Master regulatory role of p63 in epidermal development and disease

Soares, Eduardo V.; Zhou, Huiqing

doi:10.1007/s00018-017-2701-z

Cited by 147 publications

(159 citation statements)

References 98 publications

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“…We previously showed that TP63 controls the expression of high-molecular weight keratins (KRT5, KRT6, and KRT14) and suppresses EMT (Choi et al, 2014b; Tran et al, 2013). The central role of p63 in the maintenance of epithelial phenotype and EMT was confirmed in several variants of solid tumors (Soares and Zhou, 2018; Stacy et al, 2017; Tanaka et al, 2018). We therefore performed additional analyses to further characterize the role of EMT in SARC.…”

Section: Resultsmentioning

confidence: 88%

Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer

et al. 2019

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SUMMARY Sarcomatoid urothelial bladder cancer (SARC) displays a high propensity for distant metastasis and is associated with short survival. We report a comprehensive genomic analysis of 28 cases of SARC and 84 cases of conventional urothelial carcinoma (UC), with the TCGA cohort of 408 muscle- invasive bladder cancers serving as the reference. SARCs show a distinct mutational landscape, with enrichment of TP53, RB1, and PIK3CA mutations. They are related to the basal molecular subtype of conventional UCs and could be divided into epithelial-basal and more clinically aggressive mesenchymal subsets on the basis of TP63 and its target gene expression levels. Other analyses reveal that SARCs are driven by downregulation of homotypic adherence genes and dysregulation of the EMT network, and nearly half exhibit a heavily infiltrated immune phenotype. Our observations have important implications for prognostication and the development of more effective therapies for this highly lethal variant of bladder cancer.

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Section: Resultsmentioning

confidence: 88%

Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer

et al. 2019

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“…The skin, the largest organ in the body, is highly organized and endowed with a remarkable repair and turnover potential to serve as the first line defense of the internal milieu, among a multitude of other physiological roles. P63 is a master regulator of skin development, and its deficiency is known to result in severely anomalous development of skin and other ectoderm‐derived structures . Several downstream effectors of P63 have similarly been implicated in various skin disorders in human, for example, KDF1 .…”

Section: Introductionmentioning

confidence: 99%

“…P63 is a master regulator of skin development, and its deficiency is known to result in severely anomalous development of skin and other ectoderm-derived structures. 1 Several downstream effectors of P63 have similarly been implicated in various skin disorders in human, for example, KDF1. 2 Recently, dominant mutations in one such effector, PERP, have been detected in patients with keratoderma, a phenotype characterized by excessive scaling of skin.…”

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confidence: 99%

Confirming the recessive inheritance of PERP‐related erythrokeratoderma

et al. 2020

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Erythrokeratoderma (EK) is heterogeneous clinical entity characterized by excessive scaling with resulting erythrokeratotic plaques. Several genes have been linked to EK and they encode a number of proteins that are important for the integrity of the keratinocyte layer of the epidermis. PERP is a transcription factor that is activated by both p53 and p63. However, its deficiency in a mouse model appears to only recapitulate p63‐mediated role in skin development and organization. We report an extended multiplex consanguineous family in which an EK phenotype with a striking similarity to that observed in Perp−/− mice, is mapped to an autozygous region on chromosome 6 that spans PERP. Whole‐exome sequencing revealed a novel variant in PERP that fully segregated with the phenotype. Functional analysis of patient‐ and control‐derived keratinocytes revealed a deleterious effect of the identified variant on the intracellular localization of PERP. A previous report showed that PERP mutation causes a dominant form of keratoderma but a single patient in that report with a homozygous variant in PERP suggests that recessive inheritance is also possible. Our results, therefore, support the establishment of an autosomal recessive PERP‐related EK phenotype in humans.

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“…). Mutations in the TP63 gene have been associated with human developmental diseases and skin abnormalities (Li & Xiao , Soares & Zhou ), as well as with different cancer types, such as lung, breast, bladder and squamous cell carcinoma (Hu et al . , Zhang et al .…”

Section: Introductionmentioning

confidence: 99%

Potential role of TP63 in apical periodontitis development

et al. 2019

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Aim To investigate the expression of TP63 in apical periodontitis (AP) tissues and the association of single nucleotide polymorphisms (SNPs) in the TP63 gene with AP using a case‐control dataset. Methodology Expression of TP63 in human AP lesions (apical abscess, radicular cyst, periapical granuloma) was evaluated using immunohistochemistry. A case‐control association study was performed to assess the association of TP63 polymorphisms in individuals having AP with or without associated pain. Cases were defined as subjects with deep caries and AP (n = 151) and subjects with symptomatic apical periodontitis or acute apical abscess (n = 124). Subjects without AP (n = 169) and asymptomatic (n = 196) were used as controls, respectively. Saliva samples were collected as source of genomic DNA. Twelve SNPs in the TP63 gene were selected for genotyping using Taqman chemistry in real‐time PCR. Data analysis was performed using PLINK software. The Bonferroni method was applied to correct for multiple testing; α ≤ 0.004 indicates significant differences between groups. Results TP63 expression was evident in apical abscesses and radicular cysts, while weaker expression was observed in periapical granulomas. Positive expression was observed in mononuclear cells in the granulation tissues of all AP lesions. Regarding the presence of AP, a trend for allelic association was observed for rs16864812 and rs9810322 (P = 0.04) and rs9810322 genotypes were also nominally associated with AP under a dominant model (P = 0.04). When considering the presence of periapical pain, a trend for allelic and genotypic association was observed for rs10155037 (P = 0.03). Haplotypes were also associated with AP and periapical pain (P ≤ 0.05). Conclusions Apical periodontitis is a complex multifactorial condition and it is likely that multiple genes and environmental effects may influence its susceptibility, progression or both. TP63 variants may play a role in AP pathogenesis and susceptibility, individually or interactively with other genes. Additional studies in other populations and functional studies are needed to improve understanding of the role of TP63 in AP.

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Master regulatory role of p63 in epidermal development and disease

Cited by 147 publications

References 98 publications

Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer

Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer

Confirming the recessive inheritance of PERP‐related erythrokeratoderma

Potential role of TP63 in apical periodontitis development

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