p73 regulates DRAM-independent autophagy that does not contribute to programmed cell death

Crighton, Di.; O’Prey, Jim; Bell, Helen; Ryan, Kevin M.

doi:10.1038/sj.cdd.4402108

Cited by 90 publications

(80 citation statements)

References 40 publications

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“…Although previous reports have already suggested a potential link between p73 and autophagy, 38,39 we provide here, for the first time, a clear molecular link between p73 and autophagy using a significant series of analyses in vitro and in vivo. As a consequence, it might be possible to explain the diverse phenotypes of p73-deficient mice.…”

Section: Discussionmentioning

confidence: 87%

p73 regulates autophagy and hepatocellular lipid metabolism through a transcriptional activation of the ATG5 gene

Agostini

et al. 2013

Cell Death Differ

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p73, a member of the p53 tumor suppressor family, is involved in neurogenesis, sensory pathways, immunity, inflammation, and tumorigenesis. How p73 is able to participate in such a broad spectrum of different biological processes is still largely unknown. Here, we report a novel role of p73 in regulating lipid metabolism by direct transactivation of the promoter of autophagy-related protein 5 (ATG5), a gene whose product is required for autophagosome formation. Following nutrient deprivation, the livers of p73-deficient mice demonstrate a massive accumulation of lipid droplets, together with a low level of autophagy, suggesting that triglyceride hydrolysis into fatty acids is blocked owing to deficient autophagy (macrolipophagy). Compared with wild-type mice, mice functionally deficient in all the p73 isoforms exhibit decreased ATG5 expression and lower levels of autophagy in multiple organs. We further show that the TAp73a is the critical p73 isoform responsible for inducing ATG5 expression in a p53-independent manner and demonstrate that ATG5 gene transfer can correct autophagy and macrolipophagy defects in p73-deficient hepatocytes. These data strongly suggest that the p73-ATG5 axis represents a novel, key pathway for regulating lipid metabolism through autophagy. The identification of p73 as a major regulator of autophagy suggests that it may have an important role in preventing or delaying disease and aging by maintaining a homeostatic control. Cell Death and Differentiation (2013) 20, 1415-1424; doi:10.1038/cdd.2013.104; published online 2 August 2013 p73 belongs to the p53 family, a group of transcription factors that have key roles in the regulation of many cellular processes, such as apoptosis, cell cycle, and senescence, especially following DNA damage. 1-3 Whereas p53 is a tumor suppressor and often either deleted or mutated in tumors, p73 is rarely mutated; however, its expression is often deregulated in cancer. 4,5 In p73-deficient mice, unlike in p53-deficient mice, no increase in spontaneous tumorigenesis is observed. 6 It has been demonstrated, however, that p73, in the absence of DNA damage, has a role in neuronal differentiation and development. 6-9 Consequently, p73-deficient mice exhibit neurological defects and, even though no obvious deficiencies in lymphoid or granulocyte populations have been so far detected, such mice show deregulated inflammatory responses and senescence. 6,10 Because of splicing events occurring near the 3 0 end of the coding region and because of an alternative promoter located in the third intron of the gene, p73 exists as multiple protein variants. 11 The isoforms containing a transactivation (TA) domain (TAp73s) generally behave like p53 with respect to overlapping promoters and biological functions. 2,4 For instance, in contrast to p73-deficient mice, TAp73 knockout mice showed spontaneous as well as carcinogen-induced tumors, indicating that TAp73 is a tumor suppressor. 12 The alternative promoter also produces amino-terminal truncated DN isoforms, the so-called ...

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Section: Discussionmentioning

confidence: 87%

p73 regulates autophagy and hepatocellular lipid metabolism through a transcriptional activation of the ATG5 gene

Agostini

et al. 2013

Cell Death Differ

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“…However DRAM does not regulate autophagy induced by p73, another member of the p53 family. 41 It remains to be shown whether DRAM is involved in regulating autophagy in other circumstances, such as starvation; although this seems unlikely because starvationinduced autophagy is independent of the nuclear function of p53. 34 Autophagy downstream of apoptosis.…”

Section: Autophagy and Apoptosismentioning

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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“…88,89 Several chemo therapeutic agents induce TA-p73a and TA-p73b expression, 90 which are sufficient to activate autophagy through direct transcriptional regulation of the above-mentioned genes. Moreover, p73 induces the expression of several DNA repair genes, 91 thus positioning p73 in the interface between DNA repair and autophagy.…”

Section: Pathways Connecting Ddr To Autophagymentioning

confidence: 99%

“…91 Induces autophagy in a DRAM-independent manner. 89 Binds to genomic sites near to the autophagy-related genes atg5, atg7, ambra1. 128 UVRAG Was shown to partially complement sensitivity of XPC transformed cells to UVC.…”

Section: The Dual Role Of Autophagy In the Context Of Dna Damagementioning

confidence: 99%

Autophagy and genomic integrity

et al. 2013

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DNA lesions, constantly produced by endogenous and exogenous sources, activate the DNA damage response (DDR), which involves detection, signaling and repair of the damage. Autophagy, a lysosome-dependent degradation pathway that is activated by stressful situations such as starvation and oxidative stress, regulates cell fate after DNA damage and also has a pivotal role in the maintenance of nuclear and mitochondrial genomic integrity. Here, we review important evidence regarding the role played by autophagy in preventing genomic instability and tumorigenesis, as well as in micronuclei degradation. Several pathways governing autophagy activation after DNA injury and the influence of autophagy upon the processing of genomic lesions are also discussed herein. In this line, the mechanisms by which several proteins participate in both DDR and autophagy, and the importance of this crosstalk in cancer and neurodegeneration will be presented in an integrated fashion. At last, we present a hypothetical model of the role played by autophagy in dictating cell fate after genotoxic stress.

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p73 regulates DRAM-independent autophagy that does not contribute to programmed cell death

Cited by 90 publications

References 40 publications

p73 regulates autophagy and hepatocellular lipid metabolism through a transcriptional activation of the ATG5 gene

p73 regulates autophagy and hepatocellular lipid metabolism through a transcriptional activation of the ATG5 gene

Does autophagy have a license to kill mammalian cells?

Autophagy and genomic integrity

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