p53 induces ARTS to promote mitochondrial apoptosis

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.

The Program Cell Death (Apoptosis) and the Therapy of Cancer

“…Hereby, freed cytosolic p53 can activate Bax and Bak, which results in stimulation of apoptotic signaling through MOMP [44,151]. p53 increases the expression of pro-apoptotic protein level, called ARTS, and counteracts Bcl-xl to induce apoptosis [152]. Hence, the inhibition of p53 antagonists such as Mdm-2 can cause an increased level of p53, induce pro-apoptotic protein expressions.…”

Killing by Degradation: Regulation of Apoptosis by the Ubiquitin-Proteasome-System

“…p53 promotes apoptosis mainly by inducing the transcriptional upregulation of pro-apoptotic proteins, such as the death receptor 5 (DR5), TNFR1 and Fas, which results in the activation of caspase-8 [ 184 , 185 ]. In addition, p53 can induce the activation of pro-apoptotic Bcl-2 family proteins, such as BAX, PUMA, BAD, BID, BAK and NOXA [ 186 , 187 , 188 , 189 , 190 ]. The induction of BID, BAK and BAX promotes the permeabilization of the outer mitochondrial membrane and amplifies the caspase activation process [ 191 , 192 ].…”

P53 and PUMA in Pluripotent Cell Competition

“…This contributes to MOMP enhancing apoptosis (Edison et al, 2011;Edison et al, 2017). Interestingly, ARTS is induced by P53 and has a role in stem cells apoptosis (Fuchs et al, 2013;Hao et al, 2020).…”

“…BCL-2 proteins such as PUMA and NOXA are involved in apoptosis, although other nonapoptotic functions as regulation of metabolism have been described (Siddiqui et al, 2015). In ESCs, P53 function in apoptosis and cycle arrest is not clear and recent works suggest that P53 functions change depending on ESCs pluripotent status (Fu et al, 2020;Hao et al, 2020;Jaiswal et al, 2020). On the other hand, less is known about PUMA and NOXA function in ESCs.…”

“…In ESCs, previous efforts to study P53 function have produced contradictory results. Recent studies suggest that P53 functions in ESCs change depending on the pluripotent status (Fu et al, 2020;Hao et al, 2020;Jaiswal et al, 2020). Regarding BH3-only proteins, there is little information about PUMA and NOXA function in ESCs.…”