A C-Terminal Inhibitory Domain Controls the Activity of p63 by an Intramolecular Mechanism

Serber, Zach; Lai, Helen C.; Yang, Annie; Ou, Horng D.; Sigal, Martina; Kelly, Alexander E.; Darimont, Beatrice; Duijf, Pascal H.G.; Bokhoven, Hans van; McKeon, Frank; Dötsch, Volker

doi:10.1128/mcb.22.24.8601-8611.2002

Cited by 185 publications

(234 citation statements)

References 49 publications

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“…Surprisingly, the DNp51B transgenic mouse did not exhibit clear abnormality of the skin. This implies that TAp51B is much more potent inhibitor of Notch1 than DNp51B considering the fact that TAp51B is a much more labile protein than DNp51B (Serber et al, 2002). We do not have a plausible explanation for this discrepancy other than that the transgenic experiment was designed to express the proteins in early embryonic stages, whereas we used keratinocytes of much later stages.…”

Section: Discussionmentioning

confidence: 97%

“…Otherwise, it is attractive to speculate the involvement of an inhibitory domain residing in the COOH-terminus of p51B isoforms (Serber et al, 2002). Interestingly, DNp51B binds to inhibitor kappa B kinase (IKK)a through the COOH-terminus region triggering keratinocyte differentiation (Enjo et al, submitted) and many of the p51 mutation found among human hereditary syndromes reside in the COOH-terminal domain ( (Celli et al, 1999;McGrath et al, 2001;Duijf et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

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p53 homologue, p51/p63, maintains the immaturity of keratinocyte stem cells by inhibiting Notch1 activity

et al. 2007

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

p53 homologue, p51/p63, maintains the immaturity of keratinocyte stem cells by inhibiting Notch1 activity

et al. 2007

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“…In addition, the isoforms contain a Sterile Alpha-Motif (SAM) and a Trans Inhibitory Domain (TID). The former is a protein-protein interaction domain, also present in other molecules [10,11], while the latter is an inhibitory domain that blocks transactivation by masking a few residues on the N-terminal TA, (it could also be responsible for oligomerisation between different p63 isoforms) [12].…”

Section: Trp63 Gene Organization and P63 Protein Structurementioning

confidence: 99%

p63 in epithelial development

Candi

Cipollone

Cervo

et al. 2008

Cell. Mol. Life Sci.

123

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List of abbreviations: K, keratin; p63-/-, mouse knockout for p63; p63-/-;TA, p63 knockout mice complemented with TAp63; p63-/-;ΔN, p63 knockout mice complemented with ΔNp63; p63-/-;TA;ΔN, p63 knockout mice complemented with both TAp63 and ΔNp63;IKKα, IkB kinase-α; TA, transactivation domain; ΔN, amino-terminal truncated protein. AbstractThe epidermis, the outer layer of the skin composed of keratinocytes, is a stratified epithelium that functions as a barrier to protect the organism from dehydration and external insults. The epidermis develops following the action of the transcription factor p63, a member of the p53 family of transcription factors. The Trp63 gene contains two promoters, driving the production of distinct proteins, one with an N-terminal transactivation domain (TAp63) and one without (DeltaNp63), although their relative contribution to epidermal development is not clearly established. Trp63 mutations are involved in the pathogenesis of several human diseases, phenotypically characterized by ectodermal dysplasia. In this review we summarise the current advances that have been made in understanding the role of p63 in epidermal morphogenesis.

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“…24 In the a-splice forms of p63 and p73, a long stretch of amino acids (119 in p63 and 109 in p73) connects the OD to a sterile alpha motif (SAM) domain, which is followed by a transcriptional inhibitory domain. 12,25 Several invertebrate p53 proteins also contain long C-terminal stretches, however, with low sequence identity to the mammalian family members. Surprisingly, in the p53 forms of the two important model organisms, Caenorhabditis elegans (CEP-1) and Drosophila melanogaster (Dmp53), this low sequence identity includes the otherwise highly conserved OD.…”

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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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A C-Terminal Inhibitory Domain Controls the Activity of p63 by an Intramolecular Mechanism

Cited by 185 publications

References 49 publications

p53 homologue, p51/p63, maintains the immaturity of keratinocyte stem cells by inhibiting Notch1 activity

p53 homologue, p51/p63, maintains the immaturity of keratinocyte stem cells by inhibiting Notch1 activity

p63 in epithelial development

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

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