ARC, an apoptosis suppressor limited to terminally differentiated cells, is induced in human breast cancer and confers chemo- and radiation-resistance

Mercier, Isabelle Le; Vuolo, Magalis; Madan, Rashna; Xue, Xiaonan; LeValley, Aaron; Ashton, Anthony W.; Jasmin, Jean François; Czaja, Michał; Lin, Elaine Y.; Armstrong, Regina C.; Pollard, Jeffrey W.; Kitsis, Richard N.

doi:10.1038/sj.cdd.4401631

Cited by 56 publications

(91 citation statements)

References 16 publications

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“…Additionally, monoclonal antibodies against ubiquitin, HA, Myc (all from Santa Cruz Biotechnology), and ␣-tubulin (Sigma) were used. Immunostaining was performed on mouse heart sections as previously described (10). Immunoblots and immunoprecipitations were performed as described (12).…”

Section: Methodsmentioning

confidence: 99%

“…ARC 3 (apoptosis repressor with caspase recruitment domain) is an endogenous inhibitor of apoptosis that is expressed primarily in terminally differentiated cells, including cardiac and skeletal myocytes and neurons (8,9). ARC is also induced in a variety of human cancer cell lines and primary human cancers (10,11). In contrast to most endogenous inhibitors of apoptosis, ARC antagonizes both the extrinsic and intrinsic pathways (12).…”

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confidence: 99%

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The Apoptosis Inhibitor ARC Undergoes Ubiquitin-Proteasomal-mediated Degradation in Response to Death Stimuli

Nam¹,

Mani²,

Wu³

et al. 2007

Journal of Biological Chemistry

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Efficient induction of apoptosis requires not only the activation of death-promoting proteins but also the inactivation of inhibitors of cell death. ARC (apoptosis repressor with caspase recruitment domain) is an endogenous inhibitor of apoptosis that antagonizes both central apoptosis pathways. Despite its potent inhibition of cell death, cells that express abundant ARC eventually succumb. A possible explanation is that ARC protein levels decrease dramatically in response to death stimuli. The mechanisms that mediate decreases in ARC protein levels during apoptosis and whether these decreases initiate the subsequent cell death are not known. Here we show that endogenous ARC protein levels decrease in response to death stimuli in a variety of cell contexts as well as in a model of myocardial ischemia-reperfusion in intact mice. Decreases in ARC protein levels are not explained by alterations in the abundance of ARC transcripts. Rather, pulse-chase experiments show that decreases in steady state ARC protein levels during apoptosis result from marked destabilization of ARC protein. ARC protein destabilization, in turn, is mediated by the ubiquitin-proteasomal pathway, as mutation of ARC ubiquitin acceptor residues stabilizes ARC protein and preserves its steady state levels during apoptosis. In addition, this degradation-resistant ARC mutant exhibits improved cytoprotection. We conclude that decreases in ARC protein levels in response to death stimuli are mediated by increased ARC protein degradation via the ubiquitin-proteasomal pathway. Moreover, these data demonstrate that decreases in ARC protein levels are a trigger, and not merely a consequence, of the ensuing cell death.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

The Apoptosis Inhibitor ARC Undergoes Ubiquitin-Proteasomal-mediated Degradation in Response to Death Stimuli

Nam¹,

Mani²,

Wu³

et al. 2007

Journal of Biological Chemistry

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“…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.…”

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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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“…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.…”

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confidence: 99%

“…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).…”

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confidence: 99%

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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ARC, an apoptosis suppressor limited to terminally differentiated cells, is induced in human breast cancer and confers chemo- and radiation-resistance

Cited by 56 publications

References 16 publications

The Apoptosis Inhibitor ARC Undergoes Ubiquitin-Proteasomal-mediated Degradation in Response to Death Stimuli

The Apoptosis Inhibitor ARC Undergoes Ubiquitin-Proteasomal-mediated Degradation in Response to Death Stimuli

Autophagic program is regulated by miR-325

Regulation of p53 tetramerization and nuclear export by ARC

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