Deacetylation of p53 induces autophagy by suppressing Bmf expression

Chronic Obstructive Pulmonary Disease Program, Lovelace Respiratory Research Institute, Albuquerque, NM 87108.
The Journal of Cell Biology (Impact Factor: 9.83). 04/2013; 201(3):427-37. DOI: 10.1083/jcb.201205064
Source: PubMed


Interferon γ (IFN-γ)-induced cell death is mediated by the BH3-only domain protein, Bik, in a p53-independent manner. However, the effect of IFN-γ on p53 and how this affects autophagy have not been reported. The present study demonstrates that IFN-γ down-regulated expression of the BH3 domain-only protein, Bmf, in human and mouse airway epithelial cells in a p53-dependent manner. p53 also suppressed Bmf expression in response to other cell death-stimulating agents, including ultraviolet radiation and histone deacetylase inhibitors. IFN-γ did not affect Bmf messenger RNA half-life but increased nuclear p53 levels and the interaction of p53 with the Bmf promoter. IFN-γ-induced interaction of HDAC1 and p53 resulted in the deacetylation of p53 and suppression of Bmf expression independent of p53's proline-rich domain. Suppression of Bmf facilitated IFN-γ-induced autophagy by reducing the interaction of Beclin-1 and Bcl-2. Furthermore, autophagy was prominent in cultured bmf(-/-) but not in bmf(+/+) cells. Collectively, these observations show that deacetylation of p53 suppresses Bmf expression and facilitates autophagy.

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Available from: Hitendra S Chand, Oct 08, 2015
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    • "The secondary responses come from p53-regulated gene products that prevent DNA damage (sestrins) or aid in DNA repair; mediate communication between the cell and its neighbours, the extracellular matrix or more distant cells; or create intracellular or extracellular p53 feedback loops that modulate p53 activity. In addition, deacetylation of p53 facilitates autophagy (autophagocytosis by controlled lysosomal degradation) (Contreras et al., 2013). Mutated p53 (Mutp53) leads to further genomic instability (Meek, 2009). "
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    • "We prepared RNA samples using the RNeasy mini kit (Qiagen,Valencia, CA). We performed RT-RCR and quantitative analysis for WRN and GAPDH mRNA using Taqman One-Step RT-PCR Master Mix Reagents (Applied Biosystems, Carlsbad, CA) with the following probes: WRN (Hs00172155_m1) and GAPDH (Hs99999905_m1), both from Applied Biosystems (Contreras et al. 2013). "
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    • "Cellular stimulation with interferon-γ (IFN-γ) induces the deacetylation of p53, leading to suppressed Bmf expression, reduced complex formation between Beclin 1 and Bcl2, and enhanced autophagy [97]. Taken together these studies suggest a complex role of p53 in the regulation of autophagy, with opposing roles for the cytosolic and nuclear forms of p53 [98, 99]. "
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