Abstract
Neuroblastoma is one of the most common cancers in children. Neuroblastoma differentiation is linked to the presence of the promyelocytic leukemia (PML) protein. Retinoic acid, a powerful differentiation-inducer in vitro, is a potent agent for the treatment of neuroblastoma. Using two different human neuroblastoma cell lines, SH-SY5Y and LA-N-5, we show here that PML protein leads to the formation of nuclear bodies (PML-NB) after only 1 h of retinoic acid treatment and that this formation is mediated by the extracellular signal-regulated kinase (ERK) pathway. Inhibition of protein kinase C also leads to formation of PML-NB via the ERK pathway. Both sumoylation and phosphorylation of PML in an ERK-dependent pathway are also required for formation of PML-NB. Finally, we show that PML-NB formation in neuroblastoma cells is associated with neurite outgrowth. These results support the proposal that the formation of PML-NB is correlated with the differentiation of neuroblastoma cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Differentiation / drug effects*
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Cell Line, Tumor
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Cell Nucleus Structures / metabolism*
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Cell Proliferation / drug effects
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Enzyme Inhibitors / pharmacology
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Keratolytic Agents / pharmacology*
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Models, Biological
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Neuroblastoma / drug therapy*
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Neuroblastoma / pathology
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Phosphorylation / drug effects
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Promyelocytic Leukemia Protein
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Signal Transduction / drug effects
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Tretinoin / pharmacology*
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
Substances
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Enzyme Inhibitors
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Keratolytic Agents
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Neoplasm Proteins
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Nuclear Proteins
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Promyelocytic Leukemia Protein
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Transcription Factors
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Tumor Suppressor Proteins
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PML protein, human
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Tretinoin
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Extracellular Signal-Regulated MAP Kinases