Role of Ad4-binding protein/steroidogenic factor 1 in regulating NADPH production in adrenocortical Y-1 cells

Li, Bing; Baba, Takashi; Miyabayashi, Kanako; Sato, Tetsuya; Shima, Yuichi; Ichinose, Tomomi; Miura, Daisuke; Ohkawa, Yasuyuki; Suyama, Mikita; Morohashi, Ken Ichirou

doi:10.1507/endocrj.ej16-0467

Cited by 11 publications

(7 citation statements)

References 33 publications

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“…Despite the fact that MTHFD2 has been consistently described as an NAD + -dependent 5,10-CH 2 -THF dehydrogenase since its initial description in 1960 [ 30 ], several of these studies invoked MTHFD2 as the source of mitochondrial NADPH production. The kinetic analyses reported here clearly reveal the ability of MTHFD2 to use NADP + in vitro and provide a mechanistic basis for these flux analyses that implicate MTHFD2 in mitochondrial NADPH production [ 24 , 26 ].…”

Section: Discussionmentioning

confidence: 99%

Human mitochondrial MTHFD2 is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase

2017

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BackgroundFolate-dependent one-carbon metabolism provides one-carbon units for several biological processes. This pathway is highly compartmentalized in eukaryotes, with the mitochondrial pathway producing formate for use in cytoplasmic processes. The mitochondrial enzyme MTHFD2 has been reported to use NAD+ as a cofactor while the isozyme MTHFD2L utilizes NAD+ or NADP+ at physiologically relevant conditions. Because MTHFD2 is highly expressed in many cancer types, we sought to determine the cofactor preference of this enzyme.ResultsKinetic analysis shows that purified human MTHFD2 exhibits dual redox cofactor specificity, utilizing either NADP+ or NAD+ with the more physiologically relevant pentaglutamate folate substrate.ConclusionThese results show that the mitochondrial folate pathway isozymes MTHFD2 and MTHFD2L both exhibit dual redox cofactor specificity. Our kinetic analysis clearly supports a role for MTHFD2 in mitochondrial NADPH production, indicating that this enzyme is likely responsible for mitochondrial production of both NADH and NADPH in rapidly proliferating cells.

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Section: Discussionmentioning

confidence: 99%

Human mitochondrial MTHFD2 is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase

2017

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“…It participates in the regulation of cell cycle progression, genetic instability, apoptosis, and metabolism (30). Li et al (32) reported that Ad4-binding protein/steroidogenic factor 1 (Ad4BP/SF-1) directly regulated MTHFD2 expression by binding to the CHIP-peak regions, thus affecting NADPH production in adrenocortical Y-1 cells. In Ewing sarcoma (EWS), the chimeric transcription factor EWS-FLI1 was the primary oncogenic driver that positively regulated the expression of MTHFD2 and MTHFD1L and impacted cellular redox status (33).…”

Section: Regulation Of Mthfd2 In Cancersmentioning

confidence: 99%

More Than a Metabolic Enzyme: MTHFD2 as a Novel Target for Anticancer Therapy?

Zhu

Leung

2020

Front. Oncol.

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The bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) is a mitochondrial one-carbon folate metabolic enzyme whose role in cancer was not known until recently. MTHFD2 is highly expressed in embryos and a wide range of tumors but has low or absent expression in most adult differentiated tissues. Elevated MTHFD2 expression is associated with poor prognosis in both hematological and solid malignancy. Its depletion leads to suppression of multiple malignant phenotypes including proliferation, invasion, migration, and induction of cancer cell death. The non-metabolic functions of this enzyme, especially in cancers, have thus generated considerable research interests. This review summarizes current knowledge on both the metabolic functions and non-enzymatic roles of MTHFD2. Its expression, potential functions, and regulatory mechanism in cancers are highlighted. The development of MTHFD2 inhibitors and their implications in pre-clinical models are also discussed.

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“…To comprehensively understand the actions of Nr5a1, genomewide studies with DNA arrays and deep sequencing were conducted (Table 1) [40,[52][53][54][55][56][57][58]. In fact, these genome-wide studies identified many novel target genes of NR5A1, and eventually unveiled novel roles of NR5A1 in biological, physiological, and pathological processes.…”

Section: Genome-wide Techniques As Powerful Tools To Unveil Novel Funmentioning

confidence: 99%

“…This energized molecule is synthesized by multiple pathways and enzymes, such as the pentose phosphate pathway, malic enzymes, and methylenetetrahydrofolate dehydrogenases. Among these, genes encoding malic enzyme 1 and methylenetetrahydrofolate dehydrogenase 2 were identified as Nr5a1 targets [57]. NADPH concentration also decreased with Nr5a1 knockdown.…”

Section: Regulation Of Metabolism By Nr5a1mentioning

confidence: 99%

Coordination of Multiple Cellular Processes by NR5A1/Nr5a1

Morohashi¹,

Inoue²,

Baba³

2020

Endocrinol Metab

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The agenesis of the gonads and adrenal gland in revealed by knockout mouse studies strongly suggested a crucial role for Nr5a1 (SF-1 or Ad4BP) in organ development. In relation to these striking phenotypes, NR5A1/Nr5a1 has the potential to reprogram cells to steroidogenic cells, endow pluripotency, and regulate cell proliferation. However, due to limited knowledge regarding NR5A1 target genes, the mechanism by which NR5A1/Nr5a1 regulates these fundamental processes has remained unknown. Recently, newlyestablished technologies have enabled the identification of NR5A1 target genes related to multiple metabolic processes, as well as the aforementioned biological processes. Considering that active cellular processes are expected to be accompanied by active metabolism, NR5A1 may act as a key factor for processes such as cell differentiation, proliferation, and survival by coordinating these processes with cellular metabolism. A complete and definite picture of the cellular processes coordinated by NR5A1/Nr5a1 could be depicted by accumulating evidence of the potential target genes through whole genome studies.

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Role of Ad4-binding protein/steroidogenic factor 1 in regulating NADPH production in adrenocortical Y-1 cells

Cited by 11 publications

References 33 publications

Human mitochondrial MTHFD2 is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase

Human mitochondrial MTHFD2 is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase

More Than a Metabolic Enzyme: MTHFD2 as a Novel Target for Anticancer Therapy?

Coordination of Multiple Cellular Processes by NR5A1/Nr5a1

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