Positive regulation of promoter activity of human 3-phosphoglycerate dehydrogenase (PHGDH) gene is mediated by transcription factors Sp1 and NF-Y

Jun, Do Youn; Park, Hae Sun; Lee, Ji Young; Baek, Joo Youn; Park, Hwan-Ki; Fukui, Kiyoshi; Kim, Young Ho

doi:10.1016/j.gene.2008.02.018

Cited by 13 publications

(8 citation statements)

References 36 publications

(42 reference statements)

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“…This means that the regulation mechanism of human PHGDH gene expression differs from that of rats and mice. Similar to mouse PHGDH promoter, which previously demonstrated multiple transcription initiation sites at -136, -83, -81, -79, and -74 bases upstream from the first ATG codon, the human PHGDH promoter has Sp1 and NF-Ybinding sites in the absence of a TATA-box motif and thus showed multiplicity of transcriptional initiation sites [18,19]. Two different transcripts of 3-PHGDH mRNA were detected in normal human tissues.…”

Section: The Expression Of 3-phosphoglycerate Dehydrogenasementioning

confidence: 62%

The Role of D-3-Phosphoglycerate Dehydrogenase in Cancer

Zhao¹,

Fu²,

Du³

et al. 2020

Int. J. Biol. Sci.

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Serine, a non-essential amino acid, can be imported from the extracellular environment by transporters and de novo synthesized from glycolytic 3-phosphoglycerate (3-PG) in the serine biosynthetic pathway (SSP). It has been reported that active serine synthesis might be needed for the synthesis of proteins, lipids, and nucleotides and the balance of folate metabolism and redox homeostasis, which are necessary for cancer cell proliferation. Human D-3-phosphoglycerate dehydrogenase (PHGDH), the first and only rate-limiting enzyme in the de novo serine biosynthetic pathway, catalyzes the oxidation of 3-PG derived from glycolysis to 3-phosphohydroxypyruvate (3-PHP). PHGDH is highly expressed in tumors as a result of amplification, transcription, or its degradation and stability alteration, which dysregulates the serine biosynthesis pathway via metabolic enzyme activity to nourish tumors. And some recent researches reported that PHGDH promoted some tumors growth via non-metabolic way by upregulating target cancer-promoting genes. In this article, we reviewed the type, structure, expression and inhibitors of PHGDH, as well as the role it plays in cancer and tumor resistance to chemotherapy.

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Section: The Expression Of 3-phosphoglycerate Dehydrogenasementioning

confidence: 62%

The Role of D-3-Phosphoglycerate Dehydrogenase in Cancer

Zhao¹,

Fu²,

Du³

et al. 2020

Int. J. Biol. Sci.

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“…PHGDH, PSPH and PSAT are upregulated in some Myc-driven lymphomas (44). Additionally, oncogene-driven transcriptional misregulation in other malignancies (e.g., HER2, SP1, NFY, NRF2, ATF4) has been shown to increase expression of enzymes of de novo serine synthesis (45–47). EF thus appears to generate a metabolic program of upregulated serine synthesis similar to other malignancies.…”

Section: Discussionmentioning

confidence: 99%

EWS/FLI is a Master Regulator of Metabolic Reprogramming in Ewing Sarcoma

Bensard

Peng

Krah

et al. 2017

Molecular Cancer Research

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Ewing sarcoma is a bone malignancy driven by a translocation event resulting in the fusion protein EWS/FLI1 (EF). EF functions as an aberrant and oncogenic transcription factor that misregulates the expression of thousands of genes. Previous work has focused principally on determining important transcriptional targets of EF, as well as characterizing important regulatory partnerships in EF-dependent transcriptional programs. Less is known, however, about EF-dependent metabolic changes or their role in Ewing sarcoma biology. Therefore, the metabolic effects of silencing EF in Ewing sarcoma cells were determined. Metabolomic analyses revealed distinct separation of metabolic profiles in EF-knockdown vs. control-knockdown cells. Mitochondrial stress tests demonstrated that knockdown of EF increased respiratory as well as glycolytic functions. Enzymes and metabolites in several metabolic pathways were altered, including de novo serine synthesis and elements of one-carbon metabolism. Furthermore, phosphoglycerate dehydrogenase (PHGDH) was found to be highly expressed in Ewing sarcoma and correlated with worse patient survival. PHGDH knockdown or pharmacological inhibition in vitro caused impaired proliferation and cell death. Interestingly, PHGDH modulation also led to elevated histone expression and methylation. These studies demonstrate that the translocation-derived fusion protein EF is a master regulator of metabolic reprogramming in Ewing sarcoma, diverting metabolites toward biosynthesis. As such, these data suggest that the metabolic aberrations induced by EF are important contributors to the oncogenic biology of these tumors.

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“…Although hepatic cysteine levels were lower in the LP group, the magnitude of decrease does not appear to be sufficient to cause an induction of 3PGDH. We propose that the induction of 3PGDH gene transcription is mediated by transcriptional factors such as SP1 and NFy as a component of a global stress response (45,(57)(58)(59). Finally, the increase in serine flux was much greater than the decrease in methionine trans-sulfuration pathway, suggesting that the elevated serine levels were primarily the result of increased de novo synthesis rather than a decrease in the utilization of serine for cysteine and taurine production.…”

mentioning

confidence: 89%

Metabolic and Genomic Response to Dietary Isocaloric Protein Restriction in the Rat

Kalhan¹,

Uppal²,

Moorman³

et al. 2011

Journal of Biological Chemistry

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We have examined hepatic, genomic, and metabolic responses to dietary protein restriction in the non-pregnant Sprague-Dawley rat. Animals were pair-fed either a 6 or 24% casein-based diet for 7-10 days. At the end of the dietary period, a microarray analysis of the liver was performed, followed by validation of the genes of interest. The rates of appearance of phenylalanine, methionine, serine, and glucose and the contribution of pyruvate to serine and glucose were quantified using tracer methods. Plasma and tissue amino acid levels, enzyme activities, and metabolic intermediates were measured. Protein restriction resulted in significant differential expression of a number of genes involved in cell cycle, cell differentiation, transport, transcription, and metabolic processes. RT-PCR showed that the expression of genes involved in serine biosynthesis and fatty acid oxidation was higher, and those involved in fatty acid synthesis and urea synthesis were lower in the liver of protein-restricted animals. Free serine and glycine levels were higher and taurine levels lower in all tissues examined. Tracer isotope studies showed an ϳ50% increase in serine de novo synthesis. Pyruvate was the primary (ϳ90%) source of serine in both groups. Transmethylation of methionine was significantly higher in the protein-restricted group. This was associated with a higher S-adenosylmethionine/Sadenosylhomocysteine ratio and lower cystathione ␤-synthase and cystathionine ␥-lyase activity. Dietary isocaloric protein restriction results in profound changes in hepatic one-carbon metabolism within a short period. These may be related to high methylation demands placed on the organism and caused by possible changes in cellular osmolarity as a result of the efflux of the intracellular taurine.The metabolic and biochemical impact of qualitative and quantitative changes in dietary protein intake continues to be of interest because of their implications for public health and because of a number of studies showing a strong relationship between protein intake during pregnancy with cardiovascular function, hypertension, and glucose intolerance in the offspring (1-3). Studies in humans, primarily focused on whole body protein, nitrogen metabolism, and protein accretion, show that both high and low protein intake can impact these processes (4 -7). However, how humans adapt to protein deprivation or the biochemical mechanisms involved has not been examined. In the context of pregnancy, both high protein intake (in humans) and protein restriction in rodents have been shown to cause fetal metabolic programming and consequently altered physiological response in the offspring in adulthood (8 -11). In the rodent, dietary protein restriction during pregnancy results in growth retardation, impaired beta cell function and mass, impaired insulin sensitivity, hypertension, and other pathological responses in the offspring (1, 2). These have been associated with a change in the hypothalamic-pituitary-adrenal axis, changes in the renin-angiotensin system, and ...

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Positive regulation of promoter activity of human 3-phosphoglycerate dehydrogenase (PHGDH) gene is mediated by transcription factors Sp1 and NF-Y

Cited by 13 publications

References 36 publications

The Role of D-3-Phosphoglycerate Dehydrogenase in Cancer

The Role of D-3-Phosphoglycerate Dehydrogenase in Cancer

EWS/FLI is a Master Regulator of Metabolic Reprogramming in Ewing Sarcoma

Metabolic and Genomic Response to Dietary Isocaloric Protein Restriction in the Rat

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