p63 antagonizes Wnt-induced transcription

Drewelus, Isabella; Göpfert, Constanze; Hippel, Cathrin; Dickmanns, Antje; Damianitsch, Katharina; Pieler, Tomas; Dobbelstein, Matthias

doi:10.4161/cc.9.3.10593

Cited by 29 publications

(32 citation statements)

References 28 publications

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“…This is an interesting finding because in the literature, DNp63 is described as acting upstream from Wnt/b-catenin signaling, whereas here it seems to act as downstream: activation of Wnt/b-catenin signaling induces loss of p63 expression. 31 Furthermore, the observed downregulation of p63 correlates well with the finding that p63 expression is often lost from human ovarian cancers. 47 Also, DNp63 downregulation has been described as stimulating the invasive behavior of human squamous cell carcinoma and knockout of DNp63 in breast cancer cell lines induces epithelial-to-mesenchymal transformation (EMT).…”

Section: Discussionsupporting

confidence: 68%

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A mouse model for endometrioid ovarian cancer arising from the distal oviduct

Horst

Zee

Heijmans-Antonissen

et al. 2014

Intl Journal of Cancer

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Ovarian cancer is the deadliest gynecological malignancy in Western countries. Early detection, however, is hampered by the fact that the origin of ovarian cancer remains unclear. Knowing that in a high percentage of endometrioid ovarian cancers Wnt/b-catenin signaling is activated, and in view of the hypothesis that ovarian cancer may originate from the distal oviduct, we studied mice in which Wnt/b-catenin signaling was activated in M€ ullerian duct-derived tissues. Conditional adenomatous polyposis coli (Apc) knockout mice were used to study the activation of Wnt/b-catenin signaling in M€ ullerian duct-derived organs. These Pgr Cre/1 ;Apc ex15lox/lox mice (n 5 44) were sacrificed at 10, 20, 40 and 80 weeks and uterus, oviduct, ovaries and surrounding fat tissues were assessed using immunohistochemistry. Using nuclear b-catenin staining, Wnt/b-catenin signaling activation was confirmed in the entire epithelium of the adult M€ ullerian duct (fimbriae, oviduct and endometrium), but was absent in ovarian surface epithelium cells (OSEs). Besides endometrial hyperplasia, in 87.2% of mice intraepithelial lesions of the distal oviduct were found, whereas OSEs remained unaffected. In addition, 62.5% of mice developed tumors in the distal and fimbrial part of the oviduct. In the ovaries, mainly at young age, in 16.3% of mice, simple epithelial cysts were noted, which developed further into endometrioid ovarian tumors, resembling human endometrioid ovarian cancer (27.9% of mice). Next to this, locoregional growth in the utero-ovarian ligament was also shown. Here, for the first time, mutations (activation of Wnt/b-catenin) in the distal oviduct result in precursor lesions that develop into ovarian tumors, resembling human endometrioid ovarian cancer.Epithelial ovarian cancer is the deadliest gynecological malignancy in Western countries, accounting for more than 140,000 deaths each year worldwide. 1 As ovarian cancer survival is highly dependent on the tumor stage at diagnosis, early detection is key to decreasing death rate. Unfortunately, the origin of ovarian cancer remains unclear, making early discovery very difficult.For decades, ovarian surface epithelial cells (OSEs) have been appointed as the primary origin of epithelial ovarian cancer despite the fact that precursor lesions were never found.2 Over recent years, however, researchers have proposed different origins for epithelial ovarian cancer: the secondary M€ ullerian system, 3 the distal oviduct and fimbriae 4,5 and recently the transitional zone between OSEs and mesothelium at the hilial region of the ovary.6 Dubeau 3 and Piek et al. 7 were among the first to question OSEs as the only origin of ovarian cancer. In his original article, Dubeau 3 argues that the strong resemblance of ovarian epithelial tumors to tumors arising from organs embryologically derived from the M€ ullerian ducts and warrants the consideration that components of the secondary M€ ullerian system play a role in ovarian tumorigenesis. Piek et al. described dysplastic lesions in prophylac...

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Section: Discussionsupporting

confidence: 68%

“…2c). Interestingly, these lesions also displayed loss of p63-expression, a finding that, in the previously published literature 31 , is associated with increased Wnt/b-catenin signaling (Fig. 2c).…”

Section: Endometrioid Tumors In the Oviductmentioning

confidence: 56%

A mouse model for endometrioid ovarian cancer arising from the distal oviduct

Horst

Zee

Heijmans-Antonissen

et al. 2014

Intl Journal of Cancer

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“…It has been shown to be casual to a variety of tumors, including colon cancer and breast cancer, and it has been shown to be necessary and sufficient to maintain pluripotency in epidermal stem cells [135][136][137][138][139]. After overexpression, ΔNp63α promotes Wnt-inducible reporter gene activity in human cells [140]. However, in an apparent contradiction to these observations, siRNA-mediated knockdown of endogenous p63 equally enhanced the expression of Wnt-responsive genes.…”

Section: Wnt Pathwaymentioning

confidence: 40%

The role of P63 in cancer, stem cells and cancer stem cells

Nekulova

Holcakova

Coates

et al. 2011

Cellular and Molecular Biology Letters

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The transcription factor p63 has important functions in tumorigenesis, epidermal differentiation and stem cell self-renewal. The TP63 gene encodes multiple protein isoforms that have different or even antagonistic roles in these processes. The balance of p63 isoforms, together with the presence or absence of the other p53 family members, p73 and p53, has a striking biological impact. There is increasing evidence that interactions between p53-family members, whether cooperative or antagonistic, are involved in various cell processes. This review summarizes the current understanding of the role of p63 in tumorigenesis, metastasis, cell migration and senescence. In particular, recent data indicate important roles in adult stem cell and cancer stem cell regulation and in the response of cancer cells to therapy.

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“…One study suggests that overexpressed DNp63 is able to induce b-catenin accumulation by interacting with the complex responsible for b-catenin phosphorylation (Patturajan et al, 2002). The second one reports an increase of Wnt/b-catenin activity in the presence of overexpressed exogenous DNp63, but an inhibition with endogenous DNp63a, without detectable change in b-catenin level or phosphorylation (Drewelus et al, 2010). We were not able to detect any increase in b-catenin activity after DNp63 overexpression in our experiments (data not shown).…”

Section: Discussionmentioning

confidence: 99%

TP63 P2 promoter functional analysis identifies β-catenin as a key regulator of ΔNp63 expression

et al. 2011

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The DNp63 protein, a product of the TP63 gene that lacks the N-terminal domain, has a critical role in the maintenance of self renewal and progenitor capacity in several types of epithelial tissues. DNp63 is frequently overexpressed in squamous cell carcinoma (SCC) and in some other epithelial tumours. This overexpression may contribute to tumour progression through dominantnegative effects on the transcriptionally active (TA) isoforms of the p53 family (TAp63, TAp73 and p53), as well as through independent mechanisms. However, the molecular basis of DNp63 overexpression is not fully understood. Here, we show that the expression of DNp63 is regulated by the Wnt/b-catenin pathway in human hepatocellular carcinoma (HCC) and SCC cell lines. This regulation operates in particular through TCF/LEF sites present in the P2 promoter of TP63. In addition, we show that DNp63 and b-catenin are frequently coexpressed and accumulated in oesophageal SCC, but not in HCC. These results suggest that activation of the b-catenin pathway may contribute to overexpression of DNp63 during tumour progression, in a cell type-specific manner.

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p63 antagonizes Wnt-induced transcription

Cited by 29 publications

References 28 publications

A mouse model for endometrioid ovarian cancer arising from the distal oviduct

A mouse model for endometrioid ovarian cancer arising from the distal oviduct

The role of P63 in cancer, stem cells and cancer stem cells

TP63 P2 promoter functional analysis identifies β-catenin as a key regulator of ΔNp63 expression

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