Cloning and initial characterization of the human DPYD gene promoter

E S R Collie-Duguid, S J Johnston, R H Powrie, G Milano, M C Etienne, B Rochat, G C Watson, H L McLeod

Research output: Contribution to journalArticle

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Abstract

Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in the degradation of pyrimidine bases and pyrimidine-based antimetabolites. Reduced DPD activity is associated with toxicity to 5-fluorouracil (5FU) therapy in cancer patients and with neurological abnormalities in paediatric patients. Although variant DPYD alleles have been identified in DPD-deficient patients, they do not adequately explain polymorphic DPD activity or associated clinical phenotypes in vivo. DPD may be transcriptionally regulated as mRNA levels correlate with activity and are differentially regulated in human tissues. A 1.85 kb 5' flanking region of the human DPYD gene was cloned and has transcriptional activity in cultured cells. Analysis of this 5' flanking: region in rhesus and cynomolgus monkeys demonstrated conservation (>96%) between humans and primates. Putative binding sites for ubiquitous and cell-specific factors were identified. A polymorphism that disrupts a putative gamma-interferon response element was identified in a cancer patient with reduced DPD activity and severe 5FU toxicity. Further insight into regulation of DPD expression may identify new avenues for the treatment of clinical problems associated with DPD deficiency. (C) 2000 academic Press.

Original languageEnglish
Pages (from-to)28-35
Number of pages8
JournalBiochemical and Biophysical Research Communications
Volume271
Publication statusPublished - 2000

Keywords

  • dihydropyrimidine dehydrogenase
  • promoter
  • 5-fluorouracil
  • toxicity
  • transcription
  • human
  • rhesus
  • cynomolgus
  • polymorphism
  • DIHYDROPYRIMIDINE DEHYDROGENASE-DEFICIENCY
  • TRANSCRIPTION FACTORS
  • 5-FLUOROURACIL TOXICITY
  • MOLECULAR-BASIS
  • LIVER
  • FLUOROURACIL
  • INTERFERON
  • POPULATION
  • INHIBITION
  • PHENOTYPE

Cite this

Collie-Duguid, E. S. R., Johnston, S. J., Powrie, R. H., Milano, G., Etienne, M. C., Rochat, B., ... McLeod, H. L. (2000). Cloning and initial characterization of the human DPYD gene promoter. Biochemical and Biophysical Research Communications, 271, 28-35.

Cloning and initial characterization of the human DPYD gene promoter. / Collie-Duguid, E S R ; Johnston, S J ; Powrie, R H ; Milano, G ; Etienne, M C ; Rochat, B ; Watson, G C ; McLeod, H L .

In: Biochemical and Biophysical Research Communications, Vol. 271, 2000, p. 28-35.

Research output: Contribution to journalArticle

Collie-Duguid, ESR, Johnston, SJ, Powrie, RH, Milano, G, Etienne, MC, Rochat, B, Watson, GC & McLeod, HL 2000, 'Cloning and initial characterization of the human DPYD gene promoter', Biochemical and Biophysical Research Communications, vol. 271, pp. 28-35.
Collie-Duguid, E S R ; Johnston, S J ; Powrie, R H ; Milano, G ; Etienne, M C ; Rochat, B ; Watson, G C ; McLeod, H L . / Cloning and initial characterization of the human DPYD gene promoter. In: Biochemical and Biophysical Research Communications. 2000 ; Vol. 271. pp. 28-35.
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AU - Johnston, S J

AU - Powrie, R H

AU - Milano, G

AU - Etienne, M C

AU - Rochat, B

AU - Watson, G C

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AB - Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in the degradation of pyrimidine bases and pyrimidine-based antimetabolites. Reduced DPD activity is associated with toxicity to 5-fluorouracil (5FU) therapy in cancer patients and with neurological abnormalities in paediatric patients. Although variant DPYD alleles have been identified in DPD-deficient patients, they do not adequately explain polymorphic DPD activity or associated clinical phenotypes in vivo. DPD may be transcriptionally regulated as mRNA levels correlate with activity and are differentially regulated in human tissues. A 1.85 kb 5' flanking region of the human DPYD gene was cloned and has transcriptional activity in cultured cells. Analysis of this 5' flanking: region in rhesus and cynomolgus monkeys demonstrated conservation (>96%) between humans and primates. Putative binding sites for ubiquitous and cell-specific factors were identified. A polymorphism that disrupts a putative gamma-interferon response element was identified in a cancer patient with reduced DPD activity and severe 5FU toxicity. Further insight into regulation of DPD expression may identify new avenues for the treatment of clinical problems associated with DPD deficiency. (C) 2000 academic Press.

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