Transcriptional Regulation Factors of the Human Mitochondrial Aspartate/Glutamate Carrier Gene, Isoform 2 (SLC25A13): USF1 as Basal Factor and FOXA2 as Activator in Liver Cells

Convertini, Paolo; Todisco, Simona; Santis, Francesco De; Pappalardo, Ilaria; Iacobazzi, Dominga; Morelli, Massimo; Fondufe‐Mittendorf, Yvonne; Martelli, Giuseppe; Palmieri, Ferdinando; Infantino, Vittoria

doi:10.3390/ijms20081888

Cited by 25 publications

(15 citation statements)

References 68 publications

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“…Recent decades, numerous studies have revealed that the mechanism of transcriptional regulation on gene expression were complex, including DNA methylation and transcriptional factors [39][40][41][42]. In present study, we found that the expression of MAPK4 was up-regulated in the lung tissues of ALI mice.…”

Section: Discussionsupporting

confidence: 53%

Identification of Atypical Mitogen-Activated Protein Kinase MAPK4 as A Novel Regulator in Acute Lung Injury

Mao

Zhou

Chen

et al. 2020

Preprint

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Background: Acute lung injury (ALI) is a serious disease with highly morbidity and mortality that causes serious health problems worldwide. Atypical mitogen activated protein kinases (MAPKs) play critical roles in the development of tissues and have been proposed as promising therapeutic targets for various diseases. However, the potential role of atypical MAPKs in ALI remains elusive. In this study, we investigated the role of atypical MAPKs family member MAPK4 in ALI using LPS-induced murine ALI model. Results: We found that MAPK4 deficiency mice exhibited prolonged survival time after LPS challenge, accompanied by alleviated pathology in lung tissues, decreased levels of pro-inflammatory cytokines and altered composition of immune cells in BALF. Furthermore, the transduction of related signaling pathways, including MK5, AKT, JNK, and p38 MAPK pathways, was reduced obviously in LPS-treated MAPK4-/- mice. Notably, the expression of MAPK4 was up-regulated in lung tissues of ALI model, which was not related with MAPK4 promoter methylation, but negatively orchestrated by transcriptional factors NFKB1 and NR3C1. Further studies have shown that the expression of MAPK4 was also increased in LPS-treated macrophages. Meanwhile, MAPK4 deficiency reduced the expression of related pro-inflammatory cytokines in macrophage in response to LPS treatment. Finally, MAPK4 inhibition using shRNA pre-treatment could ameliorate the pathology of lung tissues and prolong the survival time of mice after LPS challenge. Conclusions: Collectively, these findings reveal an important biological function of atypical MAPK in mediating the pathology of ALI, indicating that MAPK4 might be a novel potential therapeutic target for ALI treatment.

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Section: Discussionsupporting

confidence: 53%

Identification of Atypical Mitogen-Activated Protein Kinase MAPK4 as A Novel Regulator in Acute Lung Injury

Mao

Zhou

Chen

et al. 2020

Preprint

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“…AGC1 isoform is significantly upregulated in HCC, whereas AGC2 is downregulated with respect to normal liver cells. FOXA2, a well-known tumor suppressor and a transcriptional regulator of SLC25A13 gene, can be responsible for its high expression levels in liver and its downregulation in HCC [136].…”

Section: The Malate/aspartate Shuttle (Mas)mentioning

confidence: 99%

TCA Cycle Rewiring as Emerging Metabolic Signature of Hepatocellular Carcinoma

Todisco

Convertini

Iacobazzi

et al. 2019

Cancers

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Hepatocellular carcinoma (HCC) is a common malignancy. Despite progress in treatment, HCC is still one of the most lethal cancers. Therefore, deepening molecular mechanisms underlying HCC pathogenesis and development is required to uncover new therapeutic strategies. Metabolic reprogramming is emerging as a critical player in promoting tumor survival and proliferation to sustain increased metabolic needs of cancer cells. Among the metabolic pathways, the tricarboxylic acid (TCA) cycle is a primary route for bioenergetic, biosynthetic, and redox balance requirements of cells. In recent years, a large amount of evidence has highlighted the relevance of the TCA cycle rewiring in a variety of cancers. Indeed, aberrant gene expression of several key enzymes and changes in levels of critical metabolites have been observed in many solid human tumors. In this review, we summarize the role of the TCA cycle rewiring in HCC by reporting gene expression and activity dysregulation of enzymes relating not only to the TCA cycle but also to glutamine metabolism, malate/aspartate, and citrate/pyruvate shuttles. Regarding the transcriptional regulation, we focus on the link between NF-κB-HIF1 transcriptional factors and TCA cycle reprogramming. Finally, the potential of metabolic targets for new HCC treatments has been explored.

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“…Recent decades, numerous studies have revealed that the mechanisms of transcriptional regulation on gene expression were complex, including DNA methylation and transcriptional factors [42][43][44][45]. In present study, bioinformatics analysis showed that there was a CpG island in the promoter of MAPK4.…”

Section: Discussionmentioning

confidence: 50%

NFKB1/NR3C1-MAPK4 axis regulates the pathology of acute lung injury

Mao

Zhou

et al. 2020

Preprint

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BackgroundAcute lung injury (ALI) is a serious disease with highly morbidity and mortality that causes serious health problems worldwide. MAPK4, a member of atypical MAPK family, has been implicated in the development of cancer. Herein, the current study aimed to investigate the possible role of MAPK4 in the pathology of ALI to identify potential candidates for ALI therapy. MethodsMurine ALI model was established in WT or MAPK4 -/mice and the expressions of MAPK4 were measured. The survival ratio of ALI model mice was observed. Moreover, the changes of pathologic injury and infiltration of inflammatory cells, as well as the related signaling pathways, in lung tissues were analyzed. Furthermore, the possible molecular mechanism of MAPK4 expression in ALI was analyzed by massARRAY and EMSA assay. Finally, the effect of MAPK4 silencing using shRNA interference on the pathology of ALI was identified. the expression of MAPK4 by binding to the core sequence of MAPK4 promoter. Importantly, MAPK4-shRNA treatment could significantly reduce the pathology of lung tissues and prolong survival time of ALI mice. Altogether, our study reveals an unknown role of MAPK4 in the pathology of ALI, indicating that MAPK4 might be a new therapeutic target for clinic therapy against ALI. Materials And MethodsMice MAPK4 deficiency (MAPK4 -/-) mice breeding pair in a C57BL/6 background were purchased from The Jackson Laboratory (027666). Animals were housed under specific pathogen-free conditions at Zunyi Medical University. Cell cultureRaw264.7 cells were purchased from Conservation Genetics CAS Kunming Cell Bank (KCB200603YJ), and were cultured in high glucose DEME containing 10% fetal bovine serum at 37°C in 5% CO 2 . Establishment of ALI ModelWT and MAPK4 -/mice (7 to 9 week-old) were challenged with i.p. injection of 10mg/kg LPS (Escherichia coli 0111:B4; Sigma) dissolved in sterile PBS as shown in our previous study [17]. Then the body weight and lung weight index (lung weight/body weight) was detected at indicated time. Bronchoalveolar LavageImmediately after euthanasia, 1 ml aliquots of PBS were slowly infused in the murine lungs through the tracheostomy and then withdrawn gently. This lavage was repeated three times using the same syringe. The collected lavage fluid was stored in a 10ml tube on ice. The fluid was centrifuged at 1000rpm and 4°C for 10 min, and the cell sediment was washed with PBS. The cell-free supernatant was centrifuged again at 14,000g and 4°C for 10 min, stored at −80°C and used for determination of cytokines content via ELISA. To the pellet, red blood lysis buffer (Solarbio, R1010) were used for 15 min and washed with PBS. Next, the pellet was resuspended for analysis. Lung edema determinationLungs from mice were excised and completely dried in the oven at 60°C 24h for calculation of lung wet/dry ratio.

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Transcriptional Regulation Factors of the Human Mitochondrial Aspartate/Glutamate Carrier Gene, Isoform 2 (SLC25A13): USF1 as Basal Factor and FOXA2 as Activator in Liver Cells

Cited by 25 publications

References 68 publications

Identification of Atypical Mitogen-Activated Protein Kinase MAPK4 as A Novel Regulator in Acute Lung Injury

Identification of Atypical Mitogen-Activated Protein Kinase MAPK4 as A Novel Regulator in Acute Lung Injury

TCA Cycle Rewiring as Emerging Metabolic Signature of Hepatocellular Carcinoma

NFKB1/NR3C1-MAPK4 axis regulates the pathology of acute lung injury

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