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Of note, under various physiological conditions analysed in these studies, IDH2 mRNA and protein levels remain unchanged. Lastly, C/EBPβ and CHOP proteins modulate IDH1 levels under ER stress.
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Depletion of FOXO1 and FOXO3 was shown to block IDH1 expression leading to a decrease in α-KG or D-2HG levels in specific cell lines. Next, Forkhead O family of transcription factors include FOXO1 and FOXO3, these evolutionarily conserved transcription factors regulate a spectrum of cellular functions. SREBP1a and SREBP2 were shown to bind the IDH1 promoter and regulate its mRNA and protein levels in cells cultured in lipid-deficient media. After cleavage, SREBP proteins migrate to nucleus and activate gene expressions of enzymes involved in lipid synthesis. In cue to lipid-deficiency, SREBP cleavage-activating protein Scap in ER, Site-1 and Site-2 proteases in Golgi orchestrate the transport and cleavage of SREBP proteins from ER to Golgi. Sterol regulatory element-binding proteins (SREBPs) are transcription factors anchored to the endoplasmic reticulum (ER) in lipid-replete conditions. To understand whether cytosolic IDH1 and mitochondrial IDH2 enzymes show any cell cycle dependencies, we analysed the reported IDH-specific transcription factors. As IDH1 and IDH2 are evolutionarily conserved proteins and the yeast metabolic cycle is coordinated with the cell cycle, therefore, it is possible that the expression of the IDH1 or IDH2 proteins may show periodic expressions. Thus, the expressions of some of the metabolic enzymes in tumour cells are dependent on cell cycle or circadian oscillation. Moreover, glycolysis and glutamine metabolism are linked to the circadian rhythm of cancer cells. Protein levels of the PFKB3 peak in mid-G1 phase, GLS1 in S-phase, and PKM2 in G2/M phase. But in synchronized HeLa cells, protein levels of metabolic enzymes such as PFKB3, GLS-1 and PKM2 are modulated in a cell cycle-dependent manner. However, mammalian cells grow in nutrient-replete conditions thus, a periodic expression of a majority of metabolic genes may not be the norm. Taken together, the yeast metabolic cycle was shown to be coordinated with the cell cycle in nutrient-limiting conditions. Among them, yeast mitochondrial IDH1 mRNA was also temporally induced. However, not much is known about the cellular regulation of neomorphic IDH proteins or their associated metabolite, D-2HG.Ĭontinuous cultures of budding yeast grown under nutrient-limiting conditions demonstrated periodicity in the expressions of many metabolic genes.
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Moreover, D-2HG is assumed to be constitutively produced in mutant IDH1 expressing cells, whereas the enantiomer L-2HG is selectively produced under hypoxia. To date, major research in the area of oncogenic IDH1 and IDH2 are focused on elucidation of the role of D-2HG in tumours. Consequently, the overproduced D-2HG effectively contributes to increased methylation on CpG islands and histones. A gamut of TET-hydroxylases and Jumonji domain-containing histone demethylases are inhibited by D-2HG. Furthermore, D-2HG is structurally similar to α-KG and hence has been found to competitively inhibit α-KG utilizing enzymes. This leads to increased consumption of NADPH, thus mutant IDH1 cells expedite higher rates of pentose phosphate pathway to produce NAPDH. These mutations result in neomorphic activity of IDH1/2 and reduce α-KG to d-2-hydroxyglutarate (D-2HG). Mutations in IDH1/2, especially in its catalytic domain, are known to be associated with gliomas, acute myeloid leukaemia, chondrosarcomas and cholangiocarcinomas. Isocitrate dehydrogenases 1 and 2 (IDH1/2) catalyse the conversion of isocitrate to α-ketoglutarate (α-KG) with the production of NAPDH. MIDHi, mutant isocitrate dehydrogenase inhibitor
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