Inhibition by uridine but not thymidine of p53-dependent intestinal apoptosis initiated by 5-fluorouracil: evidence for the involvement of RNA perturbation.

2.50
Hdl Handle:
http://hdl.handle.net/10541/95246
Title:
Inhibition by uridine but not thymidine of p53-dependent intestinal apoptosis initiated by 5-fluorouracil: evidence for the involvement of RNA perturbation.
Authors:
Pritchard, D M; Watson, A J; Potten, Christopher S; Jackman, A L; Hickman, John A
Abstract:
The epithelia from the crypts of the intestine are exquisitely sensitive to metabolic perturbation and undergo cell death with the classical morphology of apoptosis. Administration of 40 mg/kg 5-fluorouracil (5-FU) to BDF-1 p53+/+ mice resulted in an increase in p53 protein at cell positions in the crypts that were also those subjected to an apoptotic cell death. In p53-/- mice apoptosis was almost completely absent, even after 24 hr. 5-FU is a pyrimidine antimetabolite cytotoxin with multiple mechanisms of action, including inhibition of thymidylate synthase (TS), which gives rise to DNA damage, and incorporation into RNA. The inhibition of TS can be increased by coadministration of folinic acid and can be abrogated by administration of thymidine. The incorporation of 5-FU into RNA is inhibited by administration of uridine. p53-Dependent cell death induced by 5-FU was only inhibited by administration of uridine. Uridine had no effect on the apoptosis initiated by 1 Gy of gamma-radiation. Although thymidine abrogated apoptosis induced by the pure TS inhibitor Tomudex, it had no effect on 5-FU-induced apoptosis, and coadministration of folinic acid did not increase apoptosis. The data show that 5-FU-induced cell death of intestinal epithelial cells is p53-dependent and suggests that changes in RNA metabolism initiate events culminating in the expression of p53.
Affiliation:
Department of Epithelial Cell Biology, The Paterson Institute for Cancer Research, Christie Hospital Trust, Manchester, United Kingdom.
Citation:
Inhibition by uridine but not thymidine of p53-dependent intestinal apoptosis initiated by 5-fluorouracil: evidence for the involvement of RNA perturbation. 1997, 94 (5):1795-9 Proc. Natl. Acad. Sci. USA
Journal:
Proceedings of the National Academy of Sciences of the United States of America
Issue Date:
4-Mar-1997
URI:
http://hdl.handle.net/10541/95246
PubMed ID:
9050858
Type:
Article
Language:
en
ISSN:
0027-8424
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorPritchard, D Men
dc.contributor.authorWatson, A Jen
dc.contributor.authorPotten, Christopher Sen
dc.contributor.authorJackman, A Len
dc.contributor.authorHickman, John Aen
dc.date.accessioned2010-03-30T11:50:38Z-
dc.date.available2010-03-30T11:50:38Z-
dc.date.issued1997-03-04-
dc.identifier.citationInhibition by uridine but not thymidine of p53-dependent intestinal apoptosis initiated by 5-fluorouracil: evidence for the involvement of RNA perturbation. 1997, 94 (5):1795-9 Proc. Natl. Acad. Sci. USAen
dc.identifier.issn0027-8424-
dc.identifier.pmid9050858-
dc.identifier.urihttp://hdl.handle.net/10541/95246-
dc.description.abstractThe epithelia from the crypts of the intestine are exquisitely sensitive to metabolic perturbation and undergo cell death with the classical morphology of apoptosis. Administration of 40 mg/kg 5-fluorouracil (5-FU) to BDF-1 p53+/+ mice resulted in an increase in p53 protein at cell positions in the crypts that were also those subjected to an apoptotic cell death. In p53-/- mice apoptosis was almost completely absent, even after 24 hr. 5-FU is a pyrimidine antimetabolite cytotoxin with multiple mechanisms of action, including inhibition of thymidylate synthase (TS), which gives rise to DNA damage, and incorporation into RNA. The inhibition of TS can be increased by coadministration of folinic acid and can be abrogated by administration of thymidine. The incorporation of 5-FU into RNA is inhibited by administration of uridine. p53-Dependent cell death induced by 5-FU was only inhibited by administration of uridine. Uridine had no effect on the apoptosis initiated by 1 Gy of gamma-radiation. Although thymidine abrogated apoptosis induced by the pure TS inhibitor Tomudex, it had no effect on 5-FU-induced apoptosis, and coadministration of folinic acid did not increase apoptosis. The data show that 5-FU-induced cell death of intestinal epithelial cells is p53-dependent and suggests that changes in RNA metabolism initiate events culminating in the expression of p53.en
dc.language.isoenen
dc.subjectTumour Suppressor Protein p53en
dc.subject.meshAnimals-
dc.subject.meshApoptosis-
dc.subject.meshColon-
dc.subject.meshEnzyme Inhibitors-
dc.subject.meshFluorouracil-
dc.subject.meshFolic Acid Antagonists-
dc.subject.meshGene Expression Regulation-
dc.subject.meshHistocytochemistry-
dc.subject.meshImmunohistochemistry-
dc.subject.meshIntestinal Mucosa-
dc.subject.meshIntestine, Small-
dc.subject.meshMale-
dc.subject.meshMice-
dc.subject.meshMice, Inbred Strains-
dc.subject.meshQuinazolines-
dc.subject.meshRNA-
dc.subject.meshThiophenes-
dc.subject.meshThymidine-
dc.subject.meshThymidylate Synthase-
dc.subject.meshTumor Suppressor Protein p53-
dc.subject.meshUridine-
dc.titleInhibition by uridine but not thymidine of p53-dependent intestinal apoptosis initiated by 5-fluorouracil: evidence for the involvement of RNA perturbation.en
dc.typeArticleen
dc.contributor.departmentDepartment of Epithelial Cell Biology, The Paterson Institute for Cancer Research, Christie Hospital Trust, Manchester, United Kingdom.en
dc.identifier.journalProceedings of the National Academy of Sciences of the United States of Americaen

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