The cyclin-dependent kinase inhibitor p21 (WAF1) is required for survival of differentiating neuroblastoma cells.
We are employing recent advances in the understanding of the cell cycle to study the inverse relationship between proliferation and neuronal differentiation. Nerve growth factor and aphidicolin, an inhibitor of DNA polymerases, synergistically induce neuronal differentiation of SH-SY5Y neuroblastoma cells and the expression of p21WAF1, an inhibitor of cyclin-dependent kinases. The differentiated cells continue to express p21WAF1, even after removal of aphidicolin from the culture medium. The p21WAF1 protein coimmunoprecipitates with cyclin E and inhibits cyclin E-associated protein kinase activity. Each of three antisense oligonucleotides complementary to p21WAF1 mRNA partially blocks expression of p21WAF1 and promotes programmed cell death. These data indicate that p21WAF1 expression is required for survival of these differentiating neuroblastoma cells. Thus, the problem of neuronal differentiation can now be understood in the context of negative regulators of the cell cycle.
Poluha
W
W
Worcester Foundation for Biomedical Research, Shrewsbury, Massachusetts 01545, USA.
Poluha
D K
DK
Chang
B
B
Crosbie
N E
NE
Schonhoff
C M
CM
Kilpatrick
D L
DL
Ross
A H
AH
D016590:Aphidicolin / Q000494:pharmacology; D001483:Base Sequence; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis* / Q000302:isolation & purification; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors / Q000494:pharmacology; D009447:Neuroblastoma; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D016376:Oligonucleotides, Antisense; D011233:Precipitin Tests; D014407:Tumor Cells, Cultured
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D009414:Nerve Growth Factors; D016376:Oligonucleotides, Antisense; D016590:Aphidicolin