Regulation of skin aging and heart development by TAp63

Paris, Maryline; Rouleau, Matthieu; Pucéat, Michel; Aberdam, Daniel

doi:10.1038/cdd.2011.181

Cited by 49 publications

(37 citation statements)

References 69 publications

(103 reference statements)

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“…The p53 family is involved in many aspects of development [38][39][40][41] and, in particular, p73 regulates neuronal differentiation. First, p73 deletion results in neuronal defects, including hydrocephalus and hippocampal dysgenesis, with abnormalities in the CA1-CA3 pyramidal cell layers and in the dentate gyrus.…”

Section: Discussionmentioning

confidence: 99%

GLS2 is transcriptionally regulated by p73 and contributes to neuronal differentiation

Velletri

Romeo²,

Tucci

et al. 2013

Cell Cycle

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The amino acid Glutamine is converted into Glutamate by a deamidation reaction catalyzed by the enzyme Glutaminase (GLS). Two isoforms of this enzyme have been described, and the GLS2 isoform is regulated by the tumor suppressor gene p53. Here, we show that the p53 family member TAp73 also drives the expression of GLS2. Specifically, we demonstrate that TAp73 regulates GLS2 during retinoic acid-induced terminal neuronal differentiation of neuroblastoma cells, and overexpression or inhibition of GLS2 modulates neuronal differentiation and intracellular levels of ATP. Moreover, inhibition of GLS activity, by removing Glutamine from the growth medium, impairs in vitro differentiation of cortical neurons. Finally, expression of GLS2 increases during mouse cerebellar development. Although, p73 is dispensable for the in vivo expression of GLS2, TAp73 loss affects GABA and Glutamate levels in cortical neurons. Together, these findings suggest a role for GLS2 acting, at least in part, downstream of p73 in neuronal differentiation and highlight a possible role of p73 in regulating neurotransmitter synthesis

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Section: Discussionmentioning

confidence: 99%

GLS2 is transcriptionally regulated by p73 and contributes to neuronal differentiation

Velletri

Romeo²,

Tucci

et al. 2013

Cell Cycle

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“…[127][128][129] The more ancient members of the family include p73, involved in cancer, 130 neurodevelopment, 131,132 and aging, 133 and p63, involved in epidermal development, 119,[134][135][136] cancer, [137][138][139][140][141] reproduction, 142 and heart development. 143 Understanding the structural restrain of its structure is pivotal to understand the function of p53 [144][145][146] as well as its potential therapeutic exploitation. 147,148 The regulation of p53 protein half-life is crucial to his function 149,150 and, consequently, for cancer progression.…”

Section: Discussionmentioning

confidence: 99%

Molecular dynamics of the full-length p53 monomer

Chillemi¹,

Davidovich

D’Abramo³

et al. 2013

Cell Cycle

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The p53 protein is frequently mutated in a very large proportion of human tumors, where it seems to acquire gain-of-function activity that facilitates tumor onset and progression. A possible mechanism is the ability of mutant p53 proteins to physically interact with other proteins, including members of the same family, namely p63 and p73, inactivating their function. Assuming that this interaction might occurs at the level of the monomer, to investigate the molecular basis for this interaction, here, we sample the structural flexibility of the wild-type p53 monomeric protein. The results show a strong stability up to 850 ns in the DNA binding domain, with major flexibility in the N-terminal transactivations domains (TAD1 and TAD2) as well as in the C-terminal region (tetramerization domain). Several stable hydrogen bonds have been detected between N-terminal or C-terminal and DNA binding domain, and also between N-terminal and C-terminal. Essential dynamics analysis highlights strongly correlated movements involving TAD1 and the proline-rich region in the N-terminal domain, the tetramerization region in the C-terminal domain; Lys120 in the DNA binding region. The herein presented model is a starting point for further investigation of the whole protein tetramer as well as of its mutants

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“…3,6,14,38. We have previously investigated the molecular mechanism of Itch recognition for the p63 transcription factor 39 in particular, because this powerful transcription factor is crucial for the development of epithelia, 31,[40][41][42][43][44][45] it is involved in cancer, [46][47][48][49][50][51][52][53][54][55][56][57][58][59] and when it is mutated it causes severe genetic diseases.…”

Section: Introductionmentioning

confidence: 99%

p63 threonine phosphorylation signals the interaction with the WW domain of the E3 ligase Itch

et al. 2014

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Both in epithelial development as well as in epithelial cancers, the p53 family member p63 plays a crucial role acting as a master transcriptional regulator. P63 steady state protein levels are regulated by the E3 ubiquitin ligase Itch, via a physical interaction between the PPxY consensus sequence (PY motif) of p63 and one of the 4 WW domains of Itch; this substrate recognition process leads to protein-ubiquitylation and p63 proteasomal degradation. The interaction of the WW domains, a highly compact protein-protein binding module, with the short proline-rich sequences is therefore a crucial regulatory event that may offer innovative potential therapeutic opportunity. Previous molecular studies on the Itch-p63 recognition have been performed in vitro using the Itch-WW2 domain and the peptide interacting fragment of p63 (pep63), which includes the PY motif. Itch-WW2-pep63 interaction is also stabilized in vitro by the conformational constriction of the S-S cyclization in the p63 peptide. The PY motif of p63, as also for other proteins, is characterized by the nearby presence of a (T/S)P motif, which is a potential recognition site of the WW domain of the IV group present in the prolyl-isomerase Pin1. In this study, we demonstrate, by in silico and spectroscopical studies using both the linear pep63 and its cyclic form, that the threonine phosphorylation of the (T/S)PPPxY motif may represent a crucial regulatory event of the Itch-mediated p63 ubiquitylation, increasing the Itch-WW domains-p63 recognition event and stabilizing in vivo the Itch-WW-p63 complex. Moreover, our studies confirm that the subsequently trans/cis proline isomerization of (T/S)P motif by the Pin1 prolyl-isomerase, could modulate the E3-ligase interaction, and that the (T/S) p P trans PPxY motif represent the best conformer for the ItchWW-(T/S)PPPxY motif recognition.

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Regulation of skin aging and heart development by TAp63

Cited by 49 publications

References 69 publications

GLS2 is transcriptionally regulated by p73 and contributes to neuronal differentiation

GLS2 is transcriptionally regulated by p73 and contributes to neuronal differentiation

Molecular dynamics of the full-length p53 monomer

p63 threonine phosphorylation signals the interaction with the WW domain of the E3 ligase Itch

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