The effects of a mutant p53 protein on the proliferation and differentiation of PC12 rat phaeochromocytoma cells.
PC12 rat phaeochromocytoma cells show neuronal differentiation upon NGF treatment. NGF induces prolonged activation of the Ras/Raf/MEK/ERK pathway in which the 42/44 kDa mitogen-activated protein kinases (MAPKs), ERK 1 and 2 are thought to be the key mediators of the differentiation signals. Activation of ERKs leads to the increased transcription of early response genes resulting in cell cycle arrest. Upon NGF treatment the p53 protein, the most commonly mutated tumor suppressor in human cancers, translocates to the nucleus and may play a role in the mediation of NGF-induced cell cycle arrest and neuronal differentiation. Here we demonstrate that in PC12 cells expressing both wild-type and V143A mutant p53 proteins (p143p53PC12 cells), p53-mediated biological responses are critically influenced. p143p53PC12 cells are not able to cease their proliferation and begin their neuronal differentiation program upon NGF treatment. The presence of mutant p53 also reduces the DNA-binding activity of endogenous p53 and disturbs the regulatory machinery of p53 including both the phosphorylation of ERK 1/2, p38 and SAPK/JNK MAP kinases and itself.
Fábián
Zsolt
Z
Department of Medical Biology, Medical School, University of Pécs, H-7624 Pécs, Szigeti u 12, Hungary.
Vecsernyés
Mónika
M
Pap
Marianna
M
Szeberényi
József
J
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D004742:Enhancer Elements, Genetic; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020932:Nerve Growth Factor / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000502:physiology; D016716:PC12 Cells; D010766:Phosphorylation; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53; D020932:Nerve Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases