Cloning and initial characterization of the human DPYD gene promoter.
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.
Collie-Duguid
E S
ES
Department of Medicine and Therapeutics, University of Aberdeen, Aberdeen, Scotland, AB25 2ZD, United Kingdom. e.collie-duguid@abdn.ac.uk
Johnston
S J
SJ
Powrie
R H
RH
Milano
G
G
Etienne
M C
MC
Rochat
B
B
Watson
G C
GC
McLeod
H L
HL
D000818:Animals; D001483:Base Sequence; D003001:Cloning, Molecular; D017124:Conserved Sequence; D042943:Dihydrouracil Dehydrogenase (NADP); D006801:Humans; D008099:Liver / Q000378:metabolism; D008252:Macaca fascicularis; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000097:blood; D010088:Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D010802:Phylogeny; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D012689:Sequence Homology, Nucleic Acid; D014162:Transfection; D014407:Tumor Cells, Cultured
D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP)