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

Ruptier, Charlotte; Gasperis, A De; Ansieau, Stéphane; Granjon, A; Tanière, Philippe; Lafosse, I; Shi, Hong; Petitjean, Audrey; Taranchon-Clermont, Estelle; Tribollet, Violaine; Voeltzel, Thibault; Scoazec, J.Y.; Maguer-Satta, Véronique; Puisieux, Alain; Hainaut, Pierre; Cavard, Catherine; Fromentel, Claude Caron de

doi:10.1038/onc.2011.171

Cited by 27 publications

(33 citation statements)

References 45 publications

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“…Ectopic high levels of p63 expression were able to induce transdifferentiation and squamous metaplasia of mouse lung epithelium [56]. In addition, high p63 levels have been associated with squamous cell carcinoma and β-Catenin has been shown to regulate this protein in this disease [57], [58]. Therefore our studies suggest that stabilized β-Catenin acts to induce high levels of p63, which drives the transdifferentiation process towards a squamous fate.…”

Section: Discussionmentioning

confidence: 55%

β-Catenin Is Required for Prostate Development and Cooperates with Pten Loss to Drive Invasive Carcinoma

et al. 2013

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Prostate cancer is a major cause of male death in the Western world, but few frequent genetic alterations that drive prostate cancer initiation and progression have been identified. β-Catenin is essential for many developmental processes and has been implicated in tumorigenesis in many tissues, including prostate cancer. However, expression studies on human prostate cancer samples are unclear on the role this protein plays in this disease. We have used in vivo genetic studies in the embryo and adult to extend our understanding of the role of β-Catenin in the normal and neoplastic prostate. Our gene deletion analysis revealed that prostate epithelial β-Catenin is required for embryonic prostate growth and branching but is dispensable in the normal adult organ. During development, β-Catenin controls the number of progenitors in the epithelial buds and regulates a discrete network of genes, including c-Myc and Nkx3.1. Deletion of β-Catenin in a Pten deleted model of castration-resistant prostate cancer demonstrated it is dispensable for disease progression in this setting. Complementary overexpression experiments, through in vivo protein stabilization, showed that β-Catenin promotes the formation of squamous epithelia during prostate development, even in the absence of androgens. β-Catenin overexpression in combination with Pten loss was able to drive progression to invasive carcinoma together with squamous metaplasia. These studies demonstrate that β-Catenin is essential for prostate development and that an inherent property of high levels of this protein in prostate epithelia is to drive squamous fate differentiation. In addition, they show that β-Catenin overexpression can promote invasive prostate cancer in a clinically relevant model of this disease. These data provide novel information on cancer progression pathways that give rise to lethal prostate disease in humans.

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Section: Discussionmentioning

confidence: 55%

β-Catenin Is Required for Prostate Development and Cooperates with Pten Loss to Drive Invasive Carcinoma

et al. 2013

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“…Deregulated expression of Tp63 leading to an increased ΔNp63/Tp63 ratio promotes tumor development by inhibiting cellular senescence 85 . Inactivation of p53 function, combined with the activation of Wnt/β-catenin pathway, results in the overexpression of ΔNp63 that promotes oral mucosal tumorigenesis and early metastatic progression 30, 86 . Furthermore, in squamous cell carcinomas, the transcription factor SOX2, which is critical for the maintenance of embryonic and adult stem cells, preferentially interacts with ΔNp63 and regulates gene expression that governs undifferentiated cancer stem cells-like properties 87 .…”

Section: Discussionmentioning

confidence: 99%

CD147 and Ki-67 overexpression confers poor prognosis in squamous cell carcinoma of oral tongue: A tissue microarray study

Yu¹,

Morales

Feng

et al. 2015

Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology

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Squamous cell carcinoma of the oral tongue (SCCOT) exhibits high risk for recurrence and regional metastasis even after surgical resection. We assessed the clinicopathologic and prognostic significance of a group of functionally related biomarkers. We used a tissue microarray consisting SCCOT from 32 patients for this study. These patients were treated at the UT- M.D. Anderson Cancer Center from 1995 to 2008. Biomarker expression levels were examined by immunohistochemistry and graded semiquantitatively to determine their prognostic significance. CD147 and Tp63 expressions were significantly associated with a higher T-stage and Ki-67 labelling index as well as shorter overall survival (OS). Expression of Tp63 associated positively with poorly-differentiated histology. There was significant association of Tp63 with the expression levels of CD147 and Glut-1. Glut-1 overexpression was marginally associated with a higher T-stage. There was no prognostic significance of CD44v6 expression in SCCOT. SCCOT with CD147 overexpression in combination with high Ki-67 labelling index had poor OS. CD147 and Ki-67 overexpression is associated with aggressive disease with poor prognosis in SCCOT.

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“…We showed previously that ASPP2 partially overlaps with β-catenin at cell-cell junctions and can be detected in the same protein complex (32). A more recent study showed that nuclear β-catenin can directly transactivate ΔNp63 expression (34). We tested whether ASPP2 could repress p63's expression by inhibiting β-catenin-mediated induction of ΔNp63.…”

Section: Aspp2 Represses P63 Expression By Binding Iκb and Inducing Nmentioning

confidence: 96%

ASPP2 suppresses squamous cell carcinoma via RelA/p65–mediated repression of p63

Tordella¹,

Koch²,

Salter³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Squamous cell carcinoma (SCC) is highly malignant and refractory to therapy. The majority of existing mouse SCC models involve multiple gene mutations. Very few mouse models of spontaneous SCC have been generated by a single gene deletion. Here we report a haploinsufficient SCC mouse model in which exon 3 of the Tp53BP2 gene (a p53 binding protein) was deleted in one allele in a BALB/c genetic background. Tp53BP2 encodes ASPP2 (ankyrin repeats, SH3 domain and protein rich region containing protein 2). Keratinocyte differentiation induces ASPP2 and its expression is inversely correlated with p63 protein in vitro and in vivo. Upregulation of p63 expression is required for ASPP2 Δexon3/+ BALB/c mice to develop SCC, as heterozygosity of p63 but not p53 prevents them from developing it. Mechanistically, ASPP2 inhibits ΔNp63 expression through its ability to bind IκB and enhance nuclear Rel/A p65, a component of the NF-κB transcription complex, which mediates the repression of p63. Reduced ASPP2 expression associates with tumor metastasis and increased p63 expression in human head and neck SCCs. This study identifies ASPP2 as a tumor suppressor that suppresses SCC via inflammatory signaling through NF-κB-mediated repression of p63.inflammation | T53BP2 | stratified epithelial cell tumor

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

Cited by 27 publications

References 45 publications

β-Catenin Is Required for Prostate Development and Cooperates with Pten Loss to Drive Invasive Carcinoma

β-Catenin Is Required for Prostate Development and Cooperates with Pten Loss to Drive Invasive Carcinoma

CD147 and Ki-67 overexpression confers poor prognosis in squamous cell carcinoma of oral tongue: A tissue microarray study

ASPP2 suppresses squamous cell carcinoma via RelA/p65–mediated repression of p63

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