The tumor suppressor p53 regulates autophagosomal and lysosomal biogenesis in lung cancer cells by targeting transcription factor EB

Zhang, Zengli; Wang, Hongfeng; Ding, Qifeng; Xing, Yufei; Xu, Delai; Xu, Zhonghua; Zhou, Tong; Qi, Bin; Ji, Chenghong; Pan, Xue; Zhong, Anyuan; Ying, Zheng; Zhou, Caicun; Shi, Minhua

doi:10.1016/j.biopha.2017.02.103

Cited by 18 publications

(14 citation statements)

References 25 publications

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“…Similarly, the tumor suppressor p53 represents a master transcriptional regulator of the DNA damage response which promotes cell-cycle arrest, DNA repair, and ultimately apoptosis (Bunz et al, 1998). Much like TFEB and TFE3, p53 has also been implicated in a number of additional biological processes, including autophagy, angiogenesis, metabolism, and cell migration in response to different stress conditions (Bieging and Attardi, 2012; Tasdemir et al, 2008; Zhang et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

The transcription factors TFE3 and TFEB amplify p53 dependent transcriptional programs in response to DNA damage

Brady

Jeong

Martina

et al. 2018

eLife

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The transcription factors TFE3 and TFEB cooperate to regulate autophagy induction and lysosome biogenesis in response to starvation. Here we demonstrate that DNA damage activates TFE3 and TFEB in a p53 and mTORC1 dependent manner. RNA-Seq analysis of TFEB/TFE3 double-knockout cells exposed to etoposide reveals a profound dysregulation of the DNA damage response, including upstream regulators and downstream p53 targets. TFE3 and TFEB contribute to sustain p53-dependent response by stabilizing p53 protein levels. In TFEB/TFE3 DKOs, p53 half-life is significantly decreased due to elevated Mdm2 levels. Transcriptional profiles of genes involved in lysosome membrane permeabilization and cell death pathways are dysregulated in TFEB/TFE3-depleted cells. Consequently, prolonged DNA damage results in impaired LMP and apoptosis induction. Finally, expression of multiple genes implicated in cell cycle control is altered in TFEB/TFE3 DKOs, revealing a previously unrecognized role of TFEB and TFE3 in the regulation of cell cycle checkpoints in response to stress.

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Section: Discussionmentioning

confidence: 99%

The transcription factors TFE3 and TFEB amplify p53 dependent transcriptional programs in response to DNA damage

Brady

Jeong

Martina

et al. 2018

eLife

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“…Upon accumulation, the nuclear subpopulation of p53 acts as a transcription factor for autophagy housekeeping genes such as damage-regulated autophagy modifier (DRAM) ( Mrschtik et al, 2015 ; Zhang et al, 2013 ). In contrast, the cytosolic population of p53 counteracts autophagic induction because it inhibits the nuclear translocation of the transcription factor TFEB and, thus, the expression of autophagic genes ( Zhang et al, 2017 ). Thus, nuclear and cytosolic p53 species may play opposite roles in autophagy regulation under proteasomal inhibition.…”

Section: Crosstalk and Interplay Between The Ups And Autophagymentioning

confidence: 99%

Crosstalk and Interplay between the Ubiquitin-Proteasome System and Autophagy

Kwon

2017

Molecules and Cells

243

143

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Proteolysis in eukaryotic cells is mainly mediated by the ubiquitin (Ub)-proteasome system (UPS) and the autophagylysosome system (hereafter autophagy). The UPS is a selective proteolytic system in which substrates are recognized and tagged with ubiquitin for processive degradation by the proteasome. Autophagy is a bulk degradative system that uses lysosomal hydrolases to degrade proteins as well as various other cellular constituents. Since the inception of their discoveries, the UPS and autophagy were thought to be independent of each other in components, action mechanisms, and substrate selectivity. Recent studies suggest that cells operate a single proteolytic network comprising of the UPS and autophagy that share notable similarity in many aspects and functionally cooperate with each other to maintain proteostasis. In this review, we discuss the mechanisms underlying the crosstalk and interplay between the UPS and autophagy, with an emphasis on substrate selectivity and compensatory regulation under cellular stresses.

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“…Should the activity of these kinases diminish upon the loss of p53, nuclear localization of TFEB/TFE3/MITF and MCOLN1 expression would be increase. In agreement, loss of p53 in certain cancers leads to constitutively nuclear TFEB, and the attendant augmentation of endolysosomal biogenesis (Zhang et al, 2017). The increase in TFEB mRNA, then, would simply be a consequence of TFEB driving its own expression (Sardiello et al, 2009).…”

Section: Correlation Between Tp53 Mutations and Mcoln1 Expression In mentioning

confidence: 87%

“…Signaling that normally curtails endolysosomal gene expression morphs into drivers of vesicular biogenesis in cancer. For example, while the tumor suppressor, p53, activates TFEB and TFE3 in normal fibroblasts exposed to DNA damage, loss of p53 in cancers is also associated with the paradoxical activation of the TFEB/TFE3-endolysosome axis (Brady et al, 2018;Tasdemir et al, 2008aTasdemir et al, , 2008bZhang et al, 2017). The lack of clear insights into the regulation of TFEB/TFE3-driven endolysosomal biogenesis hinders our ability to exploit TRPML1 addiction as a therapeutic strategy.…”

Section: Introductionmentioning

confidence: 99%

ElevatedMCOLN1Expression in p53-Deficient Bladder Cancer is Necessary for Oncogene-Induced Cell proliferation, Inflammation, and Invasion

Jung

Han

Luan

et al. 2020

Preprint

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SummaryInhibition of the endolysosomal cation channel, TRPML1, which is encoded by MCOLN1, deters the proliferation of cancer cells with augmented TFEB activity. Here, we report that the tumor suppressor, p53, antagonizes TFEB-driven MCOLN1 expression in bladder cancer. Not only was the constitutive loss of p53 in bladder cancer cells associated with higher MCOLN1 mRNA, knockdown of TP53 in lines with wild type alleles of the tumor suppressor increased MCOLN1 expression. Elevated TRPML1 abundance in p53-deficient cancer cells, although not sufficient for bolstering proliferation, was necessary for the effects of oncogenic HRAS on cell division, cytokine production, and invasion. These data demonstrate that hyperactivation of the TFEB– MCOLN1 transcriptional axis in urothelial cells lacking p53 permits tumorigenesis stemming from HRAS mutations. Furthermore, the insight that loss of p53 predicts addiction to TRPML1 informs an actionable therapeutic strategy for bladder cancer.

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The tumor suppressor p53 regulates autophagosomal and lysosomal biogenesis in lung cancer cells by targeting transcription factor EB

Cited by 18 publications

References 25 publications

The transcription factors TFE3 and TFEB amplify p53 dependent transcriptional programs in response to DNA damage

The transcription factors TFE3 and TFEB amplify p53 dependent transcriptional programs in response to DNA damage

Crosstalk and Interplay between the Ubiquitin-Proteasome System and Autophagy

ElevatedMCOLN1Expression in p53-Deficient Bladder Cancer is Necessary for Oncogene-Induced Cell proliferation, Inflammation, and Invasion

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