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Transcription-dependent degradation controls the stability of the SREBP family of transcription factors
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.
2003 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 100, no 24, 13833-13838 p.Article in journal (Refereed) Published
Abstract [en]

Cholesterol metabolism is tightly controlled by members of the sterol regulatory element-binding protein (SREBP) family of transcription factors. Here we demonstrate that the ubiquitination and degradation of SREBPs depend on their transcriptional activity. Mutations in the transactivation or DNA-binding domains of SREBPs inhibit their transcriptional activity and stabilize the proteins. The transcriptional activity and degradation of these mutants are restored when fused to heterologous transactivation or DNA-binding domains. When SREBP1a was fused to the DBD of Gal4, the ubiquitination and degradation of the fusion protein depended on coexpression of a promoter-reporter gene containing Gal4-binding sites. In addition, disruption of the interaction between WT SREBP and endogenous p300/CBP resulted in inhibition of SREBP-dependent transcription and stabilization of SREBP. Chemical inhibitors of transcription reduced the degradation of transcriptionally active SREBP1a, whereas they had no effect on the stability of transcriptionally inactive mutants, demonstrating that transcriptional activation plays an important role in the degradation of SREBPs. Thus, transcription-dependent degradation of SREBP constitutes a feedback mechanism to regulate the expression of genes involved in cholesterol metabolism and may represent a general mechanism to regulate the duration of transcriptional responses.

Place, publisher, year, edition, pages
2003. Vol. 100, no 24, 13833-13838 p.
Keyword [en]
Animals, CCAAT-Enhancer-Binding Proteins/chemistry/*genetics/*metabolism, COS Cells, Cell Line, Cholesterol/metabolism, DNA-Binding Proteins/chemistry/*genetics/*metabolism, Drug Stability, Feedback, Genes; Reporter, Hela Cells, Humans, Models; Biological, Mutagenesis; Site-Directed, Protein Structure; Tertiary, Recombinant Fusion Proteins/chemistry/genetics/metabolism, Sequence Deletion, Sterol Regulatory Element Binding Protein 1, Transcription Factors/chemistry/*genetics/*metabolism, Transcription; Genetic, Ubiquitin/metabolism
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-10502DOI: 10.1073/pnas.2335135100PubMedID: 14615581OAI: oai:DiVA.org:uu-10502DiVA: diva2:38270
Available from: 2007-03-27 Created: 2007-03-27 Last updated: 2017-12-11Bibliographically approved

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Sundqvist, AndersEricsson, Johan

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