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المؤلفون: Yusuke Kawashima, Shuichi Ohkubo, Hiroaki Ochiiwa, Naoko Hashimoto, Motoi Nishimura, Masataka Yokoyama, Guzhanuer Ailiken, Akitoshi Nakayama, Tomoaki Tanaka, Tomonori Haruma, Chihoko Yoshimura, Kazuyuki Yamagata, Hidekazu Nagano, Osamu Ohara, Kazutaka Murata, Keiji Ishida, Hiromi Muraoka
المصدر: Oncogene
مصطلحات موضوعية: 0301 basic medicine, Cancer Research, NEDD8 Protein, Ubiquitin-Protein Ligases, CASP8 and FADD-Like Apoptosis Regulating Protein, Apoptosis, Article, CFLAR, Proto-Oncogene Proteins c-myc, Mice, 03 medical and health sciences, 0302 clinical medicine, Ubiquitin, Downregulation and upregulation, Cell Line, Tumor, hemic and lymphatic diseases, Genetics, Animals, Humans, Pyrroles, RNA-Seq, Enzyme Inhibitors, RNA, Small Interfering, Molecular Biology, Caspase, Haematological cancer, Caspase 8, biology, Myeloid leukemia, Xenograft Model Antitumor Assays, Cell biology, Leukemia, Myeloid, Acute, Pyrimidines, 030104 developmental biology, Proto-Oncogene Proteins c-bcl-2, 030220 oncology & carcinogenesis, biology.protein, Signal transduction, Chromatin immunoprecipitation, Signal Transduction
الوصف: TAS4464, a potent, selective small molecule NEDD8-activating enzyme (NAE) inhibitor, leads to inactivation of cullin-RING E3 ubiquitin ligases (CRLs) and consequent accumulations of its substrate proteins. Here, we investigated the antitumor properties and action mechanism of TAS4464 in acute myeloid leukemia (AML). TAS4464 induced apoptotic cell death in various AML cell lines. TAS4464 treatments resulted in the activation of both the caspase-9-mediated intrinsic apoptotic pathway and caspase-8-mediated extrinsic apoptotic pathway in AML cells; combined treatment with inhibitors of these caspases markedly diminished TAS4464-induced apoptosis. In each apoptotic pathway, TAS4464 induced the mRNA transcription of the intrinsic proapoptotic factor NOXA and decreased that of the extrinsic antiapoptotic factor c-FLIP. RNA-sequencing analysis showed that the signaling pathway of the CRL substrate c-Myc was enriched after TAS4464 treatment. Chromatin immunoprecipitation (ChIP) assay revealed that TAS4464-induced c-Myc bound to the PMAIP1 (encoding NOXA) and CFLAR (encoding c-FLIP) promoter regions, and siRNA-mediated c-Myc knockdown neutralized both TAS4464-mediated NOXA induction and c-FLIP downregulation. TAS4464 activated both caspase-8 and caspase-9 along with an increase in NOXA and a decrease in c-FLIP, resulting in complete tumor remission in a human AML xenograft model. These findings suggest that NAE inhibition leads to anti-AML activity via a novel c-Myc-dependent apoptosis induction mechanism.
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المؤلفون: Tomoaki Tanaka, Naoko Hashimoto
المصدر: Journal of human genetics. 62(2)
مصطلحات موضوعية: 0301 basic medicine, Untranslated region, Genetic Markers, medicine.medical_treatment, Type 2 diabetes, Biology, Bioinformatics, medicine.disease_cause, 03 medical and health sciences, Insulin-Secreting Cells, microRNA, Gene expression, Genetics, medicine, Diabetes Mellitus, Glucose homeostasis, Gene silencing, Humans, RNA, Messenger, Genetics (clinical), Insulin, medicine.disease, MicroRNAs, 030104 developmental biology, Gene Expression Regulation, Hyperglycemia, Cancer research, Insulin Resistance, Tumor Suppressor Protein p53, Carcinogenesis, Biomarkers, Genome-Wide Association Study
الوصف: MicroRNAs (miRNAs) are noncoding RNAs of ~22 nucleotides that regulate gene expression post-transcriptionally by binding to the 3' untranslated region of messenger RNA (mRNAs), resulting in inhibition of translation or mRNA degradation. miRNAs have a key role in fine-tuning cellular functions such as proliferation, differentiation and apoptosis, and they are involved in carcinogenesis, glucose homeostasis, inflammation and other biological processes. In this review, we focus on the role of miRNAs in the pathophysiology of the metabolic disease and diabetes mellitus, the hallmark of which is hyperglycemia caused by defective insulin secretion and/or action. A growing number of studies have revealed the association between miRNAs and the processes of insulin production and secretion in pancreatic β cells. In addition, aberrant expression of miRNAs in skeletal muscle, adipose tissue and liver has also been reported. Intriguingly, the tumor suppressor p53 has been implicated in the pathogenesis of diabetes in association with a number of miRNAs, suggesting that a p53/miRNA pathway might be a therapeutic target. Moreover, data from genome-wide association studies have revealed that several miRNA target sequences overlap type 2 diabetes susceptibility loci. Finally, the recent discovery of circulating miRNAs associated with diabetes onset/progression suggests the potential use of miRNAs as biomarkers.
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