Abstract
Retinoic acid (RA) treatment of SMS-KCNR neuroblastoma (NB) cells leads to G1 growth arrest and neuronal differentiation. To investigate the molecular mechanisms by which RA alters cell growth, we analysed the expression and activity of components of the cell cycle machinery after culture in RA. Within 2 days of RA treatment and prior to the arrest of NB cells in the G1 phase of the cell cycle, there is a complete downregulation of G1 cyclin/Cdk activities. Protein levels for the G1 cyclin/Cdks were essentially unchanged during this time although there was a decrease in the steady-state levels of p67N-Myc and hyperphosphorylated Rb proteins. The Cdk inhibitors, p21Cip1 and p27Kip1 were constitutively expressed in KCNR while p15INK4B and p16INK4A were not detected. RA induced an increase in the expression of p27Kip1 but not p21Cip1. Furthermore, coincident with the decrease in kinase activity there was an increase in G1 cyclin/Cdk bound p27Kip1. These results indicate that changes in the level of p27Kip1 and its binding to G1 cyclin/Cdks may play a key role in RA induced growth arrest of NB cells.
MeSH terms
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Antineoplastic Agents / pharmacology
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Carrier Proteins / drug effects
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Carrier Proteins / genetics
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Cell Cycle / drug effects
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Cell Cycle Proteins*
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Cell Division / drug effects
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Cell Division / physiology
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Cyclin-Dependent Kinase Inhibitor p15
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Cyclin-Dependent Kinase Inhibitor p16 / drug effects
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Cyclin-Dependent Kinase Inhibitor p16 / genetics
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Cyclin-Dependent Kinase Inhibitor p27
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Cyclin-Dependent Kinases / antagonists & inhibitors
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Cyclin-Dependent Kinases / drug effects
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Cyclin-Dependent Kinases / metabolism
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Cyclins / drug effects
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Cyclins / metabolism
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G1 Phase / drug effects
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G1 Phase / physiology
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Gene Expression / drug effects
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Gene Expression / genetics
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Genes, Tumor Suppressor
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Humans
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Microtubule-Associated Proteins* / drug effects
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Microtubule-Associated Proteins* / genetics
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Microtubule-Associated Proteins* / physiology
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Neuroblastoma / genetics
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Neuroblastoma / physiopathology
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RNA, Messenger / drug effects
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RNA, Messenger / metabolism
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Tretinoin / pharmacology
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Tumor Cells, Cultured / cytology
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Tumor Cells, Cultured / drug effects
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Tumor Cells, Cultured / metabolism
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Tumor Suppressor Proteins*
Substances
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Antineoplastic Agents
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CDKN2B protein, human
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Carrier Proteins
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p15
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Cyclin-Dependent Kinase Inhibitor p16
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Cyclins
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Microtubule-Associated Proteins
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RNA, Messenger
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Tumor Suppressor Proteins
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Cyclin-Dependent Kinase Inhibitor p27
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Tretinoin
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Cyclin-Dependent Kinases