The Adipogenic Acetyltransferase Tip60 Targets Activation Function 1 of Peroxisome Proliferator-Activated Receptor γ
The transcription factor peroxisome proliferator-activated receptor γ (PPARγ) plays a key role in the regulation of lipid and glucose metabolism in adipocytes, by regulating their differentiation, maintenance, and function. The transcriptional activity of PPARγ is dictated by the set of proteins wit...
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| Published in | Endocrinology (Philadelphia) Vol. 149; no. 4; pp. 1840 - 1849 |
|---|---|
| Main Authors | , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Bethesda, MD
Endocrine Society
01.04.2008
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| Subjects | |
| Online Access | Get full text |
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| Abstract | The transcription factor peroxisome proliferator-activated receptor γ (PPARγ) plays a key role in the regulation of lipid and glucose metabolism in adipocytes, by regulating their differentiation, maintenance, and function. The transcriptional activity of PPARγ is dictated by the set of proteins with which this nuclear receptor interacts under specific conditions. Here we identify the HIV-1 Tat-interacting protein 60 (Tip60) as a novel positive regulator of PPARγ transcriptional activity. Using tandem mass spectrometry, we found that PPARγ and the acetyltransferase Tip60 interact in cells, and through use of chimeric proteins, we established that coactivation by Tip60 critically depends on the N-terminal activation function 1 of PPARγ, a domain involved in isotype-specific gene expression and adipogenesis. Chromatin immunoprecipitation experiments showed that the endogenous Tip60 protein is recruited to PPARγ target genes in mature 3T3-L1 adipocytes but not in preadipocytes, indicating that Tip60 requires PPARγ for its recruitment to PPARγ target genes. Importantly, we show that in common with disruption of PPARγ function, small interfering RNA-mediated reduction of Tip60 protein impairs differentiation of 3T3-L1 preadipocytes. Taken together, these findings qualify the acetyltransferase Tip60 as a novel adipogenic factor. |
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| AbstractList | The transcription factor peroxisome proliferator-activated receptor gamma (PPAR gamma ) plays a key role in the regulation of lipid and glucose metabolism in adipocytes, by regulating their differentiation, maintenance, and function. The transcriptional activity of PPAR gamma is dictated by the set of proteins with which this nuclear receptor interacts under specific conditions. Here we identify the HIV-1 Tat-interacting protein 60 (Tip60) as a novel positive regulator of PPAR gamma transcriptional activity. Using tandem mass spectrometry, we found that PPAR gamma and the acetyltransferase Tip60 interact in cells, and through use of chimeric proteins, we established that coactivation by Tip60 critically depends on the N-terminal activation function 1 of PPAR gamma , a domain involved in isotype-specific gene expression and adipogenesis. Chromatin immunoprecipitation experiments showed that the endogenous Tip60 protein is recruited to PPAR gamma target genes in mature 3T3-L1 adipocytes but not in preadipocytes, indicating that Tip60 requires PPAR gamma for its recruitment to PPAR gamma target genes. Importantly, we show that in common with disruption of PPAR gamma function, small interfering RNA-mediated reduction of Tip60 protein impairs differentiation of 3T3-L1 preadipocytes. Taken together, these findings qualify the acetyltransferase Tip60 as a novel adipogenic factor. The transcription factor peroxisome proliferator-activated receptor γ (PPARγ) plays a key role in the regulation of lipid and glucose metabolism in adipocytes, by regulating their differentiation, maintenance, and function. The transcriptional activity of PPARγ is dictated by the set of proteins with which this nuclear receptor interacts under specific conditions. Here we identify the HIV-1 Tat-interacting protein 60 (Tip60) as a novel positive regulator of PPARγ transcriptional activity. Using tandem mass spectrometry, we found that PPARγ and the acetyltransferase Tip60 interact in cells, and through use of chimeric proteins, we established that coactivation by Tip60 critically depends on the N-terminal activation function 1 of PPARγ, a domain involved in isotype-specific gene expression and adipogenesis. Chromatin immunoprecipitation experiments showed that the endogenous Tip60 protein is recruited to PPARγ target genes in mature 3T3-L1 adipocytes but not in preadipocytes, indicating that Tip60 requires PPARγ for its recruitment to PPARγ target genes. Importantly, we show that in common with disruption of PPARγ function, small interfering RNA-mediated reduction of Tip60 protein impairs differentiation of 3T3-L1 preadipocytes. Taken together, these findings qualify the acetyltransferase Tip60 as a novel adipogenic factor. The transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) plays a key role in the regulation of lipid and glucose metabolism in adipocytes, by regulating their differentiation, maintenance, and function. The transcriptional activity of PPARgamma is dictated by the set of proteins with which this nuclear receptor interacts under specific conditions. Here we identify the HIV-1 Tat-interacting protein 60 (Tip60) as a novel positive regulator of PPARgamma transcriptional activity. Using tandem mass spectrometry, we found that PPARgamma and the acetyltransferase Tip60 interact in cells, and through use of chimeric proteins, we established that coactivation by Tip60 critically depends on the N-terminal activation function 1 of PPARgamma, a domain involved in isotype-specific gene expression and adipogenesis. Chromatin immunoprecipitation experiments showed that the endogenous Tip60 protein is recruited to PPARgamma target genes in mature 3T3-L1 adipocytes but not in preadipocytes, indicating that Tip60 requires PPARgamma for its recruitment to PPARgamma target genes. Importantly, we show that in common with disruption of PPARgamma function, small interfering RNA-mediated reduction of Tip60 protein impairs differentiation of 3T3-L1 preadipocytes. Taken together, these findings qualify the acetyltransferase Tip60 as a novel adipogenic factor. |
| Author | Grøntved, Lars Mandrup, Susanne Hamers, Nicole Brenkman, Arjan B Berger, Ruud van Beekum, Olivier van den Broek, Niels J. F Kalkhoven, Eric |
| Author_xml | – sequence: 1 givenname: Olivier surname: van Beekum fullname: van Beekum, Olivier – sequence: 2 givenname: Arjan B surname: Brenkman fullname: Brenkman, Arjan B – sequence: 3 givenname: Lars surname: Grøntved fullname: Grøntved, Lars – sequence: 4 givenname: Nicole surname: Hamers fullname: Hamers, Nicole – sequence: 5 givenname: Niels J. F surname: van den Broek fullname: van den Broek, Niels J. F – sequence: 6 givenname: Ruud surname: Berger fullname: Berger, Ruud – sequence: 7 givenname: Susanne surname: Mandrup fullname: Mandrup, Susanne – sequence: 8 givenname: Eric surname: Kalkhoven fullname: Kalkhoven, Eric |
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| SubjectTerms | 3T3-L1 Cells Adipogenesis Amino Acid Sequence Animals Biological and medical sciences Cell Line, Tumor Fundamental and applied biological sciences. Psychology Histone Acetyltransferases - physiology Human immunodeficiency virus 1 Humans Lysine Acetyltransferase 5 Mice Molecular Sequence Data PPAR gamma - chemistry PPAR gamma - physiology Protein Structure, Tertiary Transcription, Genetic Vertebrates: endocrinology |
| Title | The Adipogenic Acetyltransferase Tip60 Targets Activation Function 1 of Peroxisome Proliferator-Activated Receptor γ |
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