Abstract
Apoptosis related protein in TGF-β signaling pathway (ARTS) was originally discovered in cells undergoing apoptosis in response to TGF-β, but ARTS also acts downstream of many other apoptotic stimuli. ARTS induces apoptosis by antagonizing the anti-apoptotic proteins XIAP and Bcl-2. Here we identified the pro-apoptotic Sept4/ARTS gene as a p53-responsive target gene. Ectopic p53 and a variety of p53-inducing agents increased both mRNA and protein levels of ARTS, whereas ablation of p53 reduced ARTS expression in response to multiple stress conditions. Also, γ-irradiation induced p53-dependent ARTS expression in mice. Consistently, p53 binds to the responsive DNA element on the ARTS promoter and transcriptionally activated the promoter-driven expression of a luciferase reporter gene. Interestingly, ARTS binds to and sequesters p53 at mitochondria, enhancing the interaction of the latter with Bcl-XL. Ectopic ARTS markedly augments DNA damage stress- or Nutlin-3-triggered apoptosis, while ablation of ARTS preferentially impairs p53-induced apoptosis. Altogether, these findings demonstrate that ARTS collaborates with p53 in mitochondria-engaged apoptosis.
Highlights
The tumor-suppressor p53 prevents genomic instability and tumorigenesis through multiple mechanisms
Apoptosis related protein in TGF-β signaling pathway (ARTS) expression is induced by p53 in cancer cells Through a primary screen for p53-responsive genes by the p53-inducing agent INZ26,27, we identified ARTS as a possible p53 target gene
We showed that exogenous p53 induces ARTS mRNA (Fig. 1C) and protein expression (Fig. 1D) in HCT116p53+/+ colon cancer cells
Summary
The tumor-suppressor p53 prevents genomic instability and tumorigenesis through multiple mechanisms. P53 can elicit cell death through upregulation of the pro-apoptotic genes, such as BAX, NOXA, and PUMA, when cancer cells are subjected to severe DNA damage stress, such as therapeutic intervention[1,2]. Independently of its transcriptional activity, p53 has been shown to promote apoptosis via MDM2, encoded by a p53 target gene, is the master negative regulator that can inhibit p53 activity by directly concealing its transcriptional activation domain and promoting its proteolytic degradation[8,9,10,11]. 12,13), have been shown to either directly or collaborate with MDM2 to repress p53 as negative feedback regulators. This study as presented here identified ARTS (apoptosis-related protein in the TGF-β signaling pathway) as another p53 target that could play a role in regulation of p53’s apoptotic activity as well
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