ArticleThe Journal of biological chemistry2012
p14(ARF)-induced apoptosis in p53 protein-deficient cells is mediated by BH3-only protein-independent derepression of Bak protein through down-regulation of Mcl-1 and Bcl-xL proteins.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 27 citations in OpenAlex.
- Exercise effects on DNA methylation inEpigenetics · 2022Trial
- Combination Treatment with Free Doxorubicin and Inductive Moderate Hyperthermia for Sarcoma Saos-2 Cells.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Helicobacter pylori activates DOPEY1 to promote p53 degradation through the USP7/TRIP12 axis in gastric tumorigenesis.Oncogene · 2025Article
- Review
- It's Getting Complicated-A Fresh Look at p53-MDM2-ARF Triangle in Tumorigenesis and Cancer Therapy.Frontiers in cell and developmental biology · 2022Review
- Roles of ARF tumour suppressor protein in lung cancer: time to hit the nail on the head!Molecular and cellular biochemistry · 2021Review
- Defined factors to reactivate cell cycle activity in adult mouse cardiomyocytes.Scientific reports · 2019Article
- Investigation of the effect of P14 promoter aberrant methylation on the biological function of human lung cancer cells.Thoracic cancer · 2019Article
- Overexpression of CCDC69 activates p14Journal of ovarian research · 2019Article
- Inhibition of coiled coil domain containing protein 69 enhances platinum-induced apoptosis in ovarian cancer cells.Oncotarget · 2017Article
- Clinicopathological significance of p14OncoTargets and therapy · 2017Article
- Cycloheximide Can Induce Bax/Bak Dependent Myeloid Cell Death Independently of Multiple BH3-Only Proteins.PloS one · 2016Article
- Apoptosis resistance, mitotic catastrophe, and loss of ploidy control in Burkitt lymphoma.Journal of molecular medicine (Berlin, Germany) · 2015Article
- Restoration of wild-type p53 in drug-resistant mouse breast cancer cells leads to differential gene expression, but is not sufficient to overcome the malignant phenotype.Molecular and cellular biochemistry · 2013Article
- To respond or not to respond to hydroxyurea in thalassemia: a matter of stress adaptation?Haematologica · 2013Article
- p53 and Ceramide as Collaborators in the Stress Response.International journal of molecular sciences · 2013Article
- Oncomir miR-125b suppresses p14(ARF) to modulate p53-dependent and p53-independent apoptosis in prostate cancer.PloS one · 2013Article
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The p14(ARF) tumor suppressor plays a central role in regulating cell cycle arrest and apoptosis. We reported previously that p14(ARF) is capable of triggering apoptosis in a p53-independent manner. However, the mechanism remained unclear. Here we demonstrate that the p53-independent activation of the mitochondrial apoptosis pathway by p14(ARF) is primarily mediated by the pro-apoptotic Bax-homolog Bak. Expression of p14(ARF) exclusively triggers a N-terminal conformational switch of Bak, but not Bax, which allows for mitochondrial permeability shift, release of cytochrome c, activation of caspases, and subsequent fragmentation of genomic DNA. Although forced expression of Bak markedly sensitizes toward p14(ARF)-induced apoptosis, re-expression of Bax has no effect. Vice versa, knockdown of Bak by RNA interference attenuates p14(ARF)-induced apoptosis, whereas down-regulation of Bax has no effect. Bak activation coincides with a prominent, caspase-independent deprivation of the endogenous Bak inhibitors Mcl-1 and Bcl-x(L). In turn, mitochondrial apoptosis is fully blocked by overexpression of either Mcl-1 or Bcl-x(L). Taken together, these data indicate that in the absence of functional p53 and Bax, p14(ARF) triggers mitochondrial apoptosis signaling by activating Bak, which is facilitated by down-regulating anti-apoptotic Mcl-1 and Bcl-x(L). Moreover, our data suggest that the simultaneous inhibition of two central endogenous Bak inhibitors, i.e. Mcl-1 and Bcl-x(L), may be sufficient to activate mitochondrial apoptosis in the absence of BH3-only protein regulation.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.