p63 is a suppressor of tumorigenesis and metastasis interacting with mutant p53

Melino, Gerry

doi:10.1038/cdd.2011.81

Cited by 203 publications

(203 citation statements)

References 119 publications

(174 reference statements)

Supporting

Mentioning

183

Contrasting

Unclassified

Order By: Relevance

“…39,76 Physiologically, p63 and p73 protein levels are normally kept under strict control through Itch-mediated ubiquitylation, and indeed both p63 and p73 have a canonical PY motif (absent in p53 which is regulated by a different E3 ligase) located in their C-terminal which accounts for the binding to Itch through its WW domains. Both Itch and WWP1 target both isoforms of p63 for ubiquitin-mediated proteasomal degradation.…”

Section: -62mentioning

confidence: 99%

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

et al. 2014

View full text Add to dashboard Cite

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.

show abstract

Section: -62mentioning

confidence: 99%

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

et al. 2014

View full text Add to dashboard Cite

show abstract

“…In particular, the structure and role for the p63 gene as a master regulator of the development and maintenance of the stratified epithelia as well as its involvement in the control of aging and tumor growth were shown (reviewed in Koster and Roop 2007;Crum and McKeon 2010;Melino 2011;Vanbokhoven et al 2011;Su et al 2013). Furthermore, the roles of the distinct p63 and p73 isoforms in the control of cell proliferation, differentiation, and apoptosis in the skin were dissected by using a number of genetically engineered mouse models and in vitro analyses.…”

mentioning

confidence: 99%

p53/p63/p73 in the Epidermis in Health and Disease

Botchkarev

Flores

2014

Cold Spring Harbor Perspectives in Medicine

View full text Add to dashboard Cite

Although p53 has long been known as the "guardian of the genome" with a role in tumor suppression in many tissues, the discovery of two p53 ancestral genes, p63 and p73, more than a decade ago has triggered a considerable amount of research into the role of these genes in skin development and diseases. In this review, we primarily focus on mechanisms of action of p53 and p63, which are the best-studied p53 family members in the skin. The existence of multiple isoforms and their roles as transcriptional activators and repressors are key to their function in multiple biological processes including the control of skin morphogenesis, regeneration, tumorigenesis, and response to chemotherapy. Last, we provide directions for further research on this family of genes in skin biology and pathology.

show abstract

“…Thus, full-length TAp63/TAp73, which carry the N-terminal transcriptional activation (TA) domain, can induce cell cycle arrest and apoptosis similar to p53, whereas the N-terminally truncated DNp63/DNp73 often act in a dominant-negative manner by inhibiting full-length family members, including p53. [35][36][37] p63 and p73 have been implicated in oncogenesis, [35][36][37] but their role in somatic reprogramming has barely been investigated. 34,38 Here we show for the first time that DNp63 is a potent positive regulator of reprogramming.…”

mentioning

confidence: 99%

ΔNp63 regulates select routes of reprogramming via multiple mechanisms

Petrenko

Nemajerová

et al. 2013

Cell Death Differ

View full text Add to dashboard Cite

Somatic cells can be converted into induced pluripotent stem cells (iPSCs) by forced expression of various combinations of transcription factors, but the molecular mechanisms of reprogramming are poorly understood. Specifically, evidence that the reprogramming process can take many distinct routes only begins to emerge. It is definitively established that p53 deficiency greatly enhances reprogramming, revealing p53's barrier function for induced pluripotency, but the role of its homologs p63 and p73 are unknown. Here we report that in stark contrast to p53, p73 has no role in reprogramming. However, p63 is an enabling (rather than a barrier) factor for Oct4, Sox2 and Klf4 (OSK) and Oct4 and Sox2 (OS), but not for Oct4 and Klf4 (OK) reprogramming of mouse embryonic fibroblasts. Specifically, p63 is essential during reprogramming for maximum efficiency, albeit not for the ability to reprogram per se, and is dispensable for maintaining stability and pluripotency of established iPSC colonies. DNp63, but not TAp63, is the principal isoform involved. Loss of p63 can affect reprogramming via several mechanisms such as reduced expression of mesenchymal-epithelial transition and pluripotency genes, hypoproliferation and loss of the most reprogrammable cell populations. During OSK and OS reprogramming, different mechanisms seem to be critical, such as regulation of epithelial and pluripotency genes in OSK reprogramming versus regulation of proliferation in OS reprogramming. Finally, our data reveal three different routes of reprogramming by OSK, OS or OK, based on their differential p63 requirements for iPSC efficiency and pluripotency marker expression. This supports the concept that many distinct routes of reprogramming exist.

show abstract

p63 is a suppressor of tumorigenesis and metastasis interacting with mutant p53

Cited by 203 publications

References 119 publications

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

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

p53/p63/p73 in the Epidermis in Health and Disease

ΔNp63 regulates select routes of reprogramming via multiple mechanisms

Contact Info

Product

Resources

About