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Article: dUTPase in human neoplastic cells as a potential target for therapeutic intervention

TitledUTPase in human neoplastic cells as a potential target for therapeutic intervention
Authors
Issue Date2001
PublisherBentham Science Publishers Ltd. The Journal's web site is located at http://www.bentham.org/cpps/index.htm
Citation
Current Protein And Peptide Science, 2001, v. 2 n. 4, p. 349-360 How to Cite?
AbstractWith the exception of brain, most human tissues analysed contain dUTPase protein detectable by immunohistochemistry. Non-dividing tissues like untreated peripheral blood lymphocytes (PBL's) contain basal levels of cytoplasmic dUTPase and express additional, nuclear dUTPase upon mitogenic stimulation. Normal, proliferating tissues like intestinal mucosa or germinal centres within tonsils contain cytoplasmic as well as nuclear dUTPase in accordance with a proposed role for dUTPase during cell division. Notably, no dUTPase is detectable during mitosis. The failure to stain dUTPase in normal brain tissue by immunohistochemistry while mRNA is readily detectable by Northern blotting cannot be explained at this moment. Epithelial tumours, such as adenocarcinoma of the lung, breast, colon, vulva or nasopharynx contain cells which are either positive for both or only one of the subcellular forms of the dUTPase and show variable numbers of dUTPase-positive cells. High levels of dUTPase correlate with a poor prognosis regarding the progression of colorectal carcinoma. Of the intracranial tumours tested, neuroepithelial tumours show almost exclusively nuclear expression whereas meningiomas of higher grades of malignancy (WHO grade II and III) also contain cells with additional cytoplasmic dUTPase. The dUTPase is detectable in other malignancies including tumours derived from lymphatic tissues like Burkitt's lymphoma or non-Hodgkin's-lymphoma. The downregulation of dUTPase protein during apoptosis or the inhibition of dUTPase during nerve cell development in Drosophila melanogaster suggests a possible role of the enzyme during apoptosis. In line with these observations, inhibition of dUTPase by antisense in p53-deficient tumour cells hints at a possible route of treatment of p53-deficient tumours which are otherwise resistant to therapies like irradiation. The expression of the enzyme in normal tissues indicates that sublethal levels of dUTPase inhibitors may also exert an unwanted mutagenic effect.
Persistent Identifierhttp://hdl.handle.net/10722/148244
ISSN
2015 Impact Factor: 2.441
2015 SCImago Journal Rankings: 1.430
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorGrässer, FAen_US
dc.contributor.authorRomeike, BFMen_US
dc.contributor.authorNiedobitek, Gen_US
dc.contributor.authorNicholls, Jen_US
dc.contributor.authorKremmer, Een_US
dc.date.accessioned2012-05-29T06:11:45Z-
dc.date.available2012-05-29T06:11:45Z-
dc.date.issued2001en_US
dc.identifier.citationCurrent Protein And Peptide Science, 2001, v. 2 n. 4, p. 349-360en_US
dc.identifier.issn1389-2037en_US
dc.identifier.urihttp://hdl.handle.net/10722/148244-
dc.description.abstractWith the exception of brain, most human tissues analysed contain dUTPase protein detectable by immunohistochemistry. Non-dividing tissues like untreated peripheral blood lymphocytes (PBL's) contain basal levels of cytoplasmic dUTPase and express additional, nuclear dUTPase upon mitogenic stimulation. Normal, proliferating tissues like intestinal mucosa or germinal centres within tonsils contain cytoplasmic as well as nuclear dUTPase in accordance with a proposed role for dUTPase during cell division. Notably, no dUTPase is detectable during mitosis. The failure to stain dUTPase in normal brain tissue by immunohistochemistry while mRNA is readily detectable by Northern blotting cannot be explained at this moment. Epithelial tumours, such as adenocarcinoma of the lung, breast, colon, vulva or nasopharynx contain cells which are either positive for both or only one of the subcellular forms of the dUTPase and show variable numbers of dUTPase-positive cells. High levels of dUTPase correlate with a poor prognosis regarding the progression of colorectal carcinoma. Of the intracranial tumours tested, neuroepithelial tumours show almost exclusively nuclear expression whereas meningiomas of higher grades of malignancy (WHO grade II and III) also contain cells with additional cytoplasmic dUTPase. The dUTPase is detectable in other malignancies including tumours derived from lymphatic tissues like Burkitt's lymphoma or non-Hodgkin's-lymphoma. The downregulation of dUTPase protein during apoptosis or the inhibition of dUTPase during nerve cell development in Drosophila melanogaster suggests a possible role of the enzyme during apoptosis. In line with these observations, inhibition of dUTPase by antisense in p53-deficient tumour cells hints at a possible route of treatment of p53-deficient tumours which are otherwise resistant to therapies like irradiation. The expression of the enzyme in normal tissues indicates that sublethal levels of dUTPase inhibitors may also exert an unwanted mutagenic effect.en_US
dc.languageengen_US
dc.publisherBentham Science Publishers Ltd. The Journal's web site is located at http://www.bentham.org/cpps/index.htmen_US
dc.relation.ispartofCurrent Protein and Peptide Scienceen_US
dc.subject.meshApoptosisen_US
dc.subject.meshBiological Markersen_US
dc.subject.meshBrain Neoplasms - Drug Therapy - Enzymologyen_US
dc.subject.meshCell Divisionen_US
dc.subject.meshCell Lineen_US
dc.subject.meshHumansen_US
dc.subject.meshLymphoproliferative Disorders - Drug Therapy - Enzymologyen_US
dc.subject.meshNeoplasms, Glandular And Epithelial - Drug Therapy - Enzymologyen_US
dc.subject.meshPyrophosphatases - Antagonists & Inhibitors - Metabolismen_US
dc.subject.meshTumor Suppressor Protein P53 - Metabolismen_US
dc.titledUTPase in human neoplastic cells as a potential target for therapeutic interventionen_US
dc.typeArticleen_US
dc.identifier.emailNicholls, J:nicholls@pathology.hku.hken_US
dc.identifier.authorityNicholls, J=rp00364en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.2174/1389203013381053en_US
dc.identifier.pmid12369931en_US
dc.identifier.scopuseid_2-s2.0-0035217489en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0035217489&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume2en_US
dc.identifier.issue4en_US
dc.identifier.spage349en_US
dc.identifier.epage360en_US
dc.identifier.isiWOS:000172869800009-
dc.publisher.placeNetherlandsen_US

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