Δ<i>Np63</i> knockout mice reveal its indispensable role as a master regulator of epithelial development and differentiation

Romano, Rose‐Anne; Smalley, Kirsten; Magraw, Caitlin B.L.; Serna, Vanida A.; Kurita, Takeshi; Raghavan, Srikala; Sinha, Satrajit

doi:10.1242/jcs.108647

Cited by 7 publications

(18 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Order By: Relevance

“…50,63 Sfn is down-regulated in epithelial cancer, and its mutation leads to hyperplasic epithelia. 64 Besides regulating Sfn, p63 maintains EpdSCs by preventing the activation of Notch signalling, [65][66][67][68] a master differentiation programme (discussed below). p63 governs another key property of squamous epithelia, their cellular junctions and adhesions, to maintain epithelial integrity (Figure 1C).…”

Section: P63 Coordinates Epidermal Proliferation Stratification and Adhesionmentioning

confidence: 99%

Transcriptional and signalling regulation of skin epithelial stem cells in homeostasis, wounds and cancer

Guan

Yang

Nagarajan

et al. 2020

Experimental Dermatology

View full text Add to dashboard Cite

As the largest organ of the human body, our skin serves as a physical barrier between the individual and the environment. The skin preserves body fluid, guards against irradiation and pathogens and conducts sensations. The epidermis is composed of several epithelial layers. The basal cells attach to the basement membrane above the dermis, joined by hemidesmosomes and adherens junctions, and are home to the epidermal stem cells (EpdSCs), which undergo long-term self-renewal and continuously fuel the upward flux of differentiating cells, forming the skin barrier. 1 EpdSC progenies transition through the multiple differentiated layers, starting with the suprabasal spinous layer, rich in desmosomes 2 ; then the granular layer, containing keratohyalin and lamellar granules; and finally the stratum corneum, composed of flattened denucleated corneocytes with heavily crosslinked keratin cables and a cornified envelope, eventually sloughed off the skin surface. 3 Connecting to the epidermis are many epidermal appendages, among which the most abundant are the sweat glands and the pilosebaceous units. Sweat glands are responsible for thermoregulation, 4,5 while the pilosebaceous unit is composed of

show abstract

Section: P63 Coordinates Epidermal Proliferation Stratification and Adhesionmentioning

confidence: 99%

Transcriptional and signalling regulation of skin epithelial stem cells in homeostasis, wounds and cancer

Guan

Yang

Nagarajan

et al. 2020

Experimental Dermatology

View full text Add to dashboard Cite

show abstract

“…Mutant mice that do not express p63 are born lacking limbs as well as skin and its appendages , and have markedly abnormal prostate and bladder epithelia . More deepen understanding about the distinct functions of the two isoforms, achieved by the characterization of knockout mice for TA and ΔNp63 isoforms, revealed that these anomalies result from the lack of ΔNp63 . ΔNp63 is expressed in basal epithelial cells and is required for normal development of several epithelial tissues, including the bladder, prostate glands and colorectal epithelia .…”

Section: Introductionmentioning

confidence: 99%

“…ΔNp63 is expressed in basal epithelial cells and is required for normal development of several epithelial tissues, including the bladder, prostate glands and colorectal epithelia . This isoform is necessary for stem-cell renewal , as well as for terminal differentiation, , whereas TAp63 is implicated in maintaining stem cells in quiescence and preventing premature aging and senescence. , Because of its implication in both cancer and stemness, p63 may also play a relevant role in maintaining the cancer stem-cell phenotypes, particularly in tumors of epithelial origin. ,, Colorectal tumors are hierarchically organized with a minor cancer stem cells (CSCs) niche, showing self-renewal and multilineage differentiation capacity, responsible for the formation of more differentiated less malignant cells, making up the bulk of the tumor. , CSCs have also been implicated in drug resistance and tumor recurrence, although the nature of this relationship is only beginning to be clarified . Onco-proteomics may significantly contribute to explore this field, employing sensitive methodological approaches and accurate procedures to characterize proteins involved in the cellular processes responsible for maintaining the CSC pool …”

Section: Introductionmentioning

confidence: 99%

“…17 More deepen understanding about the distinct functions of the two isoforms, achieved by the characterization of knockout mice for TA and ΔNp63 isoforms, revealed that these anomalies result from the lack of ΔNp63. 18 ΔNp63 is expressed in basal epithelial cells and is required for normal development of several epithelial tissues, including the bladder, prostate glands and colorectal epithelia. 19 This isoform is necessary for stem-cell renewal 15,20 as well as for terminal differentiation, 18,21 whereas TAp63 is implicated in maintaining stem cells in quiescence and preventing premature aging 22 and senescence.…”

Section: ■ Introductionmentioning

confidence: 99%

See 1 more Smart Citation

p63 Isoforms Regulate Metabolism of Cancer Stem Cells

et al. 2014

View full text Add to dashboard Cite

p63 is an important regulator of epithelial development expressed in different variants containing (TA) or lacking (ΔN) the N-terminal transactivation domain. The different isoforms regulate stem-cell renewal and differentiation as well as cell senescence. Several studies indicate that p63 isoforms also play a role in cancer development; however, very little is known about the role played by p63 in regulating the cancer stem phenotype. Here we investigate the cellular signals regulated by TAp63 and ΔNp63 in a model of epithelial cancer stem cells. To this end, we used colon cancer stem cells, overexpressing either TAp63 or ΔNp63 isoforms, to carry out a proteomic study by chemical-labeling approach coupled to network analysis. Our results indicate that p63 is implicated in a wide range of biological processes, including metabolism. This was further investigated by a targeted strategy at both protein and metabolite levels. The overall data show that TAp63 overexpressing cells are more glycolytic-active than ΔNp63 cells, indicating that the two isoforms may regulate the key steps of glycolysis in an opposite manner. The mass-spectrometry proteomics data of the study have been deposited to the ProteomeXchange Consortium (http://proteomecentral. proteomexchange.org) via the PRIDE partner repository with data set identifiers PXD000769 and PXD000768.

show abstract

“…TAp63 has been found to exerts critical functions in the development and function of the heart [34] and oocytes [35,36], in the differentiation of cochlear neuroepithelium via the regulation of Notch pathway [37]. ΔNp63 proteins are involved in the early stages of skin developmentand being rapidly degraded when keratinocytes are induced to differentiate [38]. The hypothesis is that TAp63 and ΔNp63 isoforms work in competition, and the Notch signalling pathway is very important in epidermal stratification and in keratinocyte differentiation [39].…”

Section: Introductionmentioning

confidence: 99%

Role of p63 isoform balance in recurrent nasal polyps

Terrinoni¹,

Palombo²,

Pitolli³

et al. 2018

Otorhinolaryngol Head Neck Sur

View full text Add to dashboard Cite

Objective: Nasal polyps are, benign growths outgrowths of sinonasal tissue, affecting approximately 1-4% of the population. They have been correlated to the presence of chronic inflammation, but the molecular underlying mechanisms has not been completely defined. Defective epithelial barrier has been correlated with chronic rhinosinusitis (CRS) and nasal polyps (NPs) Moreover, a variation of ΔNp63 isoform expression has been noted in human airway epithelial cells and in the NPs epithelium. The benign lesion in some patients can have a recurrence, and the difference between recurrent and not recurrent patients is still unclear.The aim of the study was to molecularly characterise NPs patients, distinguishing between patients presenting NP recurrence after surgical treatment respect to those in which recurrence has been not reported. Methods:In the present work we analysed a cohort of patients affected by nasal polyposis, all submitted to Functional Endoscopic Sinus Surgery (FESS). The patients have been six-monthly clinical, checked in the two years following surgery. In all patients we analysed keratin 5, and p63 isoform expression, by RTqPCR using fresh NPs tissues taken after surgery. Moreover, confocal imunnofluorescence analysis again for p63 and Keratin 5 has been performed on fixed sections. Results and conclusion:The results show high ΔNp63 expression and keratin 5, in nasal polyps of patients. The analysis of the expression level of the TAp63 isoform, shows a differential expression between patients with recurrence, respect to the not recurring. A more comprehensive marker could be considered the ΔN/TAp63 ratio. In fact, even though ΔNp63 is expressed in non-recurrent patients the ratio ΔN/TAp63 result significantly lower in these patients. This clearly indicates that the status of TA63 expression, and represented by ΔN/TAp63 ratio, could be considered a prognostic markers of low recurrence probability. Since TAp63 is also upregulated by HDAC inhibitors could be the consideration of local treatment of nasal polyps with these molecules.

show abstract

ΔNp63 knockout mice reveal its indispensable role as a master regulator of epithelial development and differentiation

Cited by 7 publications

References 1 publication

Transcriptional and signalling regulation of skin epithelial stem cells in homeostasis, wounds and cancer

Transcriptional and signalling regulation of skin epithelial stem cells in homeostasis, wounds and cancer

p63 Isoforms Regulate Metabolism of Cancer Stem Cells

Role of p63 isoform balance in recurrent nasal polyps

Contact Info

Product

Resources

About