Candi, E, Rufini, A, Terrinoni, A, Dinsdale, D, Ranalli, M, Paradisi, A et al.. Differential roles of p63 isoforms in epidermal development: selective genetic complementation in p63 null mice. Cell Death Differ 13: 1037-1047
Epidermal development requires the transcription factor p63, as p63-/- mice are born dead, without skin. The gene expresses two proteins, one with an amino-terminal transactivation domain (TAp63) and one without (deltaNp63), although their relative contribution to epidermal development is unknown. To address this issue, we reintroduced TAp63alpha and/or deltaNp63alpha under the K5 promoter into p63-/- mice by in vivo genetic complementation. Whereas p63-/- and p63-/-;TA mice showed extremely rare patches of poorly differentiated keratinocytes, p63-/-;deltaN mice showed significant epidermal basal layer formation. Double TAp63alpha/deltaNp63alpha complementation showed greater patches of differentiated skin; at the ultrastructural level, there was clear reformation of a distinct basal membrane and hemidesmosomes. At the molecular level, deltaNp63 regulated expression of genes characteristic of the basal layer (K14), interacting (by Chip, luc assay) with the third p53 consensus site. Conversely, TAp63 transcribed the upper layer's genes (Ets-1, K1, transglutaminases, involucrin). Therefore, the two p63 isoforms appear to play distinct cooperative roles in epidermal formation.
"These results suggest that TAp63 opposes ΔNp63 function, thereby preventing a premature reduction in proliferative potential. Thus, it is likely that p63 function reflects a cooperative effect between TAp63 and ΔNp63 isoforms (Candi et al., 2006; Truong et al., 2006; Zhang et al., 2014). Whereas the amino (N)-terminal functions of p63 are relatively well studied, carboxy (C)-terminal functions in vivo are poorly understood. "
"p63 exerts different functions by virtue of its various isoforms. ΔNp63, which lacks an N-terminal transactivation domain, is widely expressed in epidermal keratinocytes to form the skin barrier in concert with filaggrin and involcurin, and it controls the expression of claudin-1 as well as proinflammatory cytokines , . However, whether ΔNp63 has a role in an inflammatory environment such as AD skin lesions remains elusive. "
[Show abstract][Hide abstract] ABSTRACT: In the skin lesions of atopic dermatitis (AD), keratinocytes release large quantities of thymic stromal lymphopoietin (TSLP), causing unfavorable inflammation along with skin damage. Nevertheless, how TSLP influences keratinocytes themselves is still unknown. In this study, we showed that ΔNp63, a p53-homologue, predominantly expressed in keratinocytes regulated the receptor complex of TSLP, which determines susceptibility to self-derived TSLP. Expression of TSLP receptors in skin tissues and keratinocytes was assessed by immunohistochemistry and quantitative RT-PCR, and in vitro studies were also performed to examine the functional relevance of ΔNp63 in the expression of TSLP receptors and the constituting autocrine and/or paracrine pathway of TSLP under the condition of stimuli to innate receptors sensing cell damage. The results showed that normal keratinocytes in the upper epidermis preferentially expressed TSLP receptors and conversely lacked ΔNp63, which has an inhibitory effect on the expression of TSLP receptors. Interestingly, the epidermis of AD lesions was found to abundantly contain keratinocytes with low or undetectable levels of ΔNp63 (ΔNp63lo/-). Moreover, in the absence of ΔNp63, keratinocytes readily presented TSLP and other cytokines by stimuli through Toll-like receptor 3 (TLR3). Together with the evidence that extrinsic TSLP itself augments TSLP production by keratinocytes without ΔNp63, the results indicate that ΔNp63lo/- keratinocytes generate TSLP through a putative autocrine and/or paracrine pathway upon TLR3 stimulation within AD lesions, since moieties of damaged cells and pathogens stimulate TLR3.
PLoS ONE 08/2014; 9(8):e105498. DOI:10.1371/journal.pone.0105498 · 3.23 Impact Factor
"In these studies , ΔNp63í µí»¼ was able to partially restore the epidermal basal layer, but not differentiation marker expression, whereas TAp63í µí»¼ reconstitution resulted in a phenotype similar to p63(−/−) mice . Reconstitution of a combination of ΔNp63í µí»¼ and TAp63í µí»¼ resulted in a more complete epidermis formation containing patches with a more organized structure that expressed markers of differentiation . It is possible that differences with respect to the differentiation status of the epidermis generated by reconstitution of ΔNp63í µí»¼ in the later two studies could be due to the mouse model used, but in contrast to the first model discussed, partial epidermal restoration by ΔNp63í µí»¼ is a common feature of both. "
[Show abstract][Hide abstract] ABSTRACT: Mouse models have informed us that p63 is critical for normal epidermal development and homeostasis. The p53/p63/p73 family is expressed as multiple protein isoforms due to a combination of alternative promoter usage and C-terminal alternative splicing. These isoforms can mimic or interfere with one another, and their balance ultimately determines biological outcome in a context-dependent manner. While not frequently mutated, p63, and in particular the ΔNp63 subclass, is commonly overexpressed in human squamous cell cancers. In vitro keratinocytes and murine transgenic and transplantation models have been invaluable in elucidating the contribution of altered p63 levels to cancer development, and studies have identified the roles for ΔNp63 isoforms in keratinocyte survival and malignant progression, likely due in part to their transcriptional regulatory function. These findings can be extended to human cancers; for example, the novel recognition of NF κ B/c-Rel as a downstream effector of p63 has identified a role for NF κ B/c-Rel in human squamous cell cancers. These models will be critical in enhancing the understanding of the specific molecular mechanisms of cancer development and progression.
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