Transcriptional regulation of the legumain gene by p53 in HCT116 cells

Yamane, Toshimi; Murao, Sato; Kato-Ose, Izumi; Kashima, Lisa; Yuguchi, Motoki; Kozuka, Miyuki; Takeuchi, Keisuke; Ogita, Hisakazu; Ohkubo, Iwao; Ariga, Hiroyoshi

doi:10.1016/j.bbrc.2013.08.007

Cited by 21 publications

(16 citation statements)

References 23 publications

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“…AEP plays important roles in regulation of the immune system (45) and in cancer (46,47) and has recently been shown to cleave the protein tau in Alzheimer's disease (48,49). In addition, its expression and activity are regulated by TP53 (50), and it cleaves peptide bonds carboxy terminal to asparagine (51). The asparagine residue of VDAC1 cleaved by AEP is exposed on the cytoplasmic side of the mitochondria, so this residue could come into contact with the contents of lysosomes.…”

Section: Discussionmentioning

confidence: 99%

Local Mitochondrial-Endolysosomal Microfusion Cleaves Voltage-Dependent Anion Channel 1 To Promote Survival in Hypoxia

Brahimi-Horn

Lacas‐Gervais

Adaixo

et al. 2015

Molecular and Cellular Biology

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The oxygen-limiting (hypoxic) microenvironment of tumors induces metabolic reprogramming and cell survival, but the underlying mechanisms involving mitochondria remain poorly understood. We previously demonstrated that hypoxia-inducible factor 1 mediates the hyperfusion of mitochondria by inducing Bcl-2/adenovirus E1B 19-kDa interacting protein 3 and posttranslational truncation of the mitochondrial ATP transporter outer membrane voltage-dependent anion channel 1 in hypoxic cells. In addition, we showed that truncation is associated with increased resistance to drug-induced apoptosis and is indicative of increased patient chemoresistance. We now show that silencing of the tumor suppressor TP53 decreases truncation and increases drug-induced apoptosis. We also show that TP53 regulates truncation through induction of the mitochondrial protein Mieap. While we found that truncation was independent of mitophagy, we observed local microfusion between mitochondria and endolysosomes in hypoxic cells in culture and in patients' tumor tissues. Since we found that the endolysosomal asparagine endopeptidase was responsible for truncation, we propose that it is a readout of mitochondrial-endolysosomal microfusion in hypoxia. These novel findings provide the framework for a better understanding of hypoxic cell metabolism and cell survival through mitochondrial-endolysosomal microfusion regulated by hypoxia-inducible factor 1 and TP53. Hypoxia is a natural occurring stress that results in compensatory changes in metabolism and cell survival during embryonic development and tumor growth. Hypoxia stabilizes and activates the transcription factor hypoxia-inducible factor (HIF) through inhibition of oxygen-dependent hydroxylases that earmark the alpha subunit of HIF for proteasomal degradation (1). HIF induces or represses the expression of genes implicated in a myriad of functions, including those regulating metabolism and resistance to drug-induced cell death. Genes coding for the enzymes of the glycolytic pathway, including hexokinase, are highly induced by HIF-1, and this is in part responsible for the switch in metabolism from mitochondrial respiration to glycolysis in cancer cells. Considerable studies have pointed to the Warburg effect, also termed aerobic glycolysis, as the major adaptive response of cancer cells, but mitochondrial metabolism and mitochondrial dynamics are also starting to be recognized as important adaptive strategies of cancer cells (2). Mitochondria are critical organelles that regulate both metabolism and cell death. They are dynamic organelles that continuously undergo fission and fusion during cell growth (3, 4). Under stress conditions, such as nutrient depletion or hypoxia, mitochondria either fragment or are degraded by HIF-dependent mitophagy (mitochondrial removal by autophagy) (5) or hyperfuse together to form elongated or rounded structures that optimize ATP production and promote cell survival (6-11).We reported previously that certain cell lines exposed to hypoxia contained enlarged mitochon...

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Section: Discussionmentioning

confidence: 99%

Local Mitochondrial-Endolysosomal Microfusion Cleaves Voltage-Dependent Anion Channel 1 To Promote Survival in Hypoxia

Brahimi-Horn

Lacas‐Gervais

Adaixo

et al. 2015

Molecular and Cellular Biology

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“…Analysis by mass spectrometry of VDAC1-ΔC showed cleavage at asparagine 214 and glycine 213. Of note, AEP is also regulated by TP53 (56). Moreover, we reported that BNIP3, already known to be involved in regulating mitochondria morphology in hypoxia (36), acted as a docking site for lysosomes together with clathrin, a protein involved in multiple membrane vesicle trafficking pathways (57).…”

Section: The Hypoxic Mitochondrial Phenotype and Vdac1-δcmentioning

confidence: 99%

News about VDAC1 in Hypoxia

Mazure

2016

Front. Oncol.

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The voltage-dependent anion channel (VDAC) is the main interface between the cytosol and mitochondria of cells. It plays a crucial role in both mitochondrial metabolism and cell death. The main basic function of this channel is to mediate and gate the flux of small ions, metabolites, and adenosine triphosphate. Changes in its structure, and thus conformation, are expected to affect its activity and modulate the ability of cancer cells to expand. In this review, we describe a novel mechanism by which mitochondria of cells in hypoxia, a low level of oxygen, protects from apoptosis. In hypoxia, some mitochondria become enlarged due to hyperfusion. These mitochondria possess a truncated form of VDAC1 (VDAC1-ΔC), which is linked to the higher metabolic capacity and the greater resistance to cell death of hypoxic cells. However, not all of the VDAC1 protein is truncated, but the amount of the full-length form is diminished compared to the amount in normoxic cells. First, we describe how such a decrease effects cell proliferation, respiration, glycolysis, and other processes. Second, we report on a novel mitochondrial-endolysosomal crosstalk that leads to VDAC1 truncation. By pharmacological targeting of VDAC1-ΔC, the production of energy could be turned off and the sensitivity to cell death restored. This could counteract the favorable microenvironment that gives cancer cells a growth advantage and thereby disrupts the balance between life and death, which is controlled by VDAC1.

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“…Alginates can accelerate the autocatalytic activation of pro-LGMN at pH 4.0 and 5.0 8 , with their activities increasing upon exposure to doxorubicin and reducing following knock-down of p53 9 . Similarly, intracellular LGMN activity is decreased by internalization of cystatin E/M 10 .…”

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confidence: 99%

Clinicopathologic significance of legumain overexpression in cancer: a systematic review and meta-analysis

Guo

Shen

et al. 2015

Sci Rep

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Since reports on the clinical significance of legumain in cancer have shown inconsistent results, we systematically evaluated clinical indicators of legumain in cancer. We searched the Cochrane Library, PubMed, Embase, and EBSCO databases and the Wangfang and CNKI databases in China by using “legumain” and (“neoplasms” OR “cancer”) as search terms. We included case-controlled studies of legumain and cancer. The quality of the studies was evaluated by using Lichtenstein’s guidelines, and valid data was extracted for analysis. In total, 10 articles were included in this study. Meta-analysis showed that legumain was overexpressed in cancer compared with in normal tissue and was higher in stage III–IV disease than in I–II disease. Moreover, legumain overexpression was correlated with poor prognosis and clinical stage. Furthermore, Cancer Genome Atlas data showed that among patients with rectal cancer, those with tumors overexpressing legumain had shorter overall survival than those in the low expression group (P < 0.05). Legumain appears to be involved in tumor development and deterioration; thus, it can potentially be developed into both a marker for monitoring and diagnosing tumors and a therapeutic target.

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Transcriptional regulation of the legumain gene by p53 in HCT116 cells

Cited by 21 publications

References 23 publications

Local Mitochondrial-Endolysosomal Microfusion Cleaves Voltage-Dependent Anion Channel 1 To Promote Survival in Hypoxia

Local Mitochondrial-Endolysosomal Microfusion Cleaves Voltage-Dependent Anion Channel 1 To Promote Survival in Hypoxia

News about VDAC1 in Hypoxia

Clinicopathologic significance of legumain overexpression in cancer: a systematic review and meta-analysis

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