You are not currently logged in.
Access your personal account or get JSTOR access through your library or other institution:
If You Use a Screen ReaderThis content is available through Read Online (Free) program, which relies on page scans. Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
Differential control of TAp73 and ΔNp73 protein stability by the ring finger ubiquitin ligase PIR2
Berna S. Sayan, Ai Li Yang, Franco Conforti, Paola Tucci, Maria Cristina Piro, Gareth J. Browne, Massimiliano Agostini, Sergio Bernardini, Richard A. Knight, Tak W. Mak, Gerry Melino and Michael Karin
Proceedings of the National Academy of Sciences of the United States of America
Vol. 107, No. 29 (July 20, 2010), pp. 12877-12882
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/25708632
Page Count: 6
Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
Preview not available
p73 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.
Proceedings of the National Academy of Sciences of the United States of America © 2010 National Academy of Sciences