Histone Deacetylase Inhibitors Prevent p53-Dependent and p53-Independent Bax-Mediated Neuronal Apoptosis through Two Distinct Mechanisms.
 

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03-06-09 08:24 AM
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Histone Deacetylase Inhibitors Prevent p53-Dependent and p53-Independent Bax-Mediated Neuronal Apoptosis through Two Distinct Mechanisms.
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Histone Deacetylase Inhibitors Prevent p53-Dependent and p53-Independent Bax-Mediated Neuronal Apoptosis through Two Distinct Mechanisms.

J Neurosci. 2009 Mar 4;29(9):2824-2832

Authors: Uo T, Veenstra TD, Morrison RS

Pharmacological manipulation of protein acetylation levels by histone deacetylase (HDAC) inhibitors represents a novel therapeutic strategy to treat neurodegeneration as well as cancer. However, the molecular mechanisms that determine how HDAC inhibition exerts a protective effect in neurons as opposed to a cytotoxic action in tumor cells has not been elucidated. We addressed this issue in cultured postnatal mouse cortical neurons whose p53-dependent and p53-independent intrinsic apoptotic programs require the proapoptotic multidomain protein, Bax. Despite promoting nuclear p53 accumulation, Class I/II HDAC inhibitors (HDACIs) protected neurons from p53-dependent cell death induced by camptothecin, etoposide, heterologous p53 expression or the MDM2 inhibitor, nutlin-3a. HDACIs suppressed p53-dependent PUMA expression, a critical signaling intermediate linking p53 to Bax activation, thus preventing postmitochondrial events including cleavage of caspase-9 and caspase-3. In human SH-SY5Y neuroblastoma cells, however, HDACIs were not able to prevent p53-dependent cell death. Moreover, HDACIs also prevented caspase-3 cleavage in postnatal cortical neurons treated with staurosporine, 3-nitropropionic acid and a Bcl-2 inhibitor, all of which require the presence of Bax but not p53 to promote apoptosis. Although these three toxic agents displayed a requirement for Bax, they did not promote PUMA induction. These results demonstrate that HDACIs block Bax-dependent cell death by two distinct mechanisms to prevent neuronal apoptosis, thus identifying for the first time a defined molecular target for their neuroprotective actions.

PMID: 19261878 [PubMed - as supplied by publisher]