Inhibition of Both the Extrinsic and Intrinsic Death Pathways through Nonhomotypic Death-Fold Interactions

Nam, Young-Jae; Mani, Kartik; Ashton, Anthony W.; Peng, Chang-Fu; Krishnamurthy, Barath; Hayakawa, Yukihiro; Lee, Peiyee; Korsmeyer, Stanley J.; Kitsis, Richard N.

doi:10.1016/j.molcel.2004.08.020

Cited by 159 publications

(214 citation statements)

References 53 publications

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“…6). In contrast, a deletion in the ARC caspase recruitment domain (CARD) does not interfere with p53 binding, which is notable because previously demonstrated ARC interactions with Fas, FADD, and Bax have involved the ARC CARD (11). To map the ARCinteracting domain in p53, purified recombinant p53 fragments were mixed with purified recombinant ARC (Fig.…”

Section: Resultsmentioning

confidence: 96%

Regulation of p53 tetramerization and nuclear export by ARC

Foo

Nam

Ostreicher

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Inactivation of the transcription factor p53 is central to carcinogenesis. Yet only approximately one-half of cancers have p53 loss-of-function mutations. Here, we demonstrate a mechanism for p53 inactivation by apoptosis repressor with caspase recruitment domain (ARC), a protein induced in multiple cancer cells. The direct binding in the nucleus of ARC to the p53 tetramerization domain inhibits p53 tetramerization. This exposes a nuclear export signal in p53, triggering Crm1-dependent relocation of p53 to the cytoplasm. Knockdown of endogenous ARC in breast cancer cells results in spontaneous tetramerization of endogenous p53, accumulation of p53 in the nucleus, and activation of endogenous p53 target genes. In primary human breast cancers with nuclear ARC, p53 is almost always WT. Conversely, nearly all breast cancers with mutant p53 lack nuclear ARC. We conclude that nuclear ARC is induced in cancer cells and negatively regulates p53.apoptosis ͉ breast cancer T he tumor suppressor p53 is critical in the prevention of neoplasia through its activation of programs that promote genomic stability, cell cycle arrest, and apoptosis (1). Although some p53 effects may involve nontranscriptional mechanisms, many are mediated through its function as a transcription factor (2). Inactivation of p53 signaling is essential for carcinogenesis (3). This is achieved through mutations in the p53 protein itself, most often in the DNA binding domain. Such mutations occur, however, in only Ϸ50% of tumors (4). In the remainder in which p53 is WT, the protein is degraded or relocated from the nucleus (5-7).Apoptosis repressor with caspase recruitment domain (ARC) is an endogenous inhibitor of apoptosis that is expressed primarily in terminally differentiated cells such as cardiac and skeletal myocytes and neurons (8). ARC resides in both the nucleus and cytoplasm (9, 10). Whereas cytoplasmic ARC inhibits both the death receptor and mitochondrial apoptosis pathways through direct interactions with Fas, Fas-associated death domain (FADD), and Bax (11), the function of nuclear ARC is unknown. Recently, ARC has been noted to be upregulated in a wide variety of cancer cell lines and primary human breast cancers (9, 10).In this study, we demonstrate an unexpected direct interaction in the nucleus between endogenous ARC and endogenous p53. This interaction, which involves the tetramerization domain of p53, disrupts p53 tetramerization. This, in turn, exposes a nuclear export signal in p53 that stimulates Crm1-dependent exclusion of p53 from the nucleus. The physiological significance of this mechanism is underscored by knockdown of endogenous ARC in cancer cells, which induces endogenous p53 to tetramerize, relocate to the nucleus, and transactivate its endogenous target genes. Furthermore, the observation in primary human breast cancers that nuclear ARC is almost always accompanied by WT p53, and conversely, that nuclear ARC is absent when p53 is mutant suggests that ARC serves to inactivate WT p53. Results Endogenous ARC Interacts Direct...

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Section: Resultsmentioning

confidence: 96%

Regulation of p53 tetramerization and nuclear export by ARC

Foo

Nam

Ostreicher

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…It can interact with Fas, FADD and Bax, 33,38 inhibit cytochrome c release 39 and maintain mitochondrial membrane potential. 40,41 These lines of evidence suggest that ARC is a critical factor for maintaining the cellular function.…”

Section: Discussionmentioning

confidence: 99%

“…31,32 It was originally identified to be a caspase-inhibiting protein and can inhibit apoptosis induced by a variety of stimuli. 30 Further evidence demonstrates that it also can bind to Bax 33 and Puma, 29 thereby quenching their apoptotic signal. It is not yet clear whether ARC can regulate autophagic program.…”

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confidence: 99%

Autophagic program is regulated by miR-325

Fang

et al. 2014

Cell Death Differ

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Autophagy is required for the maintenance of cardiomyocytes homeostasis. However, the abnormal autophagy could lead to the development of heart failure. Autophagy is enhanced during myocardial ischemia/reperfusion; it remains to elucidate the molecular regulation of autophagy. We report here that miR-325, ARC and E2F1 constitute an axis that regulates autophagy. Our results showed that miR-325 expression is upregulated upon anoxia/reoxygenation and ischemia/reperfusion. Cardiomyocytespecific overexpression of the miR-325 potentiates autophagic responses and myocardial infarct sizes, whereas knockdown of miR-325 inhibited autophagy and cell death. We searched for the downstream mediator of miR-325 and identified that ARC is a target of miR-325. ARC transgenic mice could attenuate autophagy and myocardial infarction sizes upon pressure-overloadinduced heart failure, whereas ARC null mice exhibited an increased autophagic accumulation in the heart. The suppression of ARC by miR-325 led to its inability to repress autophagic program. In exploring the molecular mechanism by which miR-325 expression is regulated, our results revealed that the transcription factor E2F1 contributed to promote miR-325 expression. E2F1 null mice demonstrated reduced autophagy and myocardial infarction sizes upon ischemia/reperfusion. Our present study reveals a novel autophagic regulating model that is composed of E2F1, miR-325 and ARC. Modulation of their levels may provide a new approach for tackling cardiac failure.

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“…Myocardium is intrinsically resistant to apoptosis, thought to be due at least in part to high levels of endogenous caspase inhibitors, such as X-linked inhibitor of apoptosis protein (XIAP) and apoptosis repressor with caspase recruitment domain (ARC) (Nam et al, 2004;Siu et al, 2005;Foo et al, 2007). Thus, the rate of apoptosis in normal human heart is B1 per 10 000 cardiomyocytes, but apoptosis increases several hundred-fold in ischemic and dilated cardiomyopathy and reactive cardiac hypertrophy (Narula et al, 1996;Teiger et al, 1996;Olivetti et al, 1997).…”

Section: Cardiomyocyte Apoptosis and Bcl2 Proteins In Myocardial Diseasementioning

confidence: 99%

Cardiac reanimation: targeting cardiomyocyte death by BNIP3 and NIX/BNIP3L

Dorn

Kirshenbaum

2008

Oncogene

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Programmed cardiac myocyte death contributes to pathological ventricular remodeling and the progression of myocardial infarction or pressure overload hypertrophy to dilated cardiomyopathy. Recent work has identified importance of stress-mediated transcriptional induction of BNIP3 (BCL2 and 19-kDa interacting protein-3) and NIX/BNIP3L in cardiac remodeling. Here, the regulatory mechanisms for these two factors in the heart and their effects on programmed cardiomyocyte death are reviewed, with a focus on information derived from studies using mouse models of cardiac BNIP3 and NIX/BNIP3L overexpression and gene ablation.

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Inhibition of Both the Extrinsic and Intrinsic Death Pathways through Nonhomotypic Death-Fold Interactions

Cited by 159 publications

References 53 publications

Regulation of p53 tetramerization and nuclear export by ARC

Regulation of p53 tetramerization and nuclear export by ARC

Autophagic program is regulated by miR-325

Cardiac reanimation: targeting cardiomyocyte death by BNIP3 and NIX/BNIP3L

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