{"id":30137,"date":"2024-08-22T15:13:10","date_gmt":"2024-08-22T13:13:10","guid":{"rendered":"https:\/\/fgu.antstudio.dev\/?post_type=vyzkumny-projekt&p=30137"},"modified":"2024-09-02T08:22:16","modified_gmt":"2024-09-02T06:22:16","slug":"characterizaton-of-the-interactions-between-transcription-factor-foxo4-and-tumour-supressor-p53","status":"publish","type":"vyzkumny-projekt","link":"https:\/\/fgu.cas.cz\/en\/research-project\/characterizaton-of-the-interactions-between-transcription-factor-foxo4-and-tumour-supressor-p53\/","title":{"rendered":"Characterizaton of the interactions between transcription factor FOXO4 and tumour supressor p53"},"content":{"rendered":"
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The transcription factor p53 is a key regulator of apoptosis, senescence and DNA repair, which protects cells\u00a0against tumorigenesis under various cellular stresses.\u00a0The functions of p53 are closely intertwined with the\u00a0activity of Forkhead box O (FOXO) transcription factors.<\/strong><\/p>\n<\/div>\n

Biophysical studies<\/h2>\n

Here, we characterize\u00a0the interaction between p53 and FOXO4 by NMR, chemical cross-linking, and\u00a0analytical ultracentrifugation.Our results reveal that the interaction between\u00a0p53 TAD and the FOXO4 Forkhead domain is essential for the overall stability\u00a0of the p53:FOXO4 complex. Furthermore, contacts involving the N-terminal\u00a0segment of FOXO4, the C-terminal negative regulatory domain of p53 and the\u00a0DNA-binding domains of both proteins stabilize the complex, whose formation\u00a0blocks p53 binding to DNA but without affecting the DNA-binding properties\u00a0of FOXO4. Therefore, our structural findings may help to understand the intertwined\u00a0functions of p53 and FOXO4 in cellular homeostasis, longevity, and\u00a0stress response.<\/p>\n

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Regulation of senescence via FOXO4-p53<\/strong><\/div>\n
In 2022 we analyzed the interaction between FOXO4 and p53 and found out that N-terminal region of FOXO4 stabilizes the p53:FOXO4 complex and the p53 DBD interacts with FH-DBD and NLS of FOXO4. We also mapped the p53:FOXO4 interface by NMR and it revealed that FOXO4 FH-DBD form the binding surface of p53 and p53 TAD1\/2 domains are key regions of the FOXO4-binding surface of p53. Moreover\u00a0Fluorescence anisotropy measurements using fluorescein-labelled DNAp21 or DNAIRE revealed that\u00a0the complex formation reduces the DNA-binding affinity of p53 but not FOXO4. Results were published in\u00a0Mandal et al. (2022) Protein Science<\/a>.<\/em><\/div>\n

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Left, sedimentation velocity analytical ultracentrifugation analysis of interaction between FOXO4 and p53. Middle, chemical shift perturbations obtained from 1H-15N HSQC spectra of 15N-labeled FOXO4 in the presence of p53 mapped onto the crystal structure of the FOXO4 DBD:DNA complex. Right, fluorescence anisotropy measurements showing that the complex formation reduces the DNA-binding affinity of p53 (Mandal et al. (2022) Protein Science<\/a>).<\/em><\/p>\n","protected":false},"excerpt":{"rendered":"

The transcription factor p53 is a key regulator of apoptosis, senescence and DNA repair, which protects cells\u00a0against tumorigenesis under various cellular stresses.\u00a0The functions of p53 are closely intertwined with the\u00a0activity of Forkhead box O (FOXO) transcription factors. Biophysical studies Here, we characterize\u00a0the interaction between p53 and FOXO4 by NMR, chemical cross-linking, and\u00a0analytical ultracentrifugation.Our results reveal […]<\/p>\n","protected":false},"author":1,"template":"","meta":{"_acf_changed":false,"inline_featured_image":false,"footnotes":""},"oddeleni":[181],"poskytovatel":[],"stav-projektu":[209],"class_list":["post-30137","vyzkumny-projekt","type-vyzkumny-projekt","status-publish","hentry","oddeleni-structural-biology-of-signaling-proteins","stav-projektu-current-projects"],"acf":[],"_links":{"self":[{"href":"https:\/\/fgu.cas.cz\/en\/wp-json\/wp\/v2\/vyzkumny-projekt\/30137","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/fgu.cas.cz\/en\/wp-json\/wp\/v2\/vyzkumny-projekt"}],"about":[{"href":"https:\/\/fgu.cas.cz\/en\/wp-json\/wp\/v2\/types\/vyzkumny-projekt"}],"author":[{"embeddable":true,"href":"https:\/\/fgu.cas.cz\/en\/wp-json\/wp\/v2\/users\/1"}],"version-history":[{"count":0,"href":"https:\/\/fgu.cas.cz\/en\/wp-json\/wp\/v2\/vyzkumny-projekt\/30137\/revisions"}],"wp:attachment":[{"href":"https:\/\/fgu.cas.cz\/en\/wp-json\/wp\/v2\/media?parent=30137"}],"wp:term":[{"taxonomy":"oddeleni","embeddable":true,"href":"https:\/\/fgu.cas.cz\/en\/wp-json\/wp\/v2\/oddeleni?post=30137"},{"taxonomy":"poskytovatel","embeddable":true,"href":"https:\/\/fgu.cas.cz\/en\/wp-json\/wp\/v2\/poskytovatel?post=30137"},{"taxonomy":"stav-projektu","embeddable":true,"href":"https:\/\/fgu.cas.cz\/en\/wp-json\/wp\/v2\/stav-projektu?post=30137"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}