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YY1 inhibits the activation of the p53 tumor suppressor in response to genotoxic stress
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
2004 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 101, no 33, 12165-12170 p.Article in journal (Refereed) Published
Abstract [en]

The tumor suppressor p53 regulates cell-cycle progression and apoptosis in response to genotoxic stress, and inactivation of p53 is a common feature of cancer cells. The levels and activity of p53 are tightly regulated by posttranslational modifications, including phosphorylation, ubiquitination, and acetylation. Here, we demonstrate that the transcription factor Yin Yang 1 (YY1) interacts with p53 and inhibits its transcriptional activity. We show that YY1 disrupts the interaction between p53 and the coactivator p300 and that expression of YY1 blocks p300-dependent acetylation and stabilization of p53. Furthermore, expression of YY1 inhibits the accumulation of p53 and the induction of p53 target genes in response to genotoxic stress. YY1 also interacts with Mdm2 and the expression of YY1 promotes the assembly of the p53-Mdm2 complex. Consequently, YY1 enhances Mdm2-mediated ubiquitination of p53. Inactivation of endogenous YY1 enhances the accumulation of p53 as well as the expression of p53 target genes in response to DNA damage, and it sensitizes cells to DNA damage-induced apoptosis. Hence, our results demonstrate that YY1 regulates the transcriptional activity, acetylation, ubiquitination, and stability of p53 by inhibiting its interaction with the coactivator p300 and by enhancing its interaction with the negative regulator Mdm2. YY1 may, therefore, be an important negative regulator of the p53 tumor suppressor in response to genotoxic stress.

Place, publisher, year, edition, pages
2004. Vol. 101, no 33, 12165-12170 p.
Keyword [en]
Cell Line, DNA Damage, DNA-Binding Proteins/genetics/*metabolism, Humans, Nuclear Proteins/genetics/metabolism, Promoter Regions (Genetics), Protein Binding, Protein p53/genetics/*metabolism, Proto-Oncogene Proteins/genetics/metabolism, Recombinant Proteins/genetics/metabolism, Research Support; Non-U.S. Gov't, Sequence Deletion, Trans-Activators/genetics/metabolism, Transcription Factors/genetics/*metabolism, Transcription; Genetic, Ubiquitin/metabolism
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-73040DOI: 10.1073/pnas.0402283101PubMedID: 15295102OAI: oai:DiVA.org:uu-73040DiVA: diva2:100951
Available from: 2005-05-31 Created: 2005-05-31 Last updated: 2017-12-14

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Grönroos, EvaPunga, TanelEricsson, Johan

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