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1.  Suppressing Ap1 Factor Signaling in Suprabasal Epidermis Produces A Keratoderma Phenotype 
Keratodermas comprise a heterogeneous group of highly debilitating and painful disorders characterized by thickening of the skin with marked hyperkeratosis. Some of these diseases are caused by genetic mutation, while other forms are acquired in response to environmental factors. Our understanding of signaling changes that underlie these diseases is limited. In the present study we describe a keratoderma phenotype in mice in response to suprabasal epidermis-specific inhibition of activator protein 1 transcription factor signaling. These mice develop a severe phenotype characterized by hyperplasia, hyperkeratosis, parakeratosis and impaired epidermal barrier function. The skin is scaled, constricting bands encircle the tail and digits, the footpads are thickened and scaled, and loricrin staining is markedly reduced in the cornified layers and increased in the nucleus. Features of this phenotype, including nuclear loricrin localization and pseudoainhum (autoamputation), are characteristic of Vohwinkel Syndrome. We confirm that the phenotype develops in a loricrin null genetic background, indicating that suppressed suprabasal AP1 factor function is sufficient to drive this disease. We also show that the phenotype regresses when suprabasal AP1 factor signaling is restored. Our findings suggest that suppression of AP1 factor signaling in the suprabasal epidermis is a key event in the pathogenesis of keratoderma.
doi:10.1038/jid.2014.310
PMCID: PMC4268309  PMID: 25050598
TAM67; jun; fos; AP1; keratinocyte differentiation; epidermis; keratoderma; loricrin; Vohwinkel Syndrome
2.  p38δ Regulates p53 to Control p21Cip1 Expression in Human Epidermal Keratinocytes* 
The Journal of Biological Chemistry  2014;289(16):11443-11453.
Background: Keratinocytes cease proliferation during differentiation, and the mechanism that mediates these events is not well understood.
Results: PKCδ increases p38δ activity, which increases p53 transcription and acts to increase p21Cip1 promoter activity.
Conclusion: PKCδ drives a MAPK cascade to increase p53 to control keratinocyte proliferation.
Significance: This study provides detailed information regarding the mechanisms that control cell proliferation.
PKCδ suppresses keratinocyte proliferation via a mechanism that involves increased expression of p21Cip1. However, the signaling mechanism that mediates this regulation is not well understood. Our present studies suggest that PKCδ activates p38δ leading to increased p21Cip1 promoter activity and p21Cip1 mRNA/protein expression. We further show that exogenously expressed p38δ increases p21Cip1 mRNA and protein and that p38δ knockdown or expression of dominant-negative p38 attenuates this increase. Moreover, p53 is an intermediary in this regulation, as p38δ expression increases p53 mRNA, protein, and promoter activity, and p53 knockdown attenuates the activation. We demonstrate a direct interaction of p38δ with PKCδ and MEK3 and show that exogenous agents that suppress keratinocyte proliferation activate this pathway. We confirm the importance of this regulation using a stratified epidermal equivalent model, which mimics in vivo-like keratinocyte differentiation. In this model, PKCδ or p38δ knockdown results in reduced p53 and p21Cip1 levels and enhanced cell proliferation. We propose that PKCδ activates a MEKK1/MEK3/p38δ MAPK cascade to increase p53 levels and p53 drives p21Cip1 gene expression.
doi:10.1074/jbc.M113.543165
PMCID: PMC4036280  PMID: 24599959
Cell Differentiation; Cell Proliferation; Cell Signaling; MAP Kinases (MAPKs); p38 MAPK
3.  Biochemistry of epidermal stem cells☆ 
Biochimica et biophysica acta  2012;1830(2):2427-2434.
Background
The epidermis is an important protective barrier that is essential for maintenance of life. Maintaining this barrier requires continuous cell proliferation and differentiation. Moreover, these processes must be balanced to produce a normal epidermis. The stem cells of the epidermis reside in specific locations in the basal epidermis, hair follicle and sebaceous glands and these cells are responsible for replenishment of this tissue.
Scope of review
A great deal of effort has gone into identifying protein epitopes that mark stem cells, in identifying stem cell niche locations, and in understanding how stem cell populations are related. We discuss these studies as they apply to understanding normal epidermal homeostasis and skin cancer.
Major conclusions
An assortment of stem cell markers have been identified that permit assignment of stem cells to specific regions of the epidermis, and progress has been made in understanding the role of these cells in normal epidermal homeostasis and in conditions of tissue stress. A key finding is the multiple stem cell populations exist in epidermis that give rise to different structures, and that multiple stem cell types may contribute to repair in damaged epidermis.
General significance
Understanding epidermal stem cell biology is likely to lead to important therapies for treating skin diseases and cancer, and will also contribute to our understanding of stem cells in other systems. This article is part of a Special Issue entitled Biochemistry of Stem Cells.
doi:10.1016/j.bbagen.2012.07.002
PMCID: PMC4038073  PMID: 22820019
Stem cell Hair follicle; Interfollicular stem cell; Epidermis; Keratinocyte
4.  Identification of a Population of Epidermal Squamous Cell Carcinoma Cells with Enhanced Potential for Tumor Formation 
PLoS ONE  2013;8(12):e84324.
Epidermal squamous cell carcinoma is among the most common cancers in humans. These tumors are comprised of phenotypically diverse populations of cells that display varying potential for proliferation and differentiation. An important goal is identifying cells from this population that drive tumor formation. To enrich for tumor-forming cells, cancer cells were grown as spheroids in non-attached conditions. We show that spheroid-selected cells form faster growing and larger tumors in immune-compromised mice as compared to non-selected cells. Moreover, spheroid-selected cells gave rise to tumors following injection of as few as one hundred cells, suggesting these cells have enhanced tumor-forming potential. Cells isolated from spheroid-selected tumors retain an enhanced ability to grow as spheroids when grown in non-attached culture conditions. Thus, these tumor-forming cells retain their phenotype following in vivo passage as tumors. Detailed analysis reveals that spheroid-selected cultures are highly enriched for expression of epidermal stem cell and embryonic stem cell markers, including aldehyde dehydrogenase 1, keratin 15, CD200, keratin 19, Oct4, Bmi-1, Ezh2 and trimethylated histone H3. These studies indicate that a subpopulation of cells that possess stem cell-like properties and express stem cell markers can be derived from human epidermal cancer cells and that these cells display enhanced ability to drive tumor formation.
doi:10.1371/journal.pone.0084324
PMCID: PMC3869846  PMID: 24376802

Results 1-4 (4)