Alkaline ceramidase 2 is a novel direct target of p53 and induces autophagy and apoptosis through ROS generation

Wang, Ying; Zhang, Chunxue; Jin, Yinlong; Wang, Hong; He, Qiuming; Li, Zhu; Ai, Qing; Lei, Yunlong; Li, Yang; Song, Fangzhou; Bu, Youquan

doi:10.1038/srep44573

Cited by 33 publications

(25 citation statements)

References 52 publications

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“…ACER2 is expressed in the placenta, pancreas, and heart [39]. ACER2 expression is regulated by the tumor suppressor p53 and hypoxia-inducible factor 2α [41][42][43][44]. Hence, ACER2 mRNA expression has been found to be increased in human cancer tissue in the liver and colon when compared to samples of healthy individuals [39].…”

Section: Alkaline Ceramidasesmentioning

confidence: 99%

Role of Ceramidases in Sphingolipid Metabolism and Human Diseases

Parveen

Bender

Law

et al. 2019

Cells

102

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Human pathologies such as Alzheimer’s disease, type 2 diabetes-induced insulin resistance, cancer, and cardiovascular diseases have altered lipid homeostasis. Among these imbalanced lipids, the bioactive sphingolipids ceramide and sphingosine-1 phosphate (S1P) are pivotal in the pathophysiology of these diseases. Several enzymes within the sphingolipid pathway contribute to the homeostasis of ceramide and S1P. Ceramidase is key in the degradation of ceramide into sphingosine and free fatty acids. In humans, five different ceramidases are known—acid ceramidase, neutral ceramidase, and alkaline ceramidase 1, 2, and 3—which are encoded by five different genes (ASAH1, ASAH2, ACER1, ACER2, and ACER3, respectively). Notably, the neutral ceramidase N-acylsphingosine amidohydrolase 2 (ASAH2) shows considerable differences between humans and animals in terms of tissue expression levels. Besides, the subcellular localization of ASAH2 remains controversial. In this review, we sum up the results obtained for identifying gene divergence, structure, subcellular localization, and manipulating factors and address the role of ASAH2 along with other ceramidases in human diseases.

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Section: Alkaline Ceramidasesmentioning

confidence: 99%

Role of Ceramidases in Sphingolipid Metabolism and Human Diseases

Parveen

Bender

Law

et al. 2019

Cells

102

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“…In addition, G0S2 is also a target gene for peroxisome proliferator activated receptor (PPARα), a transcription factor participating in lipid metabolism and adipogenesis 40 . ACER2 is critical in metabolism of bioactive lipid sphingolipids [41][42][43] , downregulation of ACER2 upon carnosic acid may lead to changes in serum LDL, HDL and cholesterol level 44 .…”

Section: Discussionmentioning

confidence: 99%

Evaluation of bile salt hydrolase inhibitor efficacy for modulating host bile profile and physiology using a chicken model system

Geng

Long

Chang

et al. 2020

Sci Rep

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Gut microbial enzymes, bile salt hydrolases (BSHs) are the gateway enzymes for bile acid (BA) modification in the gut. This activity is a promising target for developing innovative non-antibiotic growth promoters to enhance animal production and health. Compelling evidence has shown that inhibition of BSH activity should enhance weight gain by altering the BA pool, host signalling and lipid metabolism. We recently identified a panel of promising BSH inhibitors. Here, we address the potential of them as alternative, effective, non-antibiotic feed additives, for commercial application, to promote animal growth using a chicken model. In this study, the in vivo efficacy of three BSH inhibitors (caffeic acid phenethylester, riboflavin, carnosic acid) were evaluated. 7-day old chicks (10 birds/group) were either untreated or they received one of the specific BSH inhibitors (25 mg/kg body weight) via oral gavage for 17 days. The chicks in treatment groups consistently displayed higher body weight gain than the untreated chicks. Metabolomic analysis demonstrated that BSH inhibitor treatment led to significant changes in both circulating and intestinal BA signatures in support of blunted intestinal BSH activity. Consistent with this finding, liver and intestinal tissue RNA-Seq analysis showed that carnosic acid treatment significantly altered expression of genes involved in lipid and bile acid metabolism. Taken together, this study validates microbial BSH activity inhibition as an alternative target and strategy to antibiotic treatment for animal growth promotion.

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“…As a well-known tumor suppressor, p53 mainly functions as transcription factor to regulate the expression of various downstream target genes, consequently participating in diverse biological processes, including DNA damage response, cell cycle progression, apoptosis, autophagy, metabolism, etc. [27][28][29]. Thus, identification of novel p53-target genes would provide greater insight into the molecular mechanisms that govern the tumor suppressor functions of p53.…”

Section: Discussionmentioning

confidence: 99%

BTG4 is A Novel p53 Target Gene That Inhibits Cell Growth and Induces Apoptosis

Zhang

Jiang

Wang

et al. 2020

Genes

Self Cite

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BTG4 is the last cloned and poorly studied member of BTG/Tob family. Studies have suggested that BTG4 is critical for the degradation of maternal mRNAs in mice during the process of maternal-to-zygotic transition, and downregulated in cancers, such as gastric cancer. However, the regulatory mechanism of BTG4 and its function in cancers remain elusive. In this study, we have for the first time identified the promoter region of the human BTG4 gene. Serial luciferase reporter assay demonstrated that the core promoter of BTG4 is mainly located within the 388 bp region near its transcription initiation site. Transcription factor binding site analysis revealed that the BTG4 promoter contains binding sites for canonical transcription factors, such as Sp1, whereas its first intron contains two overlapped consensus p53 binding sites. However, overexpression of Sp1 has negligible effects on BTG4 promoter activity, and site-directed mutagenesis assay further suggested that Sp1 is not a critical transcription factor for the transcriptional regulation of BTG4. Of note, luciferase assay revealed that one of the intronic p53 binding sites is highly responsive to p53. Both exogenous p53 overexpression and adriamycin-mediated endogenous p53 activation result in the transcriptional upregulation of BTG4. In addition, BTG4 is downregulated in lung and colorectal cancers, and overexpression of BTG4 inhibits cell growth and induces apoptosis in cancer cells. Taken together, our results strongly suggest that BTG4 is a novel p53-regulated gene and probably functions as a tumor suppressor in lung and colorectal cancers.

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Alkaline ceramidase 2 is a novel direct target of p53 and induces autophagy and apoptosis through ROS generation

Cited by 33 publications

References 52 publications

Role of Ceramidases in Sphingolipid Metabolism and Human Diseases

Role of Ceramidases in Sphingolipid Metabolism and Human Diseases

Evaluation of bile salt hydrolase inhibitor efficacy for modulating host bile profile and physiology using a chicken model system

BTG4 is A Novel p53 Target Gene That Inhibits Cell Growth and Induces Apoptosis

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