IKKα Is a p63 Transcriptional Target Involved in the Pathogenesis of Ectodermal Dysplasias (original) (raw)
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Journal of Clinical Investigation, 2010
The human congenital syndromes ectrodactyly ectodermal dysplasia-cleft lip/palate syndrome, ankyloblepharon ectodermal dysplasia clefting, and split-hand/foot malformation are all characterized by ectodermal dysplasia, limb malformations, and cleft lip/palate. These phenotypic features are a result of an imbalance between the proliferation and differentiation of precursor cells during development of ectoderm-derived structures. Mutations in the p63 and interferon regulatory factor 6 (IRF6) genes have been found in human patients with these syndromes, consistent with phenotypes. Here, we used human and mouse primary keratinocytes and mouse models to investigate the role of p63 and IRF6 in proliferation and differentiation. We report that the ΔNp63 isoform of p63 activated transcription of IRF6, and this, in turn, induced proteasomemediated ΔNp63 degradation. This feedback regulatory loop allowed keratinocytes to exit the cell cycle, thereby limiting their ability to proliferate. Importantly, mutations in either p63 or IRF6 resulted in disruption of this regulatory loop: p63 mutations causing ectodermal dysplasias were unable to activate IRF6 transcription, and mice with mutated or null p63 showed reduced Irf6 expression in their palate and ectoderm. These results identify what we believe to be a novel mechanism that regulates the proliferation-differentiation balance of keratinocytes essential for palate fusion and skin differentiation and links the pathogenesis of 2 genetically different groups of ectodermal dysplasia syndromes into a common molecular pathway.
p63 is upstream of IKK in epidermal development
Journal of Cell Science, 2006
The epidermis, the outer layer of the skin composed of keratinocytes, develops following the action of the transcription factor p63. The mouse Trp63 gene contains two promoters, driving the production of distinct proteins, one with an N-terminal trans-activation domain (TAp63) and one without (ΔNp63), although their relative contribution to epidermal development is not clearly established. To identify the relative role of p63 isoforms in relation to IKKα, also known to be essential for epithelial development, we performed both molecular and in vivo analyses using genetic complementation in mice. We found that the action of TAp63 is mediated at the molecular level by direct and indirect transactivation of IKKα and Ets-1, respectively. We also found that ΔNp63 upregulates IKKα indirectly, through GATA-3. Our data are consistent with a role for p63 directly upstream of IKKα in epithelial development.
Oncotarget, 2016
IKKα plays a mandatory role in keratinocyte differentiation and exerts an important task in non-melanoma skin cancer development. However, it is not fully understood how IKKα exerts these functions. To analyze in detail the role of IKKα in epidermal stratification and differentiation, we have generated tridimensional (3D) cultures of human HaCaT keratinocytes and fibroblasts in fibrin gels, obtaining human skin equivalents that comprise an epidermal and a dermal compartments that resembles both the structure and differentiation of normal human skin. We have found that IKKα expression must be strictly regulated in epidermis, as alterations in its levels lead to histological defects and promote the development of malignant features. Specifically, we have found that the augmented expression of IKKα results in increased proliferation and clonogenicity of human keratinocytes, and leads to an accelerated and altered differentiation, augmented ability of invasive growth, induction of the e...
p63 induces key target genes required for epidermal morphogenesis
Proceedings of The National Academy of Sciences, 2007
Mice lacking p63, a single gene that encodes a group of transcription factors that either contain (TA) or lack (ΔN) a transactivation domain, fail to develop stratified epithelia as well as epithelial appendages and limbs. ΔNp63 isoforms are predominantly expressed during late embryonic and postnatal epidermal development, however, the function of these proteins remains elusive. Using an epidermal-specific inducible knockdown
Ectodermal dysplasias: An overview and update of clinical and molecular-functional mechanisms
American Journal of Medical Genetics Part A, 2009
The ectodermal dysplasias (EDs) are a large and complex group of disorders. In various combinations, they all share anomalies in hair, teeth, nails, and sweat gland function. The anomalies affecting the epidermis and epidermal appendages are extremely variable. Many are associated with malformations in other organs and systems. Clinical overlap is present among EDs. Few causative genes have been identified, to date. Most of the EDs present multisystem involvement with abnormal development of structures also derived from mesoderm. In the last few years, it has become evident that gene expression in the EDs is not limited to the ectoderm and that there is a concomitant effect on developing mesenchymal structures, with modification or abolition of ectodermal-mesenchymal signaling. It is possible to approach this group of diseases basing on functional and molecular findings and to begin to explain the complex clinical consequences of mutations affecting specific developmental pathways. We have reviewed the molecular basis of ectodermal dysplasias applying this new clinical-functional classification. For each subset of the identified ED, we will now describe the genes and related proteins involved in terms of: (1) structure of the genes and their role in differentiation of the epidermis and the ectodermal derivatives; (2) genotype-phenotype correlation.
IKKα, a critical regulator of epidermal differentiation and a suppressor of skin cancer
The EMBO Journal, 2008
New EMBO Member's Review IKKa, a critical regulator of epidermal differentiation and a suppressor of skin cancer This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits distribution, and reproduction in any medium, provided the original author and source are credited. This license does not permit commercial exploitation or the creation of derivative works without specific permission.
PloS one, 2009
One major defining characteristic of the basal keratinocytes of the stratified epithelium is the expression of the keratin genes K5 and K14. The temporal and spatial expression of these two genes is usually tightly and coordinately regulated at the transcriptional level. This ensures the obligate pairing of K5 and K14 proteins to generate an intermediate filament (IF) network that is essential for the structure and function of the proliferative keratinocytes. Our previous studies have shown that the basal-keratinocyte restricted transcription factor p63 is a direct regulator of K14 gene. Here we provide evidence that p63, specifically the DeltaN isoform also regulates the expression of the K5 gene by binding to a conserved enhancer within the 5' upstream region. By using specific antibodies against DeltaNp63, we show a concordance in the expression between basal keratins and DeltaNp63 proteins but not the TAp63 isoforms during early embryonic skin development. We demonstrate, th...
Nucleic acids research, 2015
p63 is a crucial regulator of epidermal development, but its transcriptional control has remained elusive. Here, we report the identification of a long-range enhancer (p63LRE) that is composed of two evolutionary conserved modules (C38 and C40), acting in concert to control tissue- and layer-specific expression of the p63 gene. Both modules are in an open and active chromatin state in human and mouse keratinocytes and in embryonic epidermis, and are strongly bound by p63. p63LRE activity is dependent on p63 expression in embryonic skin, and also in the commitment of human induced pluripotent stem cells toward an epithelial cell fate. A search for other transcription factors involved in p63LRE regulation revealed that the CAAT enhancer binding proteins Cebpa and Cebpb and the POU domain-containing protein Pou3f1 repress p63 expression during keratinocyte differentiation by binding the p63LRE enhancer. Collectively, our data indicate that p63LRE is composed of additive and partly redu...
Keratin gene mutations in disorders of human skin and its appendages
Archives of Biochemistry and Biophysics, 2011
Keratins, the major structural protein of all epithelia, are a diverse group of cytoskeletal scaffolding proteins that form intermediate filament networks, providing structural support to keratinocytes that maintain the integrity of the skin. Expression of keratin genes is usually regulated by differentiation of the epidermal cells within the stratifying squamous epithelium. Amongst the 54 known functional keratin genes in humans, about 21 different genes including hair and hair follicle-specific keratins have been associated with diverse hereditary disorders. The exact phenotype of each disease mostly reflects the spatial level of expression and types of the mutated keratin genes, the positions of the mutations as well as their consequences at sub-cellular levels. The identification of specific mutations in keratin disorders is the basis of our understanding that lead to reclassification, improved diagnosis with prognostic implications, prenatal testing and genetic counseling in severe cutaneous keratin genodermatoses. A disturbance in cutaneous keratins as a result of mutation(s) in the gene(s) that encode keratin intermediate filaments (KIF) causes keratinocytes and cutaneous tissue fragility, accounting for a large number of genetic disorders in human skin and its appendages. These diseases are characterized by a loss of structural integrity in keratinocytes expressing mutated keratins in vivo, often manifested as keratinocytes fragility (cytolysis), intra-epidermal blistering, hyperkeratosis, and keratin filament aggregation in severely affected tissues. Examples include epidermolysis bullosa simplex (EBS), keratinopathic ichthyosis (KPI), pachyonychia congenital (PC), monilethrix, steatocystoma multiplex and ichthyosis bullosa of Siemens (IBS). These keratins also have been identified to have roles in cell growth, apoptosis, tissue polarity, wound healing and tissue remodeling.
Journal of Cell Science, 2011
Heterozygous mutations of p63, a key transcription factor in epithelial development, are causative in a variety of human ectodermal dysplasia disorders. Although the mutation spectrum of these disorders displays a striking genotype–phenotype association, the molecular basis for this association is only superficially known. Here, we characterize the transcriptional activity and protein stability of ΔNp63 mutants (that is, mutants of a p63 isoform that lacks the N-terminal transactivation domain) that are found in ectrodactyly–ectodermal dysplasia–cleft syndrome (EEC), ankyloblepharon–ectodermal dysplasia–clefting syndrome (AEC) and nonsyndromic split-hand/split-foot malformation (SHFM). DNA-binding and sterile alpha motif (SAM) domain mutants accumulate in the skin of EEC and AEC syndrome patients, respectively, and show extended half lives in vitro. By contrast, C-terminal mutations found in SHFM patients have half-lives similar to that of the wild-type protein. The increased half-l...