Modulation of p53 activity by IκBα: Evidence suggesting a common phylogeny between NF-κB and p53 transcription factors
<p>Abstract</p> <p>Background</p> <p>In this work we present evidence that the p53 tumor suppressor protein and NF-κB transcription factors could be related through common descent from a family of ancestral transcription factors regulating cellular proliferation and apo...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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BMC
2005-06-01
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| Series: | BMC Immunology |
| Online Access: | http://www.biomedcentral.com/1471-2172/6/12 |
| _version_ | 1811286429019406336 |
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| author | Gelfand Erwin W Nagasawa Masayuki Dreyfus David H Ghoda Lucy Y |
| author_facet | Gelfand Erwin W Nagasawa Masayuki Dreyfus David H Ghoda Lucy Y |
| author_sort | Gelfand Erwin W |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>In this work we present evidence that the p53 tumor suppressor protein and NF-κB transcription factors could be related through common descent from a family of ancestral transcription factors regulating cellular proliferation and apoptosis. P53 is a homotetrameric transcription factor known to interact with the ankyrin protein 53BP2 (a fragment of the ASPP2 protein). NF-κB is also regulated by ankyrin proteins, the prototype of which is the IκB family. The DNA binding sequences of the two transcription factors are similar, sharing 8 out of 10 nucleotides. Interactions between the two proteins, both direct and indirect, have been noted previously and the two proteins play central roles in the control of proliferation and apoptosis.</p> <p>Results</p> <p>Using previously published structure data, we noted a significant degree of structural alignment between p53 and NF-κB p65. We also determined that IκBα and p53 bind <it>in vitro </it>through a specific interaction in part involving the DNA binding region of p53, or a region proximal to it, and the amino terminus of IκBα independently or cooperatively with the ankyrin 3 domain of IκBα In cotransfection experiments, κBα could significantly inhibit the transcriptional activity of p53. Inhibition of p53-mediated transcription was increased by deletion of the ankyrin 2, 4, or 5 domains of IκBα Co-precipitation experiments using the stably transfected ankyrin 5 deletion mutant of κBα and endogenous wild-type p53 further support the hypothesis that p53 and IκBα can physically interact <it>in vivo</it>.</p> <p>Conclusion</p> <p>The aggregate results obtained using bacterially produced IκBα and p53 as well as reticulocyte lysate produced proteins suggest a correlation between <it>in vitro </it>co-precipitation in at least one of the systems and <it>in vivo </it>p53 inhibitory activity. These observations argue for a mechanism involving direct binding of IκBα to p53 in the inhibition of p53 transcriptional activity, analogous to the inhibition of NF-κB by κBα and p53 by 53BP2/ASPP2. These data furthermore suggest a role for ankyrin proteins in the regulation of p53 activity. Taken together, the NFκB and p53 proteins share similarities in structure, DNA binding sites and binding and regulation by ankyrin proteins in support of our hypothesis that the two proteins share common descent from an ancestral transcriptional factor.</p> |
| first_indexed | 2024-04-13T02:59:48Z |
| format | Article |
| id | doaj.art-74bb1090092b42c4ab03ae3691c6b12a |
| institution | Directory Open Access Journal |
| issn | 1471-2172 |
| language | English |
| last_indexed | 2024-04-13T02:59:48Z |
| publishDate | 2005-06-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Immunology |
| spelling | doaj.art-74bb1090092b42c4ab03ae3691c6b12a2022-12-22T03:05:29ZengBMCBMC Immunology1471-21722005-06-01611210.1186/1471-2172-6-12Modulation of p53 activity by IκBα: Evidence suggesting a common phylogeny between NF-κB and p53 transcription factorsGelfand Erwin WNagasawa MasayukiDreyfus David HGhoda Lucy Y<p>Abstract</p> <p>Background</p> <p>In this work we present evidence that the p53 tumor suppressor protein and NF-κB transcription factors could be related through common descent from a family of ancestral transcription factors regulating cellular proliferation and apoptosis. P53 is a homotetrameric transcription factor known to interact with the ankyrin protein 53BP2 (a fragment of the ASPP2 protein). NF-κB is also regulated by ankyrin proteins, the prototype of which is the IκB family. The DNA binding sequences of the two transcription factors are similar, sharing 8 out of 10 nucleotides. Interactions between the two proteins, both direct and indirect, have been noted previously and the two proteins play central roles in the control of proliferation and apoptosis.</p> <p>Results</p> <p>Using previously published structure data, we noted a significant degree of structural alignment between p53 and NF-κB p65. We also determined that IκBα and p53 bind <it>in vitro </it>through a specific interaction in part involving the DNA binding region of p53, or a region proximal to it, and the amino terminus of IκBα independently or cooperatively with the ankyrin 3 domain of IκBα In cotransfection experiments, κBα could significantly inhibit the transcriptional activity of p53. Inhibition of p53-mediated transcription was increased by deletion of the ankyrin 2, 4, or 5 domains of IκBα Co-precipitation experiments using the stably transfected ankyrin 5 deletion mutant of κBα and endogenous wild-type p53 further support the hypothesis that p53 and IκBα can physically interact <it>in vivo</it>.</p> <p>Conclusion</p> <p>The aggregate results obtained using bacterially produced IκBα and p53 as well as reticulocyte lysate produced proteins suggest a correlation between <it>in vitro </it>co-precipitation in at least one of the systems and <it>in vivo </it>p53 inhibitory activity. These observations argue for a mechanism involving direct binding of IκBα to p53 in the inhibition of p53 transcriptional activity, analogous to the inhibition of NF-κB by κBα and p53 by 53BP2/ASPP2. These data furthermore suggest a role for ankyrin proteins in the regulation of p53 activity. Taken together, the NFκB and p53 proteins share similarities in structure, DNA binding sites and binding and regulation by ankyrin proteins in support of our hypothesis that the two proteins share common descent from an ancestral transcriptional factor.</p>http://www.biomedcentral.com/1471-2172/6/12 |
| spellingShingle | Gelfand Erwin W Nagasawa Masayuki Dreyfus David H Ghoda Lucy Y Modulation of p53 activity by IκBα: Evidence suggesting a common phylogeny between NF-κB and p53 transcription factors BMC Immunology |
| title | Modulation of p53 activity by IκBα: Evidence suggesting a common phylogeny between NF-κB and p53 transcription factors |
| title_full | Modulation of p53 activity by IκBα: Evidence suggesting a common phylogeny between NF-κB and p53 transcription factors |
| title_fullStr | Modulation of p53 activity by IκBα: Evidence suggesting a common phylogeny between NF-κB and p53 transcription factors |
| title_full_unstemmed | Modulation of p53 activity by IκBα: Evidence suggesting a common phylogeny between NF-κB and p53 transcription factors |
| title_short | Modulation of p53 activity by IκBα: Evidence suggesting a common phylogeny between NF-κB and p53 transcription factors |
| title_sort | modulation of p53 activity by iκbα evidence suggesting a common phylogeny between nf κb and p53 transcription factors |
| url | http://www.biomedcentral.com/1471-2172/6/12 |
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