Biomedical subjects

Maranke I Koster

Publications and source records attributed to Maranke I Koster.

15 recordsLinked to original sources

PubMed2007

Conflicting roles for p63 in skin development and carcinogenesis.

Epidermal morphogenesis is a complex process that culminates in the formation of a barrier that protects the organism from environmental substances and dehydration. p63, a transcription factor, is essential for normal epidermal morphogenesis as demonstrated by the failure of mice lacking p63 expression to develop an epidermis. However, since two independently generated p63(-/-) mouse models displayed different phenotypes, the role of p63 in epidermal morphogenesis has remained controversial. Furthermore, the tumor susceptibility phenotypes of both p63(-/-) mouse models were strikingly different. In this review, we discuss these conflicting findings and provide evidence for various roles of p63 in the epidermis under normal and pathological conditions.

Animals↗

PubMed2006

p63 heterozygous mutant mice are not prone to spontaneous or chemically induced tumors.

Homology between p63 and p53 has suggested that these proteins might function similarly. However, the majority of data from human tumors have not supported a similar role for p63 in tumor suppression. To investigate this issue, we studied spontaneous tumorigenesis in p63+/- mice in both WT and p53-compromised backgrounds. We found that p63+/- mice were not tumor prone and mice heterozygous for both p63 and p53 had fewer tumors than p53+/- mice. The rare tumors that developed in mice with compromised p63 were also distinct from those of p53+/- mice. Furthermore, p63+/- mice were not prone to chemically induced tumorigenesis, and p63 expression was maintained in carcinomas. These findings demonstrate that, in agreement with data from human tumors, p63 plays a markedly different biological role in cancer than p53.

Animals↗

PubMed2006

Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation.

Notch signaling promotes commitment of keratinocytes to differentiation and suppresses tumorigenesis. p63, a p53 family member, has been implicated in establishment of the keratinocyte cell fate and/or maintenance of epithelial self-renewal. Here we show that p63 expression is suppressed by Notch1 activation in both mouse and human keratinocytes through a mechanism independent of cell cycle withdrawal and requiring down-modulation of selected interferon-responsive genes, including IRF7 and/or IRF3. In turn, elevated p63 expression counteracts the ability of Notch1 to restrict growth and promote differentiation. p63 functions as a selective modulator of Notch1-dependent transcription and function, with the Hes-1 gene as one of its direct negative targets. Thus, a complex cross-talk between Notch and p63 is involved in the balance between keratinocyte self-renewal and differentiation.

Animals↗

PubMed2006

Reactivation of developmentally expressed p63 isoforms predisposes to tumor development and progression.

Genes that are active during normal development are frequently reactivated during neoplastic transformation. We now report that developmentally expressed TAp63 isoforms are frequently reactivated in human squamous cell carcinomas. To determine the consequences of TAp63 reactivation, we induced TAp63alpha expression during chemically-induced skin carcinogenesis. Deregulated TAp63alpha expression dramatically accelerated tumor development and progression, frequently resulting in epithelial-mesenchymal transitions to spindle cell carcinomas and lung metastases. Consistent with this observation, we detected high levels of Twist and N-cadherin in tumors overexpressing TAp63alpha. Thus, as observed for other developmental pathways, aberrant reactivation of TAp63 predisposes to tumor development and progression.

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PubMed2005

TAp63alpha induces AP-2gamma as an early event in epidermal morphogenesis.

Epidermal morphogenesis begins with the commitment of the single-layered surface ectoderm to initiate a stratification program, a process that requires the expression of the transcription factor TAp63alpha. To determine the molecular mechanism by which TAp63alpha induces genes associated with the commitment to stratification, such as K14, we have used a combination of in vitro and in vivo approaches. Our initial gene expression profiling studies suggested that TAp63alpha could regulate one or more AP-2 genes, which have been implicated in development and maintenance of the epidermis. We now demonstrate that TAp63alpha directly induces AP-2gamma expression in embryonic epidermis, when commitment to stratification occurs. Furthermore, we show that, in the absence of AP-2gamma, TAp63alpha fails to induce K14 expression in vitro. Our data identify AP-2gamma as the first in vivo target gene of TAp63alpha, and provide novel insights into the molecular mechanisms associated with early events in epidermal morphogenesis.

Animals↗

PubMed2005

Asymmetric cell division in skin development: a new look at an old observation.

During skin development, the single-layered surface ectoderm covering the mouse embryo must initiate stratification and terminal differentiation to develop a functional epidermis. A recent article by Lechler and Fuchs in Nature (Lechler and Fuchs, 2005) suggests that these events are triggered by asymmetric cell division.

Animals↗

PubMed2005

P63 deficiency: a failure of lineage commitment or stem cell maintenance?

A critical role for p63 in the development of stratified epithelia, such as the epidermis, has been recognized since the generation of mice lacking p63 expression. The molecular role of p63 in epidermal morphogenesis, however, remained controversial. The epidermal phenotype of p63-/- mice, which are born with a single-layered surface epithelium instead of a fully stratified epidermis, suggested that p63 could have a role in stem cell maintenance or in the commitment to stratification. In this review, we discuss evidence suggesting that p63 is required for the commitment to stratification, making p63 the earliest known gene expressed in the developing epidermis that is specific for the keratinocyte lineage.

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PubMed2004

Transgenic mouse models provide new insights into the role of p63 in epidermal development.

The epidermis is a stratified epithelium which provides a barrier between the organism and the environment protecting it from dehydration and pathogenic insult. A gene essential for development of the epidermis and other stratified epithelia is the transcription factor p63. The p63 gene is transcribed into isoforms that contain (TA) or lack (DeltaN) a transactivation domain. Of these isoforms, only TAp63 isoforms are expressed in the uncommitted surface ectoderm, while DeltaNp63 isoforms are expressed after the surface ectoderm has committed to a stratification program. Consistent with these embryonic expression profiles, we found that TAp63alpha functions as the master switch for initiation of epithelial stratification. Furthermore, TAp63alpha induces proliferation and inhibits terminal differentiation. This inhibition is overcome by the subsequent expression of DeltaNp63alpha which, in this context, acts as a dominant-negative molecule and allows basal keratinocytes to withdraw from the cell cycle and commit to terminal differentiation. These data demonstrate that TA- and DeltaNp63 isoforms have fundamentally different roles during epidermal development and provide new insight into the molecular events required for normal epidermal morphogenesis.

Animals↗

PubMed2004

p63 is the molecular switch for initiation of an epithelial stratification program.

Development of stratified epithelia, such as the epidermis, requires p63 expression. The p63 gene encodes isoforms that contain (TA) or lack (DeltaN) a transactivation domain. We demonstrate that TAp63 isoforms are the first to be expressed during embryogenesis and are required for initiation of epithelial stratification. In addition, TAp63 isoforms inhibit terminal differentiation, suggesting that TAp63 isoforms must be counterbalanced by DeltaNp63 isoforms to allow cells to respond to signals required for maturation of embryonic epidermis. Our data demonstrate that p63 plays a dual role: initiating epithelial stratification during development and maintaining proliferative potential of basal keratinocytes in mature epidermis.

Animals↗

PubMed2004

The role of p63 in development and differentiation of the epidermis.

Expression of p63, a transcription factor that is transcribed into six isoforms, is required for proper development of stratified epithelia, such as the epidermis. In the absence of p63, epithelia remain single-layered. The molecular role of p63 in development and differentiation of stratified epithelia, however, remains controversial. Based on recent studies, we now believe that p63 has a dual role and is essential for development as well as maintenance of the epidermis. During embryogenesis, p63 may be the molecular switch required for initiation of epithelial stratification. This is based on our recent data demonstrating that ectopic expression of a p63 isoform in single-layered epithelia results in the induction of a stratification program. Furthermore, in the mature epidermis, p63 may maintain the proliferative potential of basal keratinocytes. This is suggested by the observation that p63 is primarily expressed in the basal compartment of the epidermis, that p63 expression induces hyperproliferation, and that its expression needs to be downregulated for terminal differentiation to take place. In this review, we discuss recent evidence supporting this dual role for p63 and place it in the context of our increasing knowledge of epidermal development and differentiation.

Animals↗

PubMed2004

Genetic pathways required for epidermal morphogenesis.

The epidermis is composed of keratinocytes which undergo a highly reproducible terminal differentiation program resulting in the formation of a protective barrier, which is established during embryogenesis. Significant progress has recently been made in understanding the genetic pathways associated with the earliest event characteristic of epidermal morphogenesis, commitment to stratification. This process depends on the expression of p63, a transcription factor which is transcribed into isoforms that contain (TA) or lack (AN) a transactivation domain. In the absence of p63 expression, epithelia remain single-layered, while ectopic TAp63alpha expression in single-layered epithelia initiates stratification. Later events during epidermal morphogenesis require withdrawal from the cell cycle and commitment to terminal differentiation. Some of the genetic pathways underlying these events are beginning to be elucidated, however, the exact molecular events remain to be determined. In this review, we summarize the involvement of several signaling pathways in different stages of epidermal morphogenesis.

Animals↗

PubMed2004

Genes involved in stem cell fate decisions and commitment to differentiation play a role in skin disease.

Multipotent stem cells residing in the bulge region of the hair follicle give rise to cells of different fates including those forming hair follicles, interfollicular epidermis, and associated glands. Stem cell fate determination is regulated by genes involved in both proliferation and differentiation, which are tightly regulated processes. Understanding the molecular mechanisms by which proliferation and differentiation are regulated will provide useful insight into treating human diseases caused by the deregulation of these processes. Two genes involved in regulating proliferation and differentiation are c-Myc and p63, both of which have been found to be deregulated/mutated in several human diseases. Accelerating proliferation leads to neoplastic human diseases and deregulated c-Myc has been implicated in a variety of cancers. Evidence indicates that c-Myc also diverts stem cells to an epidermal and sebaceous gland fate at the expense of the hair follicle fate. Therefore, deregulation of c-Myc has the potential to not only accelerate tumorigenesis, but also influence skin tumor phenotype. In addition, the inhibition of differentiation may also predispose to the development of skin cancer. Recent evidence suggests that the transcription factor p63, is not only responsible for the initiation of an epithelial stratification program during development, but also the maintenance of the proliferative potential of basal keratinocytes in mature epidermis. Mutations in the p63 gene have been shown to cause ectodermal dysplasias and deregulated expression of p63 has been observed in squamous cell carcinomas. In this review, we will discuss recent data implicating a role for both c-Myc and p63 in human skin diseases.

Animals↗

PubMed2004

p63 and epithelial appendage development.

Abstract Epithelial appendages share a common developmental program that relies on extensive interactions between epithelia and adjacent mesenchyme. The transcription factor p63 has a critical role in epithelial appendage development in both vertebrates and non-vertebrates. Both mice and zebrafish lacking p63 expression fail to develop epithelial appendages and other structures that develop as a result of epithelial-mesenchymal interactions. Furthermore, dominantly inherited mutations in p63 are the cause of a subset of human ectodermal dysplasias, which are characterized by developmental abnormalities in epithelia and epithelial appendages. While the importance of p63 for epithelial appendage development is evident, the molecular mechanisms by which p63 functions are largely unknown. In this review, we will discuss the current knowledge of the developmental role of p63 and the implications for epithelial appendage development.

Animals↗

PubMed2003

Roles of TGFbeta signaling in epidermal/appendage development.

The transforming growth factor beta (TGFbeta) superfamily encompasses a number of structurally related proteins that can be divided into several subfamilies including TGFbetas, activins/inhibins and bone morphogenetic proteins (BMPs). The Smads are major intracellular mediators in transducing the signals of TGFbeta superfamily members, and are abundantly expressed in the developing epidermis and epidermal appendages. Moreover, the phenotypes of transgenic/knockout mice with altered components of the TGFbeta superfamily signaling pathway suggest that TGFbeta superfamily signaling is required for epidermal/appendage development. TGFbeta superfamily members are involved in most events during epidermal/appendage development through the TGFbeta signal transduction pathway and through cross talk with other signaling pathways. Future studies will be instrumental in defining the precise roles for TGFbeta superfamily signaling in epidermal/appendage development.

Activins↗

PubMed2002

Epidermal differentiation: transgenic/knockout mouse models reveal genes involved in stem cell fate decisions and commitment to differentiation.

Epidermal development and differentiation are similar processes and therefore the study of one is likely to provide insight into the other. The signaling cascades required for epidermal differentiation are largely unknown. Recent evidence, however, has implicated two proteins, p63 and c-Myc, in different stages of epidermal development and differentiation. p63 was shown to be required for embryonic epidermal development. Mice lacking p63 do not develop stratified epithelia and appendages suggesting a role for p63 in the commitment to squamous epithelial lineages. Subsequent stem cell fate decisions are required to form the different structures of stratified epithelia including hair follicles, sebaceous glands, and epidermis. Several genes of the Wnt signaling pathway have been implicated in this process, including c-Myc, a downstream target of the Wnt pathway. Interestingly, targeted overexpression of c-Myc in the basal layer of the epidermis results in an increase in sebaceous gland size and number at the expense of hair follicles. This suggests that c-Myc promotes differentiation of epidermal stem cells into sebaceous glands. In this review, we discuss transgenic/knockout mouse models that have provided evidence linking c-Myc and p63 to different stages of epidermal development and differentiation.

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