrane Attack Complex
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Cyclin B
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FOXO1 protein, human
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Forkhead Box Protein O1
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Forkhead Transcription Factors
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Muscle Proteins
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Nerve Tissue Proteins
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RGCC protein, human
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bcl-Associated Death Protein
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Proto-Oncogene Proteins c-akt
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CDC2 Protein Kinase
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CDK1 protein, human
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CDK2 protein, human
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CDK4 protein, human
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinases
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Mitogen-Activated Protein Kinase 3
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CASP8 protein, human
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Caspase 8