TAp63 and ΔNp63 in Cancer and Epidermal Development

Candi, Eleanora; Dinsdale, David; Rufini, Alessandra; Salomoni, Paolo; Knight, Richard; Mueller, M.; Krammer, Peter H.; Melino, Gerry

doi:10.4161/cc.6.3.3797

Cited by 176 publications

(191 citation statements)

References 82 publications

(122 reference statements)

Supporting

Mentioning

179

Contrasting

Order By: Relevance

“…In contrast, OSK reprogramming upregulates epithelial genes and therefore requires p63 as a known epithelial master regulator. 39,[44][45][46][47][48] Of note, we found that p63/DNp63 À / À MEFs are also strongly impaired in OSKM reprogramming, a factor combination also known to induce MET 11,14 (Supplementary Figure 8). It remains to be identified which specific p63 transcriptional targets are involved in MET and reprogramming in general, and how they differ from those that mediate p63 function in epithelial development.…”

Section: Discussionmentioning

confidence: 79%

“…The two major p63 isoforms, TAp63 and DNp63, are transcribed from alternative promoters and have different functions. 44 Specifically, DNp63 is highly expressed in the basal layer of epidermis, largely drives keratinocyte differentiation in vivo and is proposed to be responsible for maintenance of epidermal progenitor/stem cells. [45][46][47][48] Similarly, TAp63 is expressed in hair follicle bulge cells and dermal papillae cells (niches for epidermal and dermal stem cells, respectively) and is implicated in the maintenance of adult dermal and epidermal precursors.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

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

Section: Discussionmentioning

confidence: 79%

Section: Resultsmentioning

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

show abstract

“…38 Second, similar to that in other epithelial systems DNp63 most likely interferes with the proapoptotic activity of p53 or TAp73 that are also expressed in mammary cells. 11,12,22,60,61 Furthermore, DNp63 has been shown to directly regulate transcription of apoptosis-related genes. Specifically, together with HDAC1/2 it can suppress the pro-apoptotic gene PUMA.…”

Section: Discussionmentioning

confidence: 99%

“…10 In the epidermis, abundantly expressed DNp63a protein is the predominant isoform and exerts its critical pro-proliferative/ maintenance function in skin stem cells. [10][11][12][13][14][15] Selective genetic ablation of all DNp63 isoforms 14 or of the long p63a/b isoforms (Wolff et al 16 and references therein) closely reproduces the phenotypes of global p63 À / À mice. In contrast, TAp63 mRNA and protein, expressed at nearly undetectable levels in the skin, has a fine-tuning role in keratinocyte differentiation 15 and helps maintain adult skin stem cells.…”

mentioning

confidence: 99%

p63 is a prosurvival factor in the adult mammary gland during post-lactational involution, affecting PI-MECs and ErbB2 tumorigenesis

et al. 2014

View full text Add to dashboard Cite

In embryogenesis, p63 is essential to develop mammary glands. In the adult mammary gland, p63 is highly expressed in the basal cell layer that comprises myoepithelial and interspersed stem/progenitor cells, and has limited expression in luminal epithelial cells. In adult skin, p63 has a crucial role in the maintenance of epithelial stem cells. However, it is unclear whether p63 also has an equivalent role as a stem/progenitor cell factor in adult mammary epithelium. We show that p63 is essential in vivo for the survival and maintenance of parity-identified mammary epithelial cells (PI-MECs), a pregnancy-induced heterogeneous population that survives post-lactational involution and contain multipotent progenitors that give rise to alveoli and ducts in subsequent pregnancies. p63 þ / À glands are normal in virgin, pregnant and lactating states. Importantly, however, during the apoptotic phase of post-lactational involution p63 þ / À glands show a threefold increase in epithelial cell death, concomitant with increased activation of the oncostatin M/Stat3 and p53 pro-apoptotic pathways, which are responsible for this phase. Thus, p63 is a physiologic antagonist of these pathways specifically in this regressive stage. After the restructuring phase when involution is complete, mammary glands of p63 þ / À mice again exhibit normal epithelial architecture by conventional histology. However, using Rosa LSL-LacZ ;WAP-Cre transgenics (LSL-LacZ, lox-stop-lox b-galactosidase), a genetic in vivo labeling system for PI-MECs, we find that p63 þ / À glands have a 30% reduction in the number of PI-MEC progenitors and their derivatives. Importantly, PI-MECs are also cellular targets of pregnancy-promoted ErbB2 tumorigenesis. Consistent with their PI-MEC pool reduction, one-time pregnant p63 þ / À ErbB2 mice are partially protected from breast tumorigenesis, exhibiting extended tumor-free and overall survival, and reduced tumor multiplicity compared with their p63 þ / þ ErbB2 littermates. Conversely, in virgin ErbB2 mice p63 heterozygosity provides no survival advantage. In sum, our data establish that p63 is an important survival factor for pregnancy-identified PI-MEC progenitors in breast tissue in vivo.

show abstract

“…DNp63 is restricted to transit-amplifying cells and stem cells residing in the basal layer. DNp63 expression is downregulated during skin differentiation and it regulates genes that result in basal cell proliferation (34,35). Forced expression of DNp63 is sufficient to drive stem-like proliferation and tumorigenesis in primary keratinocyte (36).…”

Section: Discussionmentioning

confidence: 99%

YAP Expression and Activity Are Suppressed by S100A7 via p65/NFκB-mediated Repression of ΔNp63

Kong

Shao

et al. 2017

Molecular Cancer Research

View full text Add to dashboard Cite

In several squamous cell carcinoma (SCC) cells, it has been previously observed that induction of the S100 calcium-binding protein A7 (S100A7) is repressed by YAP via the Hippo pathway. This report now demonstrates that S100A7 also represses YAP expression and activity by DNp63 in cancer cells. Stable overexpression of S100A7 activates the NFkB pathway and inhibits the expression of DNp63. Caffeic acid phenethyl ester (CAPE), as a specific inhibitor of NFkB, counteracts the inhibitory effect of S100A7 on the expression of DNp63 and its target genes. Depletion of S100A7 significantly promotes DNp63 expression. These data indicate that S100A7 acts as a suppressor of DNp63. Mechanistic examination finds that DNp63 not only directly binds to the region of YAP promoter and induces its expression, but also inhibits the Hippo pathway and enhances YAP activity. Importantly, either the positive correlation between S100A7 and YAP phosphorylation at S127 or the negative correlation between S100A7 and DNp63 is also observed in skin SCC tissues. Chemosensitivity analysis reveals that S100A7 enhances cancer cells' resistance by inhibition of YAP expression and activity. These results demonstrate that S100A7 is an upstream modulator of the Hippo pathway and extend our understanding of S100A7 functions in cancer.Implications: S100A7 is a new upstream regulator of the Hippo signaling pathway and reduces chemosensitivity of SCC cells through inhibitions of YAP expression and activity.

show abstract

TAp63 and ΔNp63 in Cancer and Epidermal Development

Cited by 176 publications

References 82 publications

ΔNp63 regulates select routes of reprogramming via multiple mechanisms

ΔNp63 regulates select routes of reprogramming via multiple mechanisms

p63 is a prosurvival factor in the adult mammary gland during post-lactational involution, affecting PI-MECs and ErbB2 tumorigenesis

YAP Expression and Activity Are Suppressed by S100A7 via p65/NFκB-mediated Repression of ΔNp63

Contact Info

Product

Resources

About