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.

Download full-text


Available from: Hitendra S Chand
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The incidence of ocular surface squamous neoplasia (OSSN) is strongly associated with solar ultraviolet (UV) radiation, HIV and human papilloma virus (HPV). Africa has the highest incidence rates in the world. Most lesions occur at the limbus within the interpalpebral fissure particularly the nasal sector. The nasal limbus receives the highest intensity of sunlight. Limbal epithelial crypts are concentrated nasally and contain niches of limbal epithelial stem cells in the basal layer. It is possible that these are the progenitor cells in OSSN. OSSN arises in the basal epithelial cells spreading towards the surface which resembles the movement of corneo-limbal stem cell progeny before it later invades through the basement membrane below. UV radiation damages DNA producing pyrimidine dimers in the DNA chain. Specific CC -> TT base pair dimer transformations of the p53 tumour-suppressor gene occur in OSSN allowing cells with damaged DNA past the G1-S cell cycle checkpoint. UV radiation also causes local and systemic photo-immunosuppression and reactivates latent viruses such as HPV. The E7 proteins of HPV promote proliferation of infected epithelial cells via the retinoblastoma gene while E6 proteins prevent the p53 tumour suppressor gene from effecting cell-cycle arrest of DNA-damaged and infected cells. Immunosuppression from UV radiation, HIV and vitamin A deficiency impairs tumour immune surveillance allowing survival of aberrant cells. Tumour growth and metastases are enhanced by; telomerase reactivation which increases the number of cell divisions a cell can undergo; vascular endothelial growth factor for angiogenesis and matrix metalloproteinases (MMPs) that destroy the intercellular matrix between cells. Despite these potential triggers, the disease is usually unilateral. It is unclear how HPV reaches the conjunctiva. (C) 2014 The Authors. Published by Elsevier Ltd.
    Full-text · Article · Oct 2014 · Experimental Eye Research
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Acrolein is a carcinogenic and ubiquitous environmental hazard to human health. Acrolein activates the DNA damage response and induces apoptosis. However, little is known about the effects of acrolein on cellular senescence. In this study, we investigated whether acrolein induces cellular senescence in cultured normal human lung fibroblasts (NHLF). We cultured NHLF in the presence or absence of acrolein and determined the effects of acrolein on cell proliferative capacity, senescence-associated β-galactosidase activity, the known senescence-inducing pathways (e.g., p53-p21), and telomere length. We found that acrolein induced cellular senescence by increasing both p53 and p21. siRNA-mediated knockdown of p53 attenuated acrolein-induced cellular senescence. Acrolein decreased Werner's syndrome protein (WRN protein), a member of the RecQ helicase family involved in DNA repair and telomere maintenance. Acrolein-induced downregulation of WRN protein was rescued by p53 knockdown or proteasome inhibition. Finally, we found that acrolein accelerates p53-mediated telomere shortening. These results suggest that acrolein induces p53-mediated cellular senescence accompanied by enhanced telomere attrition and WRN protein downregulation.
    Full-text · Article · Apr 2014 · Environmental Health Perspectives
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Autophagy represents a homeostatic cellular mechanism for the turnover of organelles and proteins, through a lysosome-dependent degradation pathway. During starvation, autophagy facilitates cell survival through the recycling of metabolic precursors. Additionally, autophagy can modulate other vital processes such as programmed cell death (e.g., apoptosis), inflammation, and adaptive immune mechanisms and thereby influence disease pathogenesis. Selective pathways can target distinct cargoes (e.g., mitochondria and proteins) for autophagic degradation. At present, the causal relationship between autophagy and various forms of regulated or nonregulated cell death remains unclear. Autophagy can occur in association with necrosis-like cell death triggered by caspase inhibition. Autophagy and apoptosis have been shown to be coincident or antagonistic, depending on experimental context, and share cross-talk between signal transduction elements. Autophagy may modulate the outcome of other regulated forms of cell death such as necroptosis. Recent advances suggest that autophagy can dampen inflammatory responses, including inflammasome-dependent caspase-1 activation and maturation of proinflammatory cytokines. Autophagy may also act as regulator of caspase-1 dependent cell death (pyroptosis). Strategies aimed at modulating autophagy may lead to therapeutic interventions for diseases in which apoptosis or other forms of regulated cell death may play a cardinal role.
    Full-text · Article · Feb 2014 · International Journal of Cell Biology
Show more