Keratinocyte survival, differentiation, and death: many roads lead to mitogen-activated protein kinase.

The epidermis is a dynamic and continually renewing surface that provides and maintains a life-sustaining interface with the environment. The epidermal keratinocyte, the major cell type of the epidermis, undergoes a complex and carefully choreographed program of differentiation. This process requires a balance between keratinocyte proliferation, differentiation, and apoptosis. This overview will concentrate on cascades that regulate the balance between keratinocyte cell proliferation and survival, and apoptosis and cell differentiation, with a particular emphasis on the role of the mitogen-activated protein kinase cascades. A summary of the literature suggests that extracellular regulated kinases function to promote keratinocyte proliferation and survival, whereas p38 mitogen-activated protein kinase functions to promote differentiation and apoptosis.

[1]  K. Sayama,et al.  Apoptosis Signal-regulating Kinase 1 (ASK1) Is an Intracellular Inducer of Keratinocyte Differentiation* , 2001, The Journal of Biological Chemistry.

[2]  Luowei Li,et al.  Protein Kinase Cδ Targets Mitochondria, Alters Mitochondrial Membrane Potential, and Induces Apoptosis in Normal and Neoplastic Keratinocytes When Overexpressed by an Adenoviral Vector , 1999, Molecular and Cellular Biology.

[3]  S. Boyce,et al.  Calcium-regulated differentiation of normal human epidermal keratinocytes in chemically defined clonal culture and serum-free serial culture. , 1983, The Journal of investigative dermatology.

[4]  Weiya Ma,et al.  Phorbol Ester-induced Expression of Airway Squamous Cell Differentiation Marker, SPRR1B, Is Regulated by Protein Kinase Cδ/Ras/MEKK1/MKK1-dependent/AP-1 Signal Transduction Pathway* , 2000, The Journal of Biological Chemistry.

[5]  E. Fuchs,et al.  The epidermis: rising to the surface. , 1994, Current opinion in genetics & development.

[6]  R. Eckert,et al.  MEK7-dependent Activation of p38 MAP Kinase in Keratinocytes* , 2001, The Journal of Biological Chemistry.

[7]  M. Diaz,et al.  Role of NF-κB in the Apoptotic-resistant Phenotype of Keratinocytes* , 1999, The Journal of Biological Chemistry.

[8]  H. Green,et al.  Formation of a keratinizing epithelium in culture by a cloned cell line derived from a teratoma , 1975, Cell.

[9]  E. Fuchs,et al.  Hyperproliferation and Defects in Epithelial Polarity upon Conditional Ablation of α-Catenin in Skin , 2001, Cell.

[10]  A. Ishida-Yamamoto,et al.  Cornified cell envelope formation is distinct from apoptosis in epidermal keratinocytes. , 2000, Journal of dermatological science.

[11]  R. Eckert,et al.  Regulation of Human Involucrin Promoter Activity by a Protein Kinase C, Ras, MEKK1, MEK3, p38/RK, AP1 Signal Transduction Pathway* , 1998, The Journal of Biological Chemistry.

[12]  T. Kuroki,et al.  Protein Kinase Cδ-mediated Phosphorylation of α6β4 Is Associated with Reduced Integrin Localization to the Hemidesmosome and Decreased Keratinocyte Attachment , 2001 .

[13]  L. Liotta,et al.  Extracellular matrix 6: Role of matrix metalloproteinases in tumor invasion and metastasis , 1993, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[14]  N. Huh,et al.  Induction of Differentiation in Normal Human Keratinocytes by Adenovirus-Mediated Introduction of the η and δ Isoforms of Protein Kinase C , 1998, Molecular and Cellular Biology.

[15]  J. Tschopp,et al.  Death receptors in cutaneous biology and disease. , 2000, The Journal of investigative dermatology.

[16]  M. Cobb,et al.  Mitogen-activated protein kinase pathways. , 1997, Current opinion in cell biology.

[17]  S. Boyce,et al.  Rapid clonal growth and serial passage of human diploid fibroblasts in a lipid-enriched synthetic medium supplemented with epidermal growth factor, insulin, and dexamethasone. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[18]  P. Vandenabeele,et al.  p38 Mitogen-activated Protein Kinase Regulates a Novel, Caspase-independent Pathway for the Mitochondrial Cytochromec Release in Ultraviolet B Radiation-induced Apoptosis* , 2000, The Journal of Biological Chemistry.

[19]  A. Ishida-Yamamoto,et al.  Differential phosphorylation of mitogen-activated protein kinase families by epidermal growth factor and ultraviolet B irradiation in SV40-transformed human keratinocytes. , 2001, Journal of dermatological science.

[20]  U. Rodeck,et al.  Epidermal Growth Factor Receptor-dependent Control of Keratinocyte Survival and Bcl-xL Expression through a MEK-dependent Pathway* , 2001, The Journal of Biological Chemistry.

[21]  F. Watt,et al.  Signaling via beta1 integrins and mitogen-activated protein kinase determines human epidermal stem cell fate in vitro. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[22]  Y. Taya,et al.  PKCη associates with cyclin E/cdk2/p21 complex, phosphorylates p21 and inhibits cdk2 kinase in keratinocytes , 2000, Oncogene.

[23]  M. Diaz,et al.  Apoptosis in Proliferating, Senescent, and Immortalized Keratinocytes* , 1999, The Journal of Biological Chemistry.

[24]  John Mendelsohn,et al.  The EGF receptor family as targets for cancer therapy , 2000, Oncogene.

[25]  R. Eckert,et al.  Regulation of Human Involucrin Promoter Activity by Novel Protein Kinase C Isoforms* , 2000, The Journal of Biological Chemistry.

[26]  L. Ährlund‐Richter,et al.  Squamous cell carcinomas and increased apoptosis in skin with inhibited Rel/nuclear factor-kappaB signaling. , 1999, Cancer research.

[27]  P. Stein,et al.  A PKC-eta/Fyn-dependent pathway leading to keratinocyte growth arrest and differentiation. , 2000, Molecular cell.

[28]  T. Kuroki,et al.  Phorbol Ester‐induced G1 Arrest in BALB/MK‐2 Mouse Keratinocytes Is Mediated by δ and η Isoforms of Protein Kinase C , 1998, Japanese journal of cancer research : Gann.

[29]  F. Watt,et al.  A role for mitogen-activated protein kinase activation by integrins in the pathogenesis of psoriasis. , 2001, The Journal of clinical investigation.

[30]  A. Beyerle,et al.  UVB-induced Epidermal Growth Factor Receptor Phosphorylation is Critical for Downstream Signaling and Keratinocyte Survival¶ , 2000, Photochemistry and photobiology.

[31]  H. Ichijo,et al.  From receptors to stress-activated MAP kinases , 1999, Oncogene.

[32]  L. Eckhart,et al.  Caspase-14: analysis of gene structure and mRNA expression during keratinocyte differentiation. , 2000, Biochemical and biophysical research communications.

[33]  Roger J. Davis,et al.  Transcriptional regulation by MAP kinases , 1995, Molecular reproduction and development.

[34]  R. Eckert,et al.  Calcium-dependent Involucrin Expression Is Inversely Regulated by Protein Kinase C (PKC)α and PKCδ* , 2002, The Journal of Biological Chemistry.

[35]  S. Yuspa,et al.  Protein kinase C regulates keratinocyte transglutaminase (TGK) gene expression in cultured primary mouse epidermal keratinocytes induced to terminally differentiate by calcium. , 1994, The Journal of investigative dermatology.

[36]  R. Eckert,et al.  Regulation of Human Involucrin Promoter Activity by POU Domain Proteins* , 1996, The Journal of Biological Chemistry.

[37]  G. Núñez,et al.  Apoptosis in keratinocytes is not dependent on induction of differentiation. , 1997, Laboratory investigation; a journal of technical methods and pathology.

[38]  H. Green,et al.  Presence in human epidermal cells of a soluble protein precursor of the cross-linked envelope: Activation of the cross-linking by calcium ions , 1979, Cell.

[39]  K. Subbaramaiah,et al.  Regulation of Cyclooxygenase-2 by Interferon γ and Transforming Growth Factor α in Normal Human Epidermal Keratinocytes and Squamous Carcinoma Cells , 1999, The Journal of Biological Chemistry.

[40]  A. Ishida-Yamamoto,et al.  Expression of Human Cystatin A by Keratinocytes Is Positively Regulated via the Ras/MEKK1/MKK7/JNK Signal Transduction Pathway but Negatively Regulated via the Ras/Raf-1/MEK1/ERK Pathway* , 2001, The Journal of Biological Chemistry.

[41]  R. Eckert,et al.  MEK6 Regulates Human Involucrin Gene Expression via a p38α- and p38δ-dependent Mechanism , 2001, The Journal of Biological Chemistry.

[42]  M. Kuechle,et al.  Caspase-14, a keratinocyte specific caspase: mRNA splice variants and expression pattern in embryonic and adult mouse , 2001, Cell Death and Differentiation.

[43]  H. Green The keratinocyte as differentiated cell type. , 1980, Harvey lectures.

[44]  R. Eckert,et al.  The epidermal keratinocyte as a model for the study of gene regulation and cell differentiation. , 1997, Physiological reviews.

[45]  Y. Banno,et al.  Activation of p38 mitogen-activated protein kinase and caspases in UVB-induced apoptosis of human keratinocyte HaCaT cells. , 1999, The Journal of investigative dermatology.

[46]  T. Mcguire,et al.  Vitamin D(3)-induced apoptosis of murine squamous cell carcinoma cells. Selective induction of caspase-dependent MEK cleavage and up-regulation of MEKK-1. , 2001, The Journal of biological chemistry.

[47]  B. Nickoloff,et al.  Protein Kinase Cδ Is Activated by Caspase-dependent Proteolysis during Ultraviolet Radiation-induced Apoptosis of Human Keratinocytes* , 1998, The Journal of Biological Chemistry.

[48]  A. Ullrich,et al.  The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification. , 2001, Endocrine-related cancer.

[49]  G. T. Bowden,et al.  Role of cyclic AMP responsive element in the UVB induction of cyclooxygenase-2 transcription in human keratinocytes , 2001, Oncogene.

[50]  H. Ichijo,et al.  Molecular mechanisms of the decision between life and death: regulation of apoptosis by apoptosis signal-regulating kinase 1. , 2001, Journal of biochemistry.

[51]  C. López-Otín,et al.  Expression of collagenase-3 (MMP-13) and collagenase-1 (MMP-1) by transformed keratinocytes is dependent on the activity of p38 mitogen-activated protein kinase. , 2000, Journal of cell science.

[52]  Toshio Kuroki,et al.  The Isoform of Protein Kinase C Mediates Transcriptional Activation of the Human Transglutaminase 1 Gene (*) , 1996, The Journal of Biological Chemistry.

[53]  Chris Albanese,et al.  NF-κB and cell-cycle regulation: the cyclin connection , 2001 .

[54]  S. Yuspa,et al.  Natural synchrony of newborn mouse epidermal cells in vitro. , 1976, The Journal of investigative dermatology.

[55]  R. Eckert,et al.  Characterization of human involucrin promoter distal regulatory region transcriptional activator elements–a role for Sp1 and AP1 binding sites , 1998 .

[56]  J. Gutkind,et al.  Signaling from E-cadherins to the MAPK Pathway by the Recruitment and Activation of Epidermal Growth Factor Receptors upon Cell-Cell Contact Formation* , 2000, The Journal of Biological Chemistry.

[57]  R. Class,et al.  A central role of Bcl-X(L) in the regulation of keratinocyte survival by autocrine EGFR ligands. , 1999, The Journal of investigative dermatology.

[58]  S. Yuspa,et al.  Expression of an oncogenic rasHa gene in murine keratinocytes induces tyrosine phosphorylation and reduced activity of protein kinase C delta. , 1993, The Journal of biological chemistry.

[59]  A. Beyerle,et al.  UVB activates ERK1/2 and p38 signaling pathways via reactive oxygen species in cultured keratinocytes. , 1999, The Journal of investigative dermatology.

[60]  James Varani,et al.  Role of ERK and JNK pathways in regulating cell motility and matrix metalloproteinase 9 production in growth factor‐stimulated human epidermal keratinocytes , 1999, Journal of cellular physiology.

[61]  A. Gandarillas Epidermal differentiation, apoptosis, and senescence: common pathways? , 2000, Experimental Gerontology.

[62]  H. Green,et al.  Seria cultivation of strains of human epidemal keratinocytes: the formation keratinizin colonies from single cell is , 1975, Cell.

[63]  S Lippens,et al.  Terminal differentiation of human keratinocytes and stratum corneum formation is associated with caspase-14 activation. , 2000, The Journal of investigative dermatology.

[64]  J. Santibañez,et al.  Involvement of the Ras/MAPK signaling pathway in the modulation of urokinase production and cellular invasiveness by transforming growth factor-beta(1) in transformed keratinocytes. , 2000, Biochemical and biophysical research communications.

[65]  L. Goldsmith,et al.  Evidence that apoptosis and terminal differentiation of epidermal keratinocytes are distinct processes , 1999, Experimental dermatology.

[66]  U. Rodeck,et al.  Matrix-independent survival of human keratinocytes through an EGF receptor/MAPK-kinase-dependent pathway. , 2001, Molecular biology of the cell.

[67]  P. Vandenabeele,et al.  Epidermal differentiation does not involve the pro-apoptotic executioner caspases, but is associated with caspase-14 induction and processing , 2000, Cell Death and Differentiation.