Abstract
It is well known that the cell cycle is controlled by several cyclin/cyclin-dependent kinase (Cdk) complexes whose expression and phosphorylation states vary with orderly periodicity. During the cell cycle, activity of the cyclin/Cdk complexes can be regulated directly or indirectly by a number of molecules, including protein kinases and phosphatases, p53, and Cdk inhibitors. Here, we show that the addition of glial cell line-derived neurotrophic factor (GDNF) induced G2/M cell cycle delay in human SK-N-MC neuroectodermal tumor cells that express RET tyrosine kinase, accompanying actin reorganization. Cell cycle delay at G2/M was characterized by accelerated and prolonged Cdc2 phosphorylation and stabilization of cyclin B1 and Wee1 kinase expression. Interestingly, we found that phosphorylation and/or expression of Cdc2, cyclinB1, and Wee1 was controlled by the Rac1/c-Jun NH2-terminal kinase (JNK) pathway. Immunohistochemical analysis suggested that the G2/M cell cycle delay may be necessary to prevent the mitotic progression of SK-N-MC cells with perturbed actin cytoskeletons.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Actins / metabolism*
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CDC2 Protein Kinase / metabolism
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Cell Cycle Proteins / metabolism
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Cell Division*
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Cell Proliferation
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Cyclin B / metabolism
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Cyclin B1
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Enzyme Activation
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Enzyme Stability
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G2 Phase*
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Glial Cell Line-Derived Neurotrophic Factor
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Humans
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JNK Mitogen-Activated Protein Kinases / metabolism*
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Mitogens / metabolism
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Nerve Growth Factors / genetics
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Nerve Growth Factors / metabolism*
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Neuroectodermal Tumors / genetics
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Neuroectodermal Tumors / metabolism
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Nuclear Proteins / metabolism
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Oncogene Proteins / genetics
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Oncogene Proteins / metabolism*
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Phosphorylation
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins c-ret
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / metabolism*
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Signal Transduction
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Tumor Cells, Cultured
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rac1 GTP-Binding Protein / metabolism
Substances
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Actins
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CCNB1 protein, human
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Cell Cycle Proteins
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Cyclin B
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Cyclin B1
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GDNF protein, human
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Glial Cell Line-Derived Neurotrophic Factor
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Mitogens
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Nerve Growth Factors
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Nuclear Proteins
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Oncogene Proteins
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Protein-Tyrosine Kinases
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Proto-Oncogene Proteins c-ret
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RET protein, human
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Receptor Protein-Tyrosine Kinases
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WEE1 protein, human
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CDC2 Protein Kinase
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JNK Mitogen-Activated Protein Kinases
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rac1 GTP-Binding Protein