TAILIEUCHUNG - Báo cáo khoa học: Functional analysis of pyrimidine biosynthesis enzymes using the anticancer drug 5-fluorouracil in Caenorhabditis elegans

Pyrimidine biosynthesis enzymes function in many cellular processes and are closely associated with pyrimidine antagonists used in cancer chemo-therapy. These enzymes are well characterized from bacteria to mammals, but not in a simple metazoan. To study the pyrimidine biosynthesis path-way inCaenorhabditis elegans, we screened for mutants exhibiting resis-tance to the anticancer drug 5-fluorouracil (5-FU). | ỊFEBS Journal Functional analysis of pyrimidine biosynthesis enzymes using the anticancer drug 5-fluorouracil in Caenorhabditis elegans Seongseop Kim1 z Dae-Hun Park2 z Tai Hoon Kim1 Moogak Hwang1 and Jaegal Shim1 1 Cancer ExperimentalResources Branch NationalCancer Center Gyeonggi-do Korea 2 College of Pharmacy Kangwon NationalUniversity Gangwon-do Korea Keywords 5-fluorouracil C. elegans UMPK UMPS uridine phosphorylase Correspondence J. Shim Cancer Experimental Resources Branch NationalCancer Center 809 Madu 1-dong Goyang-si Gyeonggi-do 411-769 Korea Fax 82 31 920 2002 Tel 82 31 920 2262 E-mail jaegal@ These authors contributed equally to this work Received 19 May 2009 revised 22 June 2009 accepted 24 June 2009 doi Pyrimidine biosynthesis enzymes function in many cellular processes and are closely associated with pyrimidine antagonists used in cancer chemotherapy. These enzymes are well characterized from bacteria to mammals but not in a simple metazoan. To study the pyrimidine biosynthesis pathway in Caenorhabditis elegans we screened for mutants exhibiting resistance to the anticancer drug 5-fluorouracil 5-FU . In several strains mutations were identified in the worm homolog of human uridine phosphorylase UP . UP is a member of the pyrimidine biosynthesis family of enzymes and is a key regulator of uridine homeostasis. C. elegans UP homologous protein UPP-1 exhibited both uridine and thymidine phosphorylase activity in vitro. Knockdown of other pyrimidine biosynthesis enzyme homologs such as uridine monophosphate kinase and uridine monophosphate synthetase also resulted in 5-FU resistance. Uridine monophosphate kinase and uridine monophosphate synthetase proteins are redundant and show different tissue-specific expression patterns in C. ele-gans. Whereas pyrimidine biosynthesis pathways are highly conserved between worms and humans no human thymidine phosphorylase homolog has been identified in C. elegans. UPP-1

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