The role of tetramerization in p53 function

Chêne, Patrick

doi:10.1038/sj.onc.1204373

Cited by 241 publications

(207 citation statements)

References 99 publications

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“…Interestingly, in the p53 mutants with mutations potentially affecting its DNA binding capability, including R175H (conformational mutant), R248W (DNA-binding mutant), and S392A, all three mutants were still able to interact with MLL5 (Supplementary Figure S12). In the nucleus, equilibrium exists between monomers, dimers and tetramers of p53 (Friedman et al, 1993;Chene, 2001). We speculate that in the presence of chromatin-bound MLL5, p53 tetramers are excluded from the chromatin and the equilibrium is shifted towards dimers or monomers that can shuttle to cytoplasm for degradation ( Figure 8a).…”

Section: Discussionmentioning

confidence: 98%

Camptothecin-induced downregulation of MLL5 contributes to the activation of tumor suppressor p53

et al. 2011

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Mixed lineage leukemia 5 (MLL5) has been implicated in multiple aspects of cell physiology, such as hematopoiesis, cell cycle control and chromatin regulatory network. In this study, we present evidence that MLL5 is involved in the camptothecin (CPT)-induced p53 activation. CPT promoted the degradation of MLL5 protein in a time-and dose-dependent manner in actively replicating cells. The downregulation of MLL5 led to phosphorylation of p53 at Ser392, which was abrogated by exogenous overexpression of MLL5. In MLL5-knockdown cells, p53 protein was stabilized and bound to DNA with higher affinity, leading to activation of downstream genes. Co-immunoprecipitation showed that MLL5 preferentially interacted with the tetramerized form of p53, and knockdown of MLL5 promoted chromatin accumulation of p53 tetramers, suggesting that the association of MLL5 with p53 may prevent the p53 tetramers from binding to the chromatin target sites. The role of MLL5 in CPT-induced p53 activation was conserved in developing zebrafish, where CPT downregulated zebrafish Mll5 protein, and the microinjection of zebrafish mll5 mRNA substantially blocked the CPT-induced apoptosis. In summary, our study proposed MLL5 as a novel component in the regulation of p53 homeostasis and a new cellular determinant of CPT.

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Section: Discussionmentioning

confidence: 98%

Camptothecin-induced downregulation of MLL5 contributes to the activation of tumor suppressor p53

et al. 2011

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“…[16][17][18] It is a structural domain that forms a tetramer, and mutations within the OD that inhibit tetramerization of p53 result in greatly reduced transcriptional activity. 19 In addition, several protein-protein interactions and posttranslational modifications require the tetrameric state as well, 16 and mutations in the OD of p53 that prevent oligomerization have been identified in human cancers. 20,21 Owing to its functional importance, the OD of p53 has been the target of several structure determination projects.…”

mentioning

confidence: 99%

“…11 Among all p53 family members, including those from invertebrate species, the DNA binding domain is the most conserved domain, [12][13][14][15] followed by the oligomerization domain (OD), which is indispensable for the biological function of all p53 protein family members. [16][17][18] It is a structural domain that forms a tetramer, and mutations within the OD that inhibit tetramerization of p53 result in greatly reduced transcriptional activity. 19 In addition, several protein-protein interactions and posttranslational modifications require the tetrameric state as well, 16 and mutations in the OD of p53 that prevent oligomerization have been identified in human cancers.…”

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confidence: 99%

Conformational stability and activity of p73 require a second helix in the tetramerization domain

et al. 2009

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p73 and p63, the two ancestral members of the p53 family, are involved in neurogenesis, epithelial stem cell maintenance and quality control of female germ cells. The highly conserved oligomerization domain (OD) of tumor suppressor p53 is essential for its biological functions, and its structure was believed to be the prototype for all three proteins. However, we report that the ODs of p73 and p63 differ from the OD of p53 by containing an additional a-helix that is not present in the structure of the p53 OD. Deletion of this helix causes a dissociation of the OD into dimers; it also causes conformational instability and reduces the transcriptional activity of p73. Moreover, we show that ODs of p73 and p63 strongly interact and that a large number of different heterotetramers are supported by the additional helix. Detailed analysis shows that the heterotetramer consisting of two homodimers is thermodynamically more stable than the two homotetramers. No heterooligomerization between p53 and the p73/p63 subfamily was observed, supporting the notion of functional orthogonality within the p53 family. p53, a well-known tumor suppressor that is mutated in more than 50% of all human tumors, induces genes leading either to cell-cycle arrest or to apoptosis. The discovery of two proteins with a high sequence identity to p53, called p63 and p73, has sparked speculations that tumor suppression is carried out by the combined action of several members of this protein family, for example, by direct interaction through heterooligomerization. Knockout mouse studies with p63 and p73, the two ancestral members, 1 have shown functional roles distinct from p53: p63 is essential for maintaining epithelial stem cells 2,3 and for protecting the genomic stability of oocytes, 4 whereas p73 is involved in neurogenesis, sensory pathways and homeostatic control. 5 p73 is further known as an important inducer of apoptosis in response to DNA damage. 6 Although only few mutations of p63 and p73 have been found in human tumors so far, overexpression of p63 is often observed in squamous cell carcinoma, 7-10 which has been shown to suppress p73-dependent apoptosis. 11 Among all p53 family members, including those from invertebrate species, the DNA binding domain is the most conserved domain, 12-15 followed by the oligomerization domain (OD), which is indispensable for the biological function of all p53 protein family members. [16][17][18] It is a structural domain that forms a tetramer, and mutations within the OD that inhibit tetramerization of p53 result in greatly reduced transcriptional activity. 19 In addition, several protein-protein interactions and posttranslational modifications require the tetrameric state as well, 16 and mutations in the OD of p53 that prevent oligomerization have been identified in human cancers. 20,21 Owing to its functional importance, the OD of p53 has been the target of several structure determination projects. 22,23 The p53 tetramer consists of a dimer of dimers, with each monomer contributing one b-strand and o...

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“…The function of p53 is mediated by protein-DNA and by protein-protein interactions. The tetramerization domain has an essential role in its function, because only the tetrameric structure is active [31]. Peptides able to recognize this tetramerization domain and stabilize its native conformation could be of great interest in cancer research.…”

Section: P53mentioning

confidence: 99%

Computer-Aided Peptide Evolution for Virtual Drug Design

Belda

Llorà

Martinell

et al. 2004

Genetic and Evolutionary Computation – GECCO 2004

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Abstract.One of the goals of computational chemistry is the automated de novo design of bioactive molecules. Despite significant progress in computational approaches to ligand design and efficient evaluation of binding energy, novel procedures for ligand design are required. Evolutionary computation provides a new approach to this design issue. A reliable framework for obtaining ligands via evolutionary algorithms has been implemented. It provides an automatic tool for peptide de novo design, based on protein surface patches defined by user. A special emphasis has been given to the evaluation of the proposed peptides. Hence, we have devised two different evaluation heuristics to carry out this task. Then, we have tested the proposed framework in the design of ligands for the protein Prolyl oligopetidase, p53, and DNA Gyrase.

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The role of tetramerization in p53 function

Cited by 241 publications

References 99 publications

Camptothecin-induced downregulation of MLL5 contributes to the activation of tumor suppressor p53

Camptothecin-induced downregulation of MLL5 contributes to the activation of tumor suppressor p53

Conformational stability and activity of p73 require a second helix in the tetramerization domain

Computer-Aided Peptide Evolution for Virtual Drug Design

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