Deacetylation of p53 after nerve growth factor treatment in PC12 cells as a post-translational modification mechanism of neurotrophin-induced tumor suppressor activation.
The tumor suppressor protein p53 is a transcription factor that regulates the response to cellular insults such as DNA damage and growth factor withdrawal. Transcriptional activity of p53 requires post-translational modification by phosphorylation and acetylation. This study used site-specific antibodies to demonstrate that nerve growth factor (NGF) treatment of PC12 cells results in p53 deacetylation at lysine (Lys) 382. Histone deacetylase (HDAC) activity, measured by a direct fluorescent assay, was increased after NGF treatment and peaked before p53 deacetylation. Inhibition of HDAC by trichostatin blocked the deacetylation of p53 and its transcriptional activity toward a reporter gene construct. Comparison of PC12 with PC12 cells containing a temperature-sensitive, dominant-negative construct showed that p53 deacetylation required functional p53. Inhibitors of MAP kinase that block p53 transactivation and inhibitors of TrkA receptor also abolished HDAC activation, indicating that deacetylation of p53 is an NGF-dependent post-translational mechanism of p53 activation. Finally, NGF or serum withdrawal did not lead to p53 deacetylation. A model is proposed in which the acetylation status of Lys 382 of p53 discriminates between cell cycle arrest and apoptosis.
Vaghefi
Houman
H
Department of Biochemistry and Molecular Biology, Rosalind Franklin University of Medicine and Science (formerly Finch University of Health Sciences), The Chicago Medical School, 3333 Green Bay Rd., North Chicago, IL 60064, USA.
Neet
Kenneth E
KE
D000107:Acetylation; D000818:Animals; D004305:Dose-Response Relationship, Drug; D016147:Genes, Tumor Suppressor; D006655:Histone Deacetylases / Q000502:physiology; D006877:Hydroxamic Acids / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D020932:Nerve Growth Factor / Q000494:pharmacology*; D016716:PC12 Cells; D011499:Protein Processing, Post-Translational; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D006877:Hydroxamic Acids; D016159:Tumor Suppressor Protein p53; C012589:trichostatin A; D020932:Nerve Growth Factor; D006655:Histone Deacetylases