Poly(ADP-ribose) polymerase-1 is a survival factor for radiation-exposed intestinal epithelial stem cells in vivo.

2.50
Hdl Handle:
http://hdl.handle.net/10541/82355
Title:
Poly(ADP-ribose) polymerase-1 is a survival factor for radiation-exposed intestinal epithelial stem cells in vivo.
Authors:
Ishizuka, Satoshi; Martin, Kareen; Booth, Catherine; Potten, Christopher S; De Murcia, Gilbert; Bürkle, Alexander; Kirkwood, Thomas B L
Abstract:
Poly(ADP-ribose) polymerase-1 (PARP-1) is a key enzyme mediating the cellular response to DNA strand breaks. It plays a critical role in genomic stability and survival of proliferating cells in culture undergoing DNA damage. Intestinal epithelium is the most proliferative tissue in the mammalian body and its stem cells show extreme sensitivity to low-level genotoxic stress. We investigated the role of PARP-1 in the in vivo damage response of intestinal stem cells in crypts of PARP-1-/- and control mice following whole-body gamma-irradiation (1 Gy). In the PARP-1-/- mice there was a significant delay during the first 6 h in the transient p53 accumulation in stem cells whereas an increased number of cells were positive for p21(CIP1/WAF1). Either no or only marginal differences were noted in MDM2 expression, apoptosis, induction of or recovery from mitotic blockage, or inhibition of DNA synthesis. We further observed a dose-dependent reduction in crypt survival measured at 4 days post-irradiation in control mice, and this crypt-killing effect was significantly potentiated in PARP-1-/- mice. Our results thus establish that PARP-1 acts as a survival factor for intestinal stem cells in vivo and suggest a functional link with early p53 and p21(CIP1/WAF1) responses.
Affiliation:
School of Clinical Medical Sciences-Gerontology, Institute for Ageing and Health, University of Newcastle upon Tyne, Newcastle upon Tyne NE4 6BE, UK.
Citation:
Poly(ADP-ribose) polymerase-1 is a survival factor for radiation-exposed intestinal epithelial stem cells in vivo. 2003, 31 (21):6198-205 Nucleic Acids Res.
Journal:
Nucleic Acids Research
Issue Date:
1-Nov-2003
URI:
http://hdl.handle.net/10541/82355
PubMed ID:
14576306
Type:
Article
Language:
en
ISSN:
1362-4962
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorIshizuka, Satoshi-
dc.contributor.authorMartin, Kareen-
dc.contributor.authorBooth, Catherine-
dc.contributor.authorPotten, Christopher S-
dc.contributor.authorDe Murcia, Gilbert-
dc.contributor.authorBürkle, Alexander-
dc.contributor.authorKirkwood, Thomas B L-
dc.date.accessioned2009-09-23T13:25:37Z-
dc.date.available2009-09-23T13:25:37Z-
dc.date.issued2003-11-01-
dc.identifier.citationPoly(ADP-ribose) polymerase-1 is a survival factor for radiation-exposed intestinal epithelial stem cells in vivo. 2003, 31 (21):6198-205 Nucleic Acids Res.en
dc.identifier.issn1362-4962-
dc.identifier.pmid14576306-
dc.identifier.urihttp://hdl.handle.net/10541/82355-
dc.description.abstractPoly(ADP-ribose) polymerase-1 (PARP-1) is a key enzyme mediating the cellular response to DNA strand breaks. It plays a critical role in genomic stability and survival of proliferating cells in culture undergoing DNA damage. Intestinal epithelium is the most proliferative tissue in the mammalian body and its stem cells show extreme sensitivity to low-level genotoxic stress. We investigated the role of PARP-1 in the in vivo damage response of intestinal stem cells in crypts of PARP-1-/- and control mice following whole-body gamma-irradiation (1 Gy). In the PARP-1-/- mice there was a significant delay during the first 6 h in the transient p53 accumulation in stem cells whereas an increased number of cells were positive for p21(CIP1/WAF1). Either no or only marginal differences were noted in MDM2 expression, apoptosis, induction of or recovery from mitotic blockage, or inhibition of DNA synthesis. We further observed a dose-dependent reduction in crypt survival measured at 4 days post-irradiation in control mice, and this crypt-killing effect was significantly potentiated in PARP-1-/- mice. Our results thus establish that PARP-1 acts as a survival factor for intestinal stem cells in vivo and suggest a functional link with early p53 and p21(CIP1/WAF1) responses.en
dc.language.isoenen
dc.subjectTumour Suppressor Protein p53en
dc.subject.meshAnimals-
dc.subject.meshApoptosis-
dc.subject.meshCell Survival-
dc.subject.meshCyclin-Dependent Kinase Inhibitor p21-
dc.subject.meshCyclins-
dc.subject.meshDNA Replication-
dc.subject.meshEpithelial Cells-
dc.subject.meshGamma Rays-
dc.subject.meshGene Deletion-
dc.subject.meshIntestines-
dc.subject.meshMice-
dc.subject.meshMice, Knockout-
dc.subject.meshMitosis-
dc.subject.meshNuclear Proteins-
dc.subject.meshPoly(ADP-ribose) Polymerases-
dc.subject.meshProto-Oncogene Proteins-
dc.subject.meshProto-Oncogene Proteins c-mdm2-
dc.subject.meshStem Cells-
dc.subject.meshTime Factors-
dc.subject.meshTumor Suppressor Protein p53-
dc.titlePoly(ADP-ribose) polymerase-1 is a survival factor for radiation-exposed intestinal epithelial stem cells in vivo.en
dc.typeArticleen
dc.contributor.departmentSchool of Clinical Medical Sciences-Gerontology, Institute for Ageing and Health, University of Newcastle upon Tyne, Newcastle upon Tyne NE4 6BE, UK.en
dc.identifier.journalNucleic Acids Researchen

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