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Article: Differential control of TAp73 and ΔNp73 protein stability by the ring finger ubiquitin ligase PIR2

TitleDifferential control of TAp73 and ΔNp73 protein stability by the ring finger ubiquitin ligase PIR2
Authors
KeywordsUbiquitylation
p73
RNF144b
DNA damage
Issue Date2010
Citation
Proceedings of the National Academy of Sciences of the United States of America, 2010, v. 107, n. 29, p. 12877-12882 How to Cite?
Abstractp73 is a p53-related transcription factor with fundamental roles in development and tumor suppression. Transcription from two different promoters on the p73 gene results in generation of transcriptionally active TAp73 isoforms and dominant negative ΔNp73 isoforms with opposing pro- and anti-apoptotic functions. Therefore, the relative ratio of each isoform is an important determinant of the cell fate. Proteasomal degradation of p73 is mediated by polyubiquitination-dependent and -independent processes both of which appear, thus far, to lack selectivity for the TAp73 and ΔNp73 isoforms. Here, we describe the characterization of another transcriptional target of TAp73; a ring finger domain ubiquitin ligase p73 Induced RING 2 protein (PIR2). Although PIR2 was initially identified a p53-induced gene (p53RFP), low abundance of PIR2 transcript in mouse embryonic fibroblasts of TAp73 KO mice compared with WT mice and comparison of PIR2 mRNA and protein levels following TAp73 or p53 overexpression substantiate TAp73 isoforms as strong inducers of PIR2. Although PIR2 expression was induced by DNA damage, its expression did not alter apoptotic response or cell cycle profile per se. However, coexpression of PIR2 with TAp73 or ΔNp73 resulted in an increase of the TA/ΔNp73 ratio, due to preferential degradation of ΔNp73. Finally, PIR2 was able to relieve the inhibitory effect of ΔNp73 on TAp73 induced apoptosis following DNA damage. These results suggest that PIR2, by being induced by TAp73 and degrading ΔNp73, differentially regulates TAp73/ΔNp73 stability, and, hence, it may offer a therapeutic approach to enhance the chemosensitivity of tumor cells.
Persistent Identifierhttp://hdl.handle.net/10722/291982
ISSN
2023 Impact Factor: 9.4
2023 SCImago Journal Rankings: 3.737
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorSayan, Berna S.-
dc.contributor.authorYang, Ai Li-
dc.contributor.authorConforti, Franco-
dc.contributor.authorTucci, Paola-
dc.contributor.authorPiro, Maria Cristina-
dc.contributor.authorBrowne, Gareth J.-
dc.contributor.authorAgostini, Massimiliano-
dc.contributor.authorBernardini, Sergio-
dc.contributor.authorKnight, Richard A.-
dc.contributor.authorMak, Tak W.-
dc.contributor.authorMelino, Gerry-
dc.date.accessioned2020-11-17T14:55:31Z-
dc.date.available2020-11-17T14:55:31Z-
dc.date.issued2010-
dc.identifier.citationProceedings of the National Academy of Sciences of the United States of America, 2010, v. 107, n. 29, p. 12877-12882-
dc.identifier.issn0027-8424-
dc.identifier.urihttp://hdl.handle.net/10722/291982-
dc.description.abstractp73 is a p53-related transcription factor with fundamental roles in development and tumor suppression. Transcription from two different promoters on the p73 gene results in generation of transcriptionally active TAp73 isoforms and dominant negative ΔNp73 isoforms with opposing pro- and anti-apoptotic functions. Therefore, the relative ratio of each isoform is an important determinant of the cell fate. Proteasomal degradation of p73 is mediated by polyubiquitination-dependent and -independent processes both of which appear, thus far, to lack selectivity for the TAp73 and ΔNp73 isoforms. Here, we describe the characterization of another transcriptional target of TAp73; a ring finger domain ubiquitin ligase p73 Induced RING 2 protein (PIR2). Although PIR2 was initially identified a p53-induced gene (p53RFP), low abundance of PIR2 transcript in mouse embryonic fibroblasts of TAp73 KO mice compared with WT mice and comparison of PIR2 mRNA and protein levels following TAp73 or p53 overexpression substantiate TAp73 isoforms as strong inducers of PIR2. Although PIR2 expression was induced by DNA damage, its expression did not alter apoptotic response or cell cycle profile per se. However, coexpression of PIR2 with TAp73 or ΔNp73 resulted in an increase of the TA/ΔNp73 ratio, due to preferential degradation of ΔNp73. Finally, PIR2 was able to relieve the inhibitory effect of ΔNp73 on TAp73 induced apoptosis following DNA damage. These results suggest that PIR2, by being induced by TAp73 and degrading ΔNp73, differentially regulates TAp73/ΔNp73 stability, and, hence, it may offer a therapeutic approach to enhance the chemosensitivity of tumor cells.-
dc.languageeng-
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of America-
dc.subjectUbiquitylation-
dc.subjectp73-
dc.subjectRNF144b-
dc.subjectDNA damage-
dc.titleDifferential control of TAp73 and ΔNp73 protein stability by the ring finger ubiquitin ligase PIR2-
dc.typeArticle-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1073/pnas.0911828107-
dc.identifier.pmid20615966-
dc.identifier.pmcidPMC2919933-
dc.identifier.scopuseid_2-s2.0-77955648341-
dc.identifier.volume107-
dc.identifier.issue29-
dc.identifier.spage12877-
dc.identifier.epage12882-
dc.identifier.eissn1091-6490-
dc.identifier.isiWOS:000280144500033-
dc.identifier.issnl0027-8424-

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