The autophagic inducer smARF interacts with and is stabilized by the mitochondrial p32 protein

Reef, Sharon; Shifman, Ohad; Oren, Moshe; Kimchi, Adi

doi:10.1038/sj.onc.1210485

Cited by 49 publications

(48 citation statements)

References 25 publications

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“…The stimulation of autophagy and dissipation of the mitochondrial membrane potential seem to depend on the stabilization of smARF in the mitochondrial membrane by its interaction with the p32 protein. 79 …”

Section: Cell Death (Apoptosis)mentioning

confidence: 99%

Does autophagy have a license to kill mammalian cells?

et al. 2008

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Macroautophagy is an evolutionarily conserved vacuolar, self-digesting mechanism for cellular components, which end up in the lysosomal compartment. In mammalian cells, macroautophagy is cytoprotective, and protects the cells against the accumulation of damaged organelles or protein aggregates, the loss of interaction with the extracellular matrix, and the toxicity of cancer therapies. During periods of nutrient starvation, stimulating macroautophagy provides the fuel required to maintain an active metabolism and the production of ATP. Macroautophagy can inhibit the induction of several forms of cell death, such as apoptosis and necrosis. However, it can also be part of the cascades of events that lead to cell death, either by collaborating with other cell death mechanisms or by causing cell death on its own. Loss of the regulation of bulk macroautophagy can prime selfdestruction by cells, and some forms of selective autophagy and non-canonical forms of macroautophagy have been shown to be associated with cell demise. There is now mounting evidence that autophagy and apoptosis share several common regulatory elements that are crucial in any attempt to understand the dual role of autophagy in cell survival and cell death. The term 'autophagy' embraces several different mechanisms: microautophagy, macroautophagy and chaperone-mediated autophagy, 1 all of which are involved in the lysosomal degradation of cellular components. In this review, we will focus essentially on macroautophagy, because of the large body of data available about its cross talk with cell death. Macroautophagy (hereafter called 'autophagy') is a mechanism conserved among eukaryotic cells that starts with the formation of a multi-membrane-bound vacuole, known as an autophagosome, which ultimately fuses with the lysosomal compartment and the degradation of the sequestered material. 2 The seminal discovery of autophagy-related (ATG) genes initially in yeast and then in multicellular organisms 3,4 has led to an important breakthrough in the understanding of how autophagosomes are formed and of the part autophagy plays in cell physiology and human diseases. 1,5 To clarify how macroautophagy is modulated in response to stress situations, it is also absolutely essential to elucidate how the macroautophagy is regulated upstream of the Atg machinery. 6 Macroautophagy occurs at a basal rate in most cells, where it acts as a cytoplasmic quality-control mechanism to eliminate protein aggregates and damaged organelles. 1,5 The physiological importance of basal autophagy in maintaining tissue homeostasis has recently been demonstrated in conditional brain and liver Atg knockout mouse models. [7][8][9] These studies have demonstrated the role of autophagy in preventing the cytotoxic deposition of aggregate-prone proteins in the cytoplasm, and the contribution of autophagy to the elimination of ubiquitinated proteins that are efficient substrates for the proteasome.On the other hand, when the supply of nutrients is limited, starvation-induced autophagy contrib...

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Section: Cell Death (Apoptosis)mentioning

confidence: 99%

Does autophagy have a license to kill mammalian cells?

et al. 2008

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“…Within a proteinase K-resistant compartment of the mitochondria, smARF interacts with the p32 mitochondrial protein, which stabilizes smARF and as a consequence, increases its ability to cause mitochondrial membrane dissipation and autophagy. 65 Fulllength p19ARF and its N-terminal domain were also shown to induce autophagy on overexpression in p53-containing cells and in p53-deficient cells, the latter indicating a mechanism that does not involve the p53-mediated autophagy described above. 66 Yet, a further detailed study established that nucleolar localized full-length p19ARF, unlike the mitochondrial smARF, is incapable of inducing p53-independent autophagy.…”

Section: Cross-talk Between Autophagy and Apoptosismentioning

confidence: 99%

Life and death partners: apoptosis, autophagy and the cross-talk between them

et al. 2009

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It is not surprising that the demise of a cell is a complex well-controlled process. Apoptosis, the first genetically programmed death process identified, has been extensively studied and its contribution to the pathogenesis of disease well documented. Yet, apoptosis does not function alone to determine a cell's fate. More recently, autophagy, a process in which de novo-formed membrane-enclosed vesicles engulf and consume cellular components, has been shown to engage in a complex interplay with apoptosis. In some cellular settings, it can serve as a cell survival pathway, suppressing apoptosis, and in others, it can lead to death itself, either in collaboration with apoptosis or as a back-up mechanism when the former is defective. The molecular regulators of both pathways are inter-connected; numerous death stimuli are capable of activating either pathway, and both pathways share several genes that are critical for their respective execution. The cross-talk between apoptosis and autophagy is therefore quite complex, and sometimes contradictory, but surely critical to the overall fate of the cell. Furthermore, the crosstalk is a key factor in the outcome of death-related pathologies such as cancer, its development and treatment. Autophagy, a process long known to provide a survival advantage to cells undergoing nutrient deprivation or other stresses, has also been more recently linked to the actual death process itself. Thus apoptosis is not the sole means by which the cell can undergo a genetically programmed regulated process by which it undergoes self-elimination. Cell death can occur by several mechanisms and the phenotypic changes that accompany cell death can vary depending on the stimulus and cell setting. In any given death scenario, the cell decides which pathway to use, depending on the nature of the stimulus and the particulars of the cell environment. Furthermore, apoptosis and autophagy are not mutually exclusive pathways. They have been shown to act in synergy and also to counter each other. They share many of the same molecular regulators. In a clinical setting, one cannot predict the outcome of inhibition or activation of one death program without considering the effect on the other. This review will focus on the cross-talk between the autophagic and apoptotic pathways, with an analysis of how this may affect the clinical applications of death suppression/activation to cancer. The process of necrosis, the third means by which the cell can undergo a genetically programmed self-elimination, will not be discussed in detail. Although not intended to provide an exhaustive summary of the recent literature, the discussion will include salient experimental results as examples of the different facets of the apoptosis/autophagy interplay.An issue that has been raised and discussed in the literature is that in many cell settings, autophagy accompanies, rather than causes, cell death. 1 This argument is based on the fact that many studies that claim autophagic cell death prove that autophagy occurs, and that ...

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“…In various cellular model systems, ARF interacts with p32 and induces mitochondrial membrane depolarization, leading to apoptotic or autophagic cell death responses 38,54 . Small fractions of endogenous ARF have been demonstrated in mitochondrial preparations from MEFs and human tumour cells 55 ; however, the functional significance of endogenous mitochondrial ARF has not been determined, partly because cellular signals or mechanisms that could trigger translocation of ARF to mitochondria have remained elusive.…”

Section: Discussionmentioning

confidence: 99%

A short acidic motif in ARF guards against mitochondrial dysfunction and melanoma susceptibility

et al. 2014

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ARF is a small, highly basic protein that can be induced by oncogenic stimuli and exerts growth-inhibitory and tumour-suppressive activities through the activation of p53. Here we show that, in human melanocytes, ARF is cytoplasmic, constitutively expressed, and required for maintaining low steady-state levels of superoxide under conditions of mitochondrial dysfunction. This mitochondrial activity of ARF is independent of its known autophagic and p53-dependent functions, and involves the evolutionarily conserved acidic motif GHDDGQ, which exhibits weak homology to BCL-2 homology 3 (BH3) domains and mediates interaction with BCL-xL-an important regulator of mitochondrial redox homeostasis. Melanomapredisposing CDKN2A germline mutations, which affect conserved glycine and aspartate residues within the GHDDGQ motif, impair the ability of ARF to control superoxide production and suppress growth of melanoma cells in vivo. These results reveal an important cell-protective function of ARF that links mitochondrial dysfunction and susceptibility to melanoma.

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The autophagic inducer smARF interacts with and is stabilized by the mitochondrial p32 protein

Cited by 49 publications

References 25 publications

Does autophagy have a license to kill mammalian cells?

Does autophagy have a license to kill mammalian cells?

Life and death partners: apoptosis, autophagy and the cross-talk between them

A short acidic motif in ARF guards against mitochondrial dysfunction and melanoma susceptibility

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