p53 mediates mitochondria dysfunction-triggered autophagy activation and cell death in rat striatum

Zhang, Xingding; Wang, Ye; Wang, Yan; Zhang, Xuan; Han, Rong; Wu, Jun; Liang, Zhong Qin; Gu, Zhen Lun; Han, Feng; Fukunaga, Kohji; Qin, Zheng

doi:10.4161/auto.5.3.8174

Cited by 106 publications

(89 citation statements)

References 49 publications

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“…It is a tumour suppressor that promotes autophagy by phosphorylating Beclin 1 and hence relieving its association with B-cell CLL/lymphoma 2 (BCL2) (Zhang et al, 2009;Zalckvar et al, 2009). DAPK1 also inhibits microtubule-associated protein 1B (MAP1B; an LC3-interacting protein that inhibits autophagy).…”

Section: Regulation Of Autophagy By Oncogenes and Tumour Suppressorsmentioning

confidence: 99%

Autophagy and cancer – issues we need to digest

Liu

Ryan

2012

Journal of Cell Science

193

152

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SummaryAutophagy is an evolutionarily conserved catabolic pathway that has multiple roles in carcinogenesis and cancer therapy. It can inhibit the initiation of tumorigenesis through limiting cytoplasmic damage, genomic instability and inflammation, and the loss of certain autophagy genes can lead to cancer. Conversely, autophagy can also assist cells in dealing with stressful metabolic environments, thereby promoting cancer cell survival. In fact, some cancers rely on autophagy to survive and progress. Furthermore, tumour cells can exploit autophagy to cope with the cytotoxicity of certain anticancer drugs. By contrast, it appears that certain therapeutics require autophagy for the effective killing of cancer cells. Despite these dichotomies, it is clear that autophagy has an important, if complex, role in cancer. This is further exemplified by the fact that autophagy is connected with major cancer networks, including those driven by p53, mammalian target of rapamycin (mTOR), RAS and glutamine metabolism. In this Commentary, we highlight recent advances in our understanding of the role that autophagy has in cancer and discuss current strategies for targeting autophagy for therapeutic gain.This article is part of a Minifocus on Autophagy. For further reading, please see related articles: 'Ubiquitin-like proteins and autophagy at a glance' by Tomer Shpilka et al. (J. Cell Sci. 125, 2343-2348 and 'Autophagy and cell growth -the yin and yang of nutrient responses' by Thomas Neufeld (J. Cell Sci. 125, 2359-2368).

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Section: Regulation Of Autophagy By Oncogenes and Tumour Suppressorsmentioning

confidence: 99%

Autophagy and cancer – issues we need to digest

Liu

Ryan

2012

Journal of Cell Science

193

152

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“…It has been found that p53 induces successful autophagy in a DRAM1-dependent manner [44] . It has also been demonstrated that the p53 specific inhibitor PFT effectively blocks the 3-NP-induced induction of DRAM1, LC3-II and striatal cell death [43] . In the absence of DRAM1, GFP-LC3 was diffuse within the cytoplasm with occasional puncta representing the basal level of autophagosomes within the cell.…”

Section: The Role Of P53 In Autophagy Pathwaymentioning

confidence: 99%

“…Recent studies have shown that cytoplasmic p53 can play a direct role in the inhibition of autophagy [41] (Figure 1), which can be induced in response to nutrient deprivation and provides ATP that can prolong viability [42] . On the other hand, p53 can also activate autophagy preceding the apoptotic process [43] . The process of autophagy is regulated by p53 through the pathway of mTOR and damage-regulated autophagy modulator 1 (DRAM1) [9,44] .…”

Section: The Role Of P53 In Autophagy Pathwaymentioning

confidence: 99%

The role of p53 in cell metabolism

2010

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IntroductionIn the past decades, p53 is probably one of the most widely studied proteins because of its pivotal role in tumorogenesis, cell death and survival. p53 is a transcription factor that mediates cell response to various detrimental stresses through a complex signaling network [1] . When cell endures a variety of insults including DNA damage, hypoxia, and oxidative stress, p53 becomes modified, which promotes both its stabilization and translocation into the nucleus, where p53 activates the expression of genes that induce cell cycle regulation, DNA repair, senescence, and cell death [2] .It has been found that the metabolism in cancer cells was altered. The metabolic alterations in cancer cells determine how cells respond to variable nutrient and oxygen availability and promote cell proliferation, growth and survival [3] . Recent findings indicated that p53 plays an important role in metabolic shifting in cancerous cells, suggesting a new function of p53 in regulating cell metabolism. However, how p53 regulates metabolism is complicated. In this review, we will try to elucidate the complex network of p53 regulation of different metabolic pathways. The role of p53 in cell metabolismXing-ding ZHANG, Zheng-hong QIN, Jin WANG * Department of Pharmacology and Aging and Nervous Diseases, Soochow University School of Medicine, Suzhou 215123, ChinaThe p53 tumor suppressor gene has recently been shown to mediate metabolic changes in cells under physiological and pathological conditions. It has been revealed that p53 regulates energy metabolism, oxidative stress, and amino acid metabolism through balancing glycolysis and oxidative phosphorylation (OXPHOS) as well as the autophagy pathway. p53 is activated by metabolic stress through AMP-activated protein kinase (AMPK) and the mammalian target of rapamycin (mTOR) signaling pathways. p53 regulates OXPHOS through the transcriptional regulation of fructose-2,6-bisphosophatase, TP53-induced glycolysis regulator (TIGAR) and synthesis of cytochrome c oxidase (SCO2) subunit of complex IV of the electron transport chain. p53 also indirectly influences the energy metabolism through regulating glucose transporter (GLUT) expression, glutaminase 2 (GLS2) and fatty acid synthase (FAS). In addition, p53 regulates autophagy to provide cell metabolites for surviving through damage regulated autophagy modulator (DRAM1). Here we review the recent findings to elucidate the important role of p53 in cell metabolism.

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“…Recent studies have shown that p53, a well-known tumor suppressor gene, plays a direct role in the inhibition of autophagy [1][2][3]. Autophagy is a membrane-trafficking process that mediates the delivery of cytoplasmic constituents to the lysosome for degradation [4].…”

Section: Editorialmentioning

confidence: 99%

Mechanism of DRAM1's Regulation of Autophagy and Apoptosis

Zhang¹

2015

J Pharmacogenomics Pharmacoproteomics

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EditorialRecent studies have shown that p53, a well-known tumor suppressor gene, plays a direct role in the inhibition of autophagy [1][2][3]. Autophagy is a membrane-trafficking process that mediates the delivery of cytoplasmic constituents to the lysosome for degradation [4]. DNA-Damage Regulated Autophagy Modulator 1 (DRAM1), a novel TP53 target gene, is an evolutionarily conserved lysosomal protein that has been reported to play an essential role in TP53-dependent autophagy activation and apoptosis [1]. However, the mechanisms by which DRAM1 promotes autophagy and apoptosis are not fully understood. In this editorial article, I will elucidate the network by which DRAM1 regulates autophagy and apoptosis. DRAM1 Regulates Autophagy Flux through Lysosomesp53 induces successful autophagy in a DRAM1-dependent manner, and GFP-LC3 was found to diffuse within the cytoplasm, with occasional puncta representing the basal level of autophagosomes within the cell in the absence of DRAM1 [1]. Upon DRAM1 induction, an increase in GFP-LC3 puncta was observed, indicating a clear role for DRAM1 and p53 in the regulation of autophagy [1]. The mechanisms through which DRAM1 causes the formation of autophagosomes are not clear. DRAM1 may send a feedback signal to proteins that are involved in the initiation of autophagy; alternatively, it may work in conjunction with other factors downstream of p53 [5].In the present study, I demonstrated that rapamycin increased the abundance of autophagosomes and that knock-down of DRAM1 reduced the rate autophagosome clearance after rapamycin withdrawal. The results also support the involvement of DRAM1 in the degradation of autophagosomes [6]. However, Galavotti et al found that DRAM1 was not involved in starvation-and mTORmediated autophagy activation [7]. Therefore, the role of DRAM1 in autophagy activation induced by other stimuli needs to be studied further. Lysosomes are rich in hydrolytic enzymes and are responsible for the degradation of intracellular materials captured by autophagy [8]. The increase in acidic lysosomes was noticeable, as indicated by a fluorescent dye.Knock-down of DRAM1 resulted in the impairment of lysosomal acidification and the accumulation of LC3-II, indicating reduced autophagy flux [6]. DRAM1 appeared to regulate autophagy in both the early and later stages. It also increased the formation of and clearance of autophagosomes [6]. The mechanism of DRAM1 is a lysosomal protein, and it may regulate the dynamics of lysosomal membranes to increase V-ATPase activity and facilitate membrane recycling for autophagosomal formation. DRAM1 Regulates Apoptosis Involving Protein Levels and Lysosomal Localization of BAXDRAM1 was first reported as a TP53 target gene that modulated autophagy [1]. Although DRAM1 cannot induce apoptosis by itself, it is a critical component of TP53-induced apoptosis [1,5]. Classic apoptosis is triggered by the translocation of the proapoptotic protein BAX from the cytosol to the mitochondria and is induced by the release of cytochrome c, which le...

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p53 mediates mitochondria dysfunction-triggered autophagy activation and cell death in rat striatum

Cited by 106 publications

References 49 publications

Autophagy and cancer – issues we need to digest

Autophagy and cancer – issues we need to digest

The role of p53 in cell metabolism

Mechanism of DRAM1's Regulation of Autophagy and Apoptosis

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