p63 – an Important Player in Epidermal and Tumour Development p63 – důležitý hráč ve vývoji epidermálních struktur a nádorových onemocnění

Orzol P., Nekulova M., Vojtesek B., Holcakova J. Regional Centre for Applied Molecular Oncology, Masaryk Memorial Institute, Brno, Czech Republic

Summary p63 is a factor which plays an important role in epidermal development, diffe­ This study was supported by grant of G rant rentiation and tumourigenesis. p63 belongs to the family and at least six isoforms Agency Czech Republic No. P301/10/P431 and by the European Regional Development Fund were identified to date. p63 isoforms play contrary roles during the development and forma­ and the State Budget of the Czech Republic tion of the epidermis as well as in cancer. p63 participates in epithelial development, where (RECAMO, CZ.1.05/2.1.00/03.0101). it affects proliferation and differentiation of epidermal cells. Inherited mutations in the TP63 generate different developmental defects and p63 knockout in mice results in the ab­ Práce byla podpořena grantem GA MZ ČR sence of epidermis. Another important role of p63 is the control of cell-cell adhesion, where it P301/10/P431 a Evropským fondem pro regio- nální rozvoj a státním rozpočtem České republiky regulates desmosomes. The loss of proliferation and cell-cell adhesion control are important for (OP VaVpI – RECAMO, CZ.1.05/2.1.00/03.0101). tumourigenesis and overexpression of p63 can enhance tumour growth and inhibit . This review briefly summarises the roles of p63 in epithelial development, cellular proliferation, The authors declare they have no potential adhesion and migration and reveals its share in tumourigenesis and metastasis. conflicts of interest concerning drugs, products, or services used in the study. Autoři deklarují, že v souvislosti s předmětem Key words studie nemají žádné komerční zájmy. p63 – cell development – cell proliferation – cell adhesion – tumourigenesis – epidermis The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for Souhrn biomedical papers. Protein p63 je transkripční faktor, který má významnou funkci ve vývoji a diferenciaci epider­ Redakční rada potvrzuje, že rukopis práce málních struktur a v průběhu tumorigeneze. Je členem rodiny nádorového supresoru p53 a vy­ splnil ICMJE kritéria pro publikace zasílané do bi omedicínských časopisů. skytuje se minimálně v počtu šesti izoforem, které mají během vývoje epidermis a při vzniku a progresi nádorů opačné funkce. Protein p63 ovlivňuje proliferaci a diferenciaci epidermál­ ních buněk v průběhu ontogeneze: vrozené mutace v genu TP63 vedou k různým vývojovým  deformacím a odstranění tohoto genu u myší má za následek ztrátu epidermis. Protein p63 Jitka Holcakova, M.Sc., Ph.D. také ovlivňuje buněčnou adhezi prostřednictvím regulace desmozomů. Ztráta kontroly pro­ Masaryk Memorial Cancer Institute liferace buněk a mezibuněčné adheze je přitom důležitou událostí při vývoji nádorů a vysoká Regional Centre for Applied hladina p63 podporuje růst nádorů a brání apoptóze nádorových buněk. Tento přehledový člá­ Molecular Oncology nek stručně shrnuje úlohy proteinu p63 ve vývoji epitelů, buněčné proliferaci, adhezi a migraci Zluty kopec 7 a poodhaluje jeho význam při vzniku nádorových onemocnění a tvorbě metastáz. 656 53 Brno Czech Republic Klíčová slova e-mail: [email protected] p63 – epidermální vývoj – buněčná proliferace – buněčná adheze – vývoj nádorového onemoc­ nění – epidermis Submitted/Obdrženo: 28. 9. 2012 Accepted/Přijato: 24. 10. 2012

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Introduction p63 defines the compartment cognised as a dominant negative inhibi­ The epidermis is a peripheral skin layer for this tissue [5]. In this article we would tor of TAp63 isoforms and other p53 fa­ that provides the human body with like to summarise the role of p63 in the mily members [8]. Despite the fact that a natural physical protection from de­ development of epidermis and demon­ ΔNp63 lacks the transactivation domain hydration and pathogens. It is com­ strate the link between p63 expression prevalent in TA isoforms, it can demon­ posed of proliferating basal and diffe­ and tumourigenesis. strate transactivation through the trans­ rentiated suprabasal keratinocytes [1]. activation domain present in its N-termi­ The self-renewing ability of the epider­ p63 Isoforms and Their nal end [14]. mis requires an appropriate prolifera­ Transactivation Properties tion and differentiation program in the p63 protein is one of the most signifi­ The Role of p63 in Proliferation basal layer [2]. Basal stem cells prolife­ cant transcription factors engaged in and Differentiation Processes in rate to produce daughter transit am­ the growth of keratinocytes and skin de­ Epidermal Cells plifying cells whose proliferative capa­ velopment (Fig. 1) [6,7]. Protein p63 be­ Though TAp63 isoforms appear ear­ city is more limited compared with basal longs to the p53 family [8,9] and like the lier than ΔNp63 during embryogenesis, stem cells. After the set of cellular divi­ other family members it contains three ΔNp63 is much more abundant in the sions, TA cells migrate through the epi­ typical domains: amino-terminal trans­ embryo [15,16]. Transgenic mice with dermis layers and begin the process of activation domain (TA), DNA-binding overexpressed TAp63α in the epidermis differentiation towards the formation domain and carboxy-terminal oligome­ revealed hyperplasia and inhibited diffe­ of external skin components [3]. Recent risation domain (OD) (Fig. 2) [8]. p63 is rentiation [15] indicating that the cor­ studies have established an important encoded by the TP63 gene. The expres­ rect development of epidermis needs an develop­mental role for p63 in stratified sion of TP63 is directed from two dis­ adequate balance between TA and ΔN tissue formation. p63 regulates trans­ tinct promoters, resulting in protein iso­ isoform levels. cription of multiple which encode forms either containing (TA) or lacking p63 with its‘ transactivation and inhi­ transcription factors, adhesion and sig­ (ΔN) the N-terminal transactivation do­ bition capacities is required for the pro­ nalling molecules, involved in main [8]. Furthermore, these transcripts liferation of epidermal cells [17] and the the , apoptosis and also tissue can then be subjected to alternative level strictly correlates with the prolifera­ specific proteins such as keratins, invo­ splicing to generate at least three diffe­ tive abilities of keratinocytes in vitro [18]. lucrin and loricrin [4]. The importance rent C-terminal isoforms termed α, β Experiments on developing zebrafish of p63 in skin development was mainly and γ [10] and newly described δ and ε embryos with down-regulated ΔNp63 supported by observations in knock­ isoforms [11]. Only the α isoforms pos­ displayed a total loss of epidermal pro­ out mice, that after birth lacked multi­ sess a sterile alpha motif (SAM) – a pro­ liferation. Later studies in p63 knock­ layered epithelia and any skin appen­ tein-protein interaction domain – and down epidermis showed that most of dages, such as teeth, hair follicles and a transcription inhibitory domain (TI) the cells ceased in followed by mammary glands which indicates that (Fig. 2) [12,13]. ΔNp63 isoforms are re­ an additional decrease of cells in S and G2/M phase. This phenomenon was ac­ companied by a reduced level of the proliferation marker Ki67 and by increa­ sed levels of cell cycle inhibitors such as WAF1 or . These findings thus clearly indicate that p63 knockdown cells are growth-arrested [17]. Besides playing roles in cellular pro­ liferation processes, p63 performs an important function in the regulation of differentiation. Epidermis created from pan-p63 knockdown keratinocytes showed defects in stratification and dif­ ferentiation and the expression of cha­ racteristic differentiation markers was not observed in the absence of p63. On the contrary, the loss of p63 led to the Fig. 1. Roles of p63 in epidermis formation. Epidermis consists of keratinocyte layers. expression of markers of simple epithe­ Stem cells located in the basal layer divide and produce transit amplifying stem cells, lium (keratins 8 and 18) which normally which are located in the basal layer. Transit amplifying stem cells initiate terminal diffe­ are not present in stratified tissues [17]. rentiation and form spinous layer. Continuation of this process gives rise to granular and A proposed model for p63 function in cornified layers. p63 is engaged during the whole process of formation of the epidermis. the differentiation process is based on

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Fig. 2. Structure of the TP63 gene and p63 protein isoforms. Depending on the promoter there are two distinct N-terminal isoforms: TAp63 – full-length and ΔNp63 – N-terminally truncated. Due to alternative splicing at the 3’ end, TAp63 transcripts can produce three different C-terminal isoforms termed α, β, γ. p63 protein comprises DNA binding domain, oligomerization domain and N-terminal trans­ activation (TA) domain (only TA isoforms), α isoforms possess also a sterile alpha motif (SAM) and a transcription inhibitory domain (TI).

the correct balance between protein le­ such as Notch, inhibitor of nuclear factor pression in keratinocytes while perma­ vels of p63 isoforms [15]. In the basal la­ kappa-B kinase subunit alpha (IKKα) [20] nent p63 function inhibits the ability of yers of the epidermis, ΔNp63 is the pre­ or keratin 14 which are only expressed Notch to induce cell cycle ar­ dominantly expressed isoform, but its in basal cells within stratified epithe­ rest. Moreover, promoting cell cycle ar­ abundance is reduced in the suprabasal lia [21]. IKKα plays an important role in rest by Notch signalling involves induc­ layer of stratified epithelium. In contrast, the proliferation and differentiation pro­ tion of WAF1 protein, which can be increased levels of TAp63 can be obser­ cess and mice with IKKα dis­ controlled by p63 [24]. ved in the upper parts of the epithelium played incorrect proliferation and diffe­ The differentiation program is based inhibiting terminal differentiation [8,15]. rentiation of skin cells. p63 isoforms can on the cooperation between specific While ΔNp63 seems to play a major role directly transactivate IKKα by attaching sets of genes being part of the epider­ in stratification as well as in differentia­ to the p53-like sequence on its promoter mal differentiation complex (EDC) within tion of epithelium, TAp63 appears to be or via protein C-ets1 mouse 3 and encoding important in its’ late differentiation [17]. (Ets-1) [20,22]. components of the cornified layer [26]. Recent studies revealed that diffe­ Notch signalling is a major pathway Chromatin architecture within the tis­ rentiation of epidermal cells begins that fosters stem cells to begin the pro­ sue-specific EDC can be remodel­ through asymmetric in the cess of differentiation towards keratino­ led by special AT-rich sequence-bind­ basal layer [19]. This process was not ob­ cytes [23,24]. One of the ligands for Notch ing protein-1 (Satb1). Satb1 functions served in p63-null keratinocytes. In ad­ receptor is jagged 1 protein (JAG-1), as a genome organiser, directing chro­ dition, p63 activity has been related to which was found to be a p63 target [25]. matin-remodelling enzymes and trans­ many genes significant in differentiation Notch activation can suppress p63 ex­ cription factors and therefore playing

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an important role in the regulation of pression of TA isoforms was observed at by controlling cell cycle arrest and apop­ tissue-specific pro­ later stages [16]. Research in zebrafish tosis and therefore it is also important in grams [27,28]. It was shown that Satb1 revealed ΔNp63α to be the most abun­ cancer development. Probably, it does stimulates the differentiation of proge­ dantly expressed isoform during embry­ not function as a basic tumour suppres­ nitor cells in the basal layer towards ke­ onic development [34] and mutations sor because it is rarely mutated in human ratinocytes and can be directly regula­ in p63-associated syndromes are mostly . In most cases, tumours main­ ted by p63 [26]. Satb1 is co-expressed found within regions specific for the tain p63 expression and moreover the with p63 in basal cells during embryonic α iso­form [35]. These observations sug­ TP63 locus is sometimes amplified and and postnatal development and mice gest that ΔNp63α is the essential isoform thus p63 is overexpressed [9,44]. High that have lost expression of p63 exhibi­ participating in the development of skin level of p63 was found in more than 80% ted severely decreased levels of Satb1 and skin appendages. of SCCHN and other squamous epithe­ and also loricrin (a marker of differen­ lial malignancies [45,46]. As ΔNp63 in­ tiated keratinocytes). Additionally, Satb1 Role of p63 in Cellular Adhesion duces proliferation it can also enhance knockout mice showed diminished epi­ Among other things, p63 plays an im­ tumour growth [47,48]. ΔNp63 binds to dermal cell proliferation and their skin portant role in the regulation of proces­ and suppresses activity that results appeared to be much thinner in compa­ ses mediating cell-cell adhesion within in the inhibition of apoptosis [45,49] rison with wild-type Satb1 mice [29]. the epidermis. Reduced p63 expres­ and also functions as a transcriptio­ sion in cultured mammary cells cau­ nal repressor of Bcl-2 family members, p63 and Skin Appendages sed impaired cell adhesion and de­ as it was found to bind to their promo­ Development creased expression of desmosomal ters [49,50]. p63 is a key survival factor Skin appendages which include teeth, components [36,37]. Furthermore, p63 for SCC, because its inhibition by interfe­ hairs and glands are derived from ec­ was stated to directly regulate the ex­ ring RNA induces apoptosis. It is also de­ todermal and mesodermal tissues [30]. pression of membrane protein Perp – graded after cisplatin treatment in SCC, The first step of skin appendage forma­ one of the most important elements for which seems to be an important chemo­ tion is very similar for all types, when the desmosome development [38]. Desmo­ therapy response [49,51]. What is more, placodes start to form a bud. However, somes are cell to cell junction protein it was found that ΔNp63 is a novel ATM the following events differ among them complexes, necessary to provide skin regulator, which controls p53 serine-15 and depend on the kind of skin deriva­ with the strength needed to withstand phosphorylation through transcription tive [30,31]. Genes which control the de­ mechanical stress. They attach cell sur­ of the ATM kinase. This research proved velopment of skin derivatives are highly face proteins to the intermediate cyto­ that, loss of ΔNp63 results in reduction conserved across species [31]. The essen­ skeletal filaments [39,40]. Beaudry et al of ATM-dependent phosphorylation and tial role of p63 in skin appendage develop­ showed that Perp-deficient mouse epi­ inversely overexpressed ΔNp63 stimula­ ment was observed in the p63-knock­out thelium had a decreased number of tes ATM signalling. These observations mice where animals lacking p63 expres­ desmosomes and was filled with blisters suggest that ΔNp63 isoform may play sion died perinatally and demonstrated leading to postnatal lethality [41]. Fur­ a significant role in response to DNA da­ a dramatic phenotype. Their epithelium thermore, they revealed that Perp acts mage [52]. Regarding TAp63 isoforms, stayed single-layered and lacked all the as a significant tumour suppressor in they are expressed in some malignant appendages such as hair follicles, teeth, UVB-induced lymphomas, while ΔNp63 isoform is not whiskers and glands [5]. Analogically, (SCC). It plays an important role as a me­ present [53]. However, the role of parti­ mutations in p63 are related to such phe­ diator of p53-induced apoptosis. In vivo cular isoforms of p63 in cancer is still not notype in humans as ectrodactyly, ecto­ experiments performed in mice confir­ clear and needs further investigation. dermal dysplasia and cleft lip/palate syn­ med that loss of Perp protein promo­ As mentioned above, p63 can regu­ drome (EEC), limb-mammary syndrome tes tumourigenesis and contributes to late expression of desmosomes compo­ (LMS), ankyloblepharon-ectodermal de­ tumour progression. nents. Some studies suggest that a de­ fects-cleft lip/palate syndrome (AEC), Studies in squamous cell carcinoma of crease in desmosomes components acro-dermato-ungual-lacrimal-tooth head and neck (SCCHN) cell lines, revea­ occurs during cancer progression in hu­ syndrome (ADULT) or Rapp-Hodgkin syn­ led that p63 regulates genes responsible mans and can be correlated with tumour drome (RHS) [32]. When developing hair, for cellular adhesion which plays a cru­ metastasis [54,55]. Furthermore, the loss teeth and vibrissae during embryogene­ cial role in cell invasiveness and metasta­ of Perp expression, a direct p63 target, sis, p63 is initially expressed through­out tic potential of this cancer type [42] and can promote tumour initiation [41]. the epithelium. With the progressive de­ the loss of p63 results in increased cell Barbieri et al showed that disruption velopment the level of p63 decreases wi­ migration [43]. of p63 expression in squamous cell lines thin the inner layers [16,33]. At the begin­ led to a decrease of transcripts speci­ ning, as well as during the whole process p63 in Tumourigenesis fic for squamous tissues and significant of ectoderm development, only ΔN iso­ p63 participates in the cellular signal­ modifications in keratinocytes differen­ forms were detected, whereas the ex­ ling processes following DNA damage tiation. Furthermore, it resulted in the

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