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• W2020671917 abstract "Unraveling the signaling pathways that transmit information from the cell surface to the nucleus has been a major accomplishment of modern cell and molecular biology. The benefit to humans is seen in the multitude of new therapeutics based on the illumination of these pathways. Although considerable insight has been gained in understanding homeostatic and pathological signaling in the epidermis and other skin compartments, the translation into therapy has been lacking. This review will outline advances made in understanding fundamental signaling in several of the most prominent pathways that control cutaneous development, cell-fate decisions, and keratinocyte growth and differentiation with the anticipation that this insight will contribute to new treatments for troubling skin diseases. Unraveling the signaling pathways that transmit information from the cell surface to the nucleus has been a major accomplishment of modern cell and molecular biology. The benefit to humans is seen in the multitude of new therapeutics based on the illumination of these pathways. Although considerable insight has been gained in understanding homeostatic and pathological signaling in the epidermis and other skin compartments, the translation into therapy has been lacking. This review will outline advances made in understanding fundamental signaling in several of the most prominent pathways that control cutaneous development, cell-fate decisions, and keratinocyte growth and differentiation with the anticipation that this insight will contribute to new treatments for troubling skin diseases. adenosine triphosphate calcium calcium-sensing receptor chemokine (C-C motif) ligand 2 chemokine (C-X-C motif) ligand 10 diacylglycerol endoplasmic reticulum extracellular signal–regulated kinases 1 and 2 protein kinase C phospholipase C 12-O-tetradecanoyl-phorbol-13-acetate It has been three decades since awareness of the unique role of calcium in the regulation of growth and differentiation of keratinocytes first came to light through studies of cultured keratinocytes (Hennings et al., 1980Hennings H. Michael D. Cheng C. et al.Calcium regulation of growth and differentiation of mouse epidermal cells in culture.Cell. 1980; 19: 245-254Abstract Full Text PDF PubMed Scopus (1502) Google Scholar. Since that time, modulation of calcium in vivo and in vitro has been the major tool used to illuminate the fine structure of keratinocyte and epidermal biology and has contributed to understanding the molecular basis of several skin diseases. Beyond keratinocytes, calcium is increasingly recognized as a central transmitter of signals in all cells, and calcium signaling is dynamically controlled during normal cell cycles and in resting states (Roderick and Cook, 2008Roderick H.L. Cook S.J. Ca2+ signalling checkpoints in cancer: remodelling Ca2+ for cancer cell proliferation and survival.Nat Rev Cancer. 2008; 8: 361-375Crossref PubMed Scopus (545) Google Scholar; Putney, 2009Putney J.W. Capacitative calcium entry: from concept to molecules.Immunol Rev. 2009; 231: 10-22Crossref PubMed Scopus (196) Google Scholar; Dupont et al., 2011Dupont G. Combettes L. Bird G.S. et al.Calcium oscillations.Cold Spring Harb Perspect Biol. 2011; 3: a004226Crossref Scopus (189) Google Scholar. The central importance of calcium in cell physiology is clearly demonstrated by its complex regulation involving channels, pumps, sensors, binding proteins, hormones, and receptors, both on the plasma membrane and intracellular organelles. Furthermore, in both excitable and nonexcitable cells, there is a constant flux of calcium exchanged from intracellular compartments and across the plasma membrane, a process termed calcium oscillations. Under differing conditions, the cytosolic free calcium can range from 100nM to 1μM, and return to equilibrium may occur in seconds, minutes, or hours depending on the nature of the stimulus and the requirements of the functional response. The plasma membrane of most cells is inhabited by a variety of channels for the influx of calcium from the extracellular space (Figure 1). Among these are store-operated calcium channels (SOCE) that activate influx in response to depletion of intracellular stores. Proteins known to be associated with this pathway include stromal interaction molecules (STIMs) that monitor calcium content of endoplasmic reticulum (ER) stores. Depletion of intracellular stores is sensed by STIMs that then translocate to the plasma membrane and interact with Orai, the pore-forming unit of the channel, and TRPC (transient receptor potential C) to stimulate calcium influx. Additional influx is regulated by second messenger–operated channels (SMOC) responsive to diacylglycerol (DAG), receptor-operated channels (ROC) responsive to hormones, and voltage-gated calcium channels (VGCC). Calcium influx is also downstream from receptor tyrosine kinases including EGFR. Adenosine triphosphate (ATP)-dependent calcium pumps reside on the plasma membrane and the membranes of intracellular storage sites such as ER, golgi, and mitochondria. These serve to pump out excess cytosolic calcium through the plasma membrane (plasma membrane Ca2+ ATPase (PMCA), Na+/Ca2+ exchanger (NCX)) or into storage sites sarco (endo)plasmic recticulum Ca2+ ATPase (SERCA) where calcium remains bound to high-capacity calcium storage proteins such as calreticulin of the ER. Of particular importance in calcium signaling are G-protein–coupled receptors, including the calcium-sensing receptor (CaR) on the plasma membrane, that activate membrane-bound phospholipase C (PLC) to generate inositol phosphates, particularly IP3, that stimulate receptors on intracellular organelles to release calcium stores. This elevation of intracellular free calcium is translated into functional responses through calmodulin and other downstream effectors. What has become apparent in the past three decades is that all of these components of calcium signaling are major regulators of keratinocyte biology. For almost 25 years, skin biologists have known that the avascular intact epidermis maintains a calcium gradient that is lower in the basal compartment and enriched in granular cells before a steep drop off in the stratum corneum (Elias et al., 2002Elias P. Ahn S. Brown B. et al.Origin of the epidermal calcium gradient: regulation by barrier status and role of active vs passive mechanisms.J Invest Dermatol. 2002; 119: 1269-1274Crossref PubMed Scopus (119) Google Scholar. Disturbance of this gradient by barrier dysfunction or other means prevents normal keratinocyte differentiation and accelerates lamellar body secretion. Although several methods available to early investigators using fixed tissues confirmed the existence of the gradient, newer techniques in living tissues suggest that the variation in the strata arise from differences in intracellular calcium stores and variations exist within populations in the basal cell compartment (Celli et al., 2010Celli A. Sanchez S. Behne M. et al.The epidermal Ca(2+) gradient: measurement using the phasor representation of fluorescent lifetime imaging.Biophys J. 2010; 98: 911-921Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar; Behne et al., 2011Behne M.J. Sanchez S. Barry N.P. et al.Major translocation of calcium upon epidermal barrier insult: imaging and quantification via FLIM/Fourier vector analysis.Arch Dermatol Res. 2011; 303: 103-115Crossref PubMed Scopus (20) Google Scholar. This is not surprising as it is well documented that graded levels of extracellular calcium elicit a graded differentiation response in keratinocytes (Yuspa et al., 1989Yuspa S.H. Kilkenny A.E. Steinert P.M. et al.Expression of murine epidermal differentiation markers is tightly regulated by restricted extracellular calcium concentrations in vitro.J Cell Biol. 1989; 109: 1207-1217Crossref PubMed Scopus (513) Google Scholar, buffering of intracellular calcium prevents terminal differentiation of keratinocytes (Li et al., 1995aLi L. Tucker R.W. Hennings H. et al.Chelation of intracellular Ca 2+ inhibits murine keratinocyte differentiation in vitro.JCell Physiol. 1995; 163: 105-114Crossref PubMed Scopus (84) Google Scholar, and the expression of early and late markers of differentiation are regulated by different intracellular calcium compartments (Li et al., 1995bLi L. Tucker R.W. Hennings H. et al.Inhibitors of the intracellular Ca 2+ -ATPase in cultured mouse keratinocytes reveal components of terminal differentiation that are regulated by distinct intracellular Ca 2+ compartments.Cell Growth Differ. 1995; 6: 1171-1184PubMed Google Scholar. How could these compartmental changes be physiologically regulated? Elevation of extracellular calcium activates several second-messenger systems. In particular, elevated calcium activates PLC-γ1 and PLC-δ1 to increase inositol lipids and catalyze the release of calcium from intracellular stores, acutely increasing cytosolic calcium (Jaken and Yuspa, 1988Jaken S. Yuspa S.H. Early signals for keratinocyte differentiation: role of Ca 2+ -mediated inositol lipid metabolism in normal and neoplastic epidermal cells.Carcinogenesis. 1988; 9: 1033-1038Crossref PubMed Scopus (112) Google Scholar; Lee and Yuspa, 1991Lee E. Yuspa S.H. Changes in inositol phosphate metabolism are associated with terminal differentiation and neoplasia in mouse keratinocytes.Carcinogenesis. 1991; 12: 1651-1658Crossref PubMed Scopus (60) Google Scholar; Punnonen et al., 1993Punnonen K. Denning M. Lee E. et al.Keratinocyte differentiation is associated with changes in the expression and regulation of phospholipase C isoenzymes.J Invest Dermatol. 1993; 101: 719-726Abstract Full Text PDF PubMed Google Scholar. What follows is not completely understood but involves CaR, SOCE, TRPC, and other plasma membrane cation channels (Mauro et al., 1997Mauro T. Dixon D.B. Komuves L. et al.Keratinocyte K+ channels mediate Ca2+-induced differentiation.J Invest Dermatol. 1997; 108: 864-870Crossref PubMed Scopus (52) Google Scholar; Denda et al., 2006Denda M. Fujiwara S. Hibino T. Expression of voltage-gated calcium channel subunit alpha1C in epidermal keratinocytes and effects of agonist and antagonists of the channel on skin barrier homeostasis.Exp Dermatol. 2006; 15: 455-460Crossref PubMed Scopus (40) Google Scholar to sustain the rise in intracellular calcium and restore calcium levels in storage sites. Interference with CaR expression blocks both differentiation and adherens junction formation in human keratinocytes, and keratinocyte differentiation is defective in CaR-null mice (Tu et al., 2004Tu C.L. Oda Y. Komuves L. et al.The role of the calcium-sensing receptor in epidermal differentiation.Cell Calcium. 2004; 35: 265-273Crossref PubMed Scopus (102) Google Scholar, Tu et al., 2008Tu C.L. Chang W. Xie Z. et al.Inactivation of the calcium sensing receptor inhibits E-cadherin-mediated cell-cell adhesion and calcium-induced differentiation in human epidermal keratinocytes.J Biol Chem. 2008; 283: 3519-3528Crossref PubMed Scopus (110) Google Scholar. The observation that keratinocytes from all species tested proliferate actively in calcium below 0.1mM whereas most other cells undergo growth arrest or die suggests that an evolutionary function is conserved. Barrier formation and specialized cell adhesions are obvious unique functions for keratinocytes, and calcium is essential for crosslinking cornified envelopes, desmosome assembly, and creation of adherens junctions. Furthermore, depletion of ER calcium by barrier disruption or chemical stress results in rapid secretion of lamellar bodies in the stratum granulosum to repair the damage (Celli et al., 2010Celli A. Sanchez S. Behne M. et al.The epidermal Ca(2+) gradient: measurement using the phasor representation of fluorescent lifetime imaging.Biophys J. 2010; 98: 911-921Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar. The importance of assembling these structures sequentially and repairing the barrier is clear and could account for compartmental regulation of calcium signaling. Consistent with an evolutionary view is the remarkable clustering of genes essential for terminal differentiation together with calcium-binding S100 proteins on human chromosome 1q21. Beyond the barrier what are the downstream effectors of calcium signaling that carry out the other messages? Activation of calcium-dependent protein kinase Cα (PKCα) is one effector linked closely to transcriptional regulation of spinous and granular cell proteins through activator protein-1 activity (Denning et al., 1995Denning M.F. Dlugosz A.A. Williams E.K. et al.Specific protein kinase C isozymes mediate the induction of keratinocyte differentiation markers by calcium.Cell Growth Differ. 1995; 6: 149-157PubMed Google Scholar; Rutberg et al., 1997Rutberg S.E. Saez E. Lo S. et al.Opposing activities of c-Fos and Fra-2 on AP-1 regulated transcriptional activity in mouse keratinocytes induced to differentiate by calcium and phorbol esters.Oncogene. 1997; 15: 1337-1346Crossref PubMed Scopus (66) Google Scholar. Furthermore, genes expressed during keratinocyte differentiation contain calcium-dependent regulatory elements (Rothnagel et al., 1993Rothnagel J.A. Greenhalgh D.A. Gagne T.A. et al.Identification of a calcium-inducible, epidermal-specific regulatory element in the 3′-flanking region of the human keratin 1 gene.J Invest Dermatol. 1993; 101: 506-513Abstract Full Text PDF PubMed Google Scholar. The calcium–calmodulin response pathway modifies a number of pathways regulating cell behavior (Wayman et al., 2011Wayman G.A. Tokumitsu H. Davare M.A. et al.Analysis of CaM-kinase signaling in cells.Cell Calcium. 2011; 50: 1-8Crossref PubMed Scopus (94) Google Scholar. Among the proteins activated through calcium–calmodulin is the serine phosphatase calcineurin. In keratinocytes and other cells, calcineurin dephosphorylates NFAT (nuclear factor of activated T cells), allowing NFAT to enter the nucleus and regulate keratinocyte proliferation and stem cell quiescence through p21 in conjunction with Notch signaling (Dotto, 2011Dotto G.P. Calcineurin signaling as a negative determinant of keratinocyte cancer stem cell potential and carcinogenesis.Cancer Res. 2011; 71: 2029-2033Crossref PubMed Scopus (23) Google Scholar. Recent studies have implicated TRPV1, TRPV3, and TRPA1 calcium channels that are highly expressed in keratinocytes to also contribute to epidermal differentiation and inflammation in addition to sensory responses (Toth et al., 2009Toth B.I. Geczy T. Griger Z. et al.Transient receptor potential vanilloid-1 signaling as a regulator of human sebocyte biology.J Invest Dermatol. 2009; 129: 329-339Crossref PubMed Scopus (65) Google Scholar; Cheng et al., 2010Cheng X. Jin J. Hu L. et al.TRP channel regulates EGFR signaling in hair morphogenesis and skin barrier formation.Cell. 2010; 141: 331-343Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar. A compelling role for calcium signaling in keratinocyte homeostasis comes with the discovery of inactivating mutations in SERCA2 (ATP2A2), the ER calcium ATPase in Darier's disease, and mutations in ATP2C1 (SPCA1), the Golgi calcium ATPase in Hailey–Hailey disease (Sudbrak et al., 2000Sudbrak R. Brown J. Dobson-Stone C. et al.Hailey-Hailey disease is caused by mutations in ATP2C1 encoding a novel Ca(2+) pump.Hum Mol Genet. 2000; 9: 1131-1140Crossref PubMed Scopus (260) Google Scholar; Savignac et al., 2011Savignac M. Edir A. Simon M. et al.Darier disease: a disease model of impaired calcium homeostasis in the skin.Biochim Biophys Acta. 2011; 1813: 1111-1117Crossref PubMed Scopus (69) Google Scholar. In both cases, the mutation results in calcium depletion in the organelles and disturbances of skin barrier and keratinocyte adhesion and differentiation. It is likely that future studies will reveal additional cutaneous pathology as a consequence of altered calcium homeostasis. The discovery in the early 1980s that PKC was the primary receptor for tumor-promoting phorbol esters used in mouse skin chemical carcinogenesis studies captured the imagination of skin carcinogenesis researchers (Nishizuka, 1984Nishizuka Y. The role of protein kinase C in cell surface signal transduction and tumour promotion.Nature. 1984; 308: 693-698Crossref PubMed Scopus (5757) Google Scholar. This revelation identified the phorbol ester receptor as a central molecule in PLC-coupled growth factor receptor signaling and promised to significantly simplify and focus mechanistic studies on the promotion stage of mouse skin 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoyl-phorbol-13-acetate (TPA) chemical carcinogenesis. From this early perspective, phorbol esters were simply substituting for chronic mitogenic growth factor stimulation, and thus directly driving proliferation of keratinocytes. Almost three decades of intensive research on PLC/PKC signaling in cutaneous biology have unearthed multiple criss-crossing pathways involving lipid-derived messengers, phosphorylation, and protein interactions, and have expanded from skin carcinogenesis to epidermal differentiation, wound healing, and inflammation (Figure 2). The basic architecture of PLC/PKC signaling consists of PLC activation via coupling to either G-protein–coupled receptors or receptor tyrosine kinases, resulting in the hydrolysis of phosphatidylinositol 4,5-bisphosphate (Suh et al., 2008Suh P.G. Park J.I. Manzoli L. et al.Multiple roles of phosphoinositide-specific phospholipase C isozymes.BMB Rep. 2008; 41: 415-434Crossref PubMed Google Scholar. The two second messengers produced by this cleavage are DAG, which binds C1 domains and activates PKC, and IP3, which binds to the IP3 receptor and triggers the release of Ca2+ from intracellular stores. Phorbol esters, such as TPA, are potent long-lived DAG mimetics that have strong agonist activity, but at high dose trigger proteasome-dependent and -independent degradation of PKC resulting in a type of receptor desensitization (Leontieva and Black, 2004Leontieva O.V. Black J.D. Identification of two distinct pathways of protein kinase Calpha down-regulation in intestinal epithelial cells.J Biol Chem. 2004; 279: 5788-5801Crossref PubMed Scopus (92) Google Scholar. The discovery and characterization of multiple genes encoding both PLC and PKC have been major driving forces in the mapping of their interconnected signaling mechanisms. The PLC gene family has 13 members (β1, β2, β3, β4, γ1, γ2, δ1, δ3, δ4, ε, η1, η2, ζ) and is more diverse than the nine-member PKC family (α, β, γ, δ, ε, η, θ, ζ, ι; Parker and Murray-Rust, 2004Parker P.J. Murray-Rust J. PKC at a glance.J Cell Sci. 2004; 117: 131-132Crossref PubMed Scopus (311) Google Scholar; Suh et al., 2008Suh P.G. Park J.I. Manzoli L. et al.Multiple roles of phosphoinositide-specific phospholipase C isozymes.BMB Rep. 2008; 41: 415-434Crossref PubMed Google Scholar. Each gene family has subfamilies defined by functional domain composition. These domains dictate the activation mechanisms and specificity, as well as the effector functions. For example, the classical, Ca2+-responsive PKC isoforms (α, β, γ) are responsive to both DAG/TPA by virtue of their C1 domains, and to Ca2+ by virtue of their C2 domains. Other PKC subfamilies lack canonical C2 domains (δ, ε, η, θ) and C1 domains (ζ, ι) influencing the cofactor requirements and kinetics of activation (Lenz et al., 2002Lenz J.C. Reusch H.P. Albrecht N. et al.Ca2+-controlled competitive diacylglycerol binding of protein kinase C isoenzymes in living cells.J Cell Biol. 2002; 159: 291-302Crossref PubMed Scopus (80) Google Scholar. Effector specificity is determined primarily by selective substrate access dictated by scaffolding proteins that bind to unique targeting sequences in each PKC isoform (Kheifets and Mochly-Rosen, 2007Kheifets V. Mochly-Rosen D. Insight into intra- and inter-molecular interactions of PKC: design of specific modulators of kinase function.Pharmacol Res. 2007; 55: 467-476Crossref PubMed Scopus (85) Google Scholar. Thus, despite PKC isoforms having remarkably similar kinase substrate specificity, they mediate very different functions in the cell because of unique subcellular localization, cellular substrate phosphorylation, and activation mechanisms. The PLC/PKC signaling modules relevant to normal skin biology involve primarily terminal differentiation. PKCδ and PKCη are linked to keratinocyte squamous differentiation (Denning, 2004Denning M.F. Epidermal keratinocytes: regulation of multiple cell phenotypes by multiple protein kinase C isoforms.Int J Biochem Cell Biol. 2004; 36: 1141-1146Crossref PubMed Scopus (74) Google Scholar; Adhikary et al., 2010Adhikary G. Chew Y.C. Reece E.A. et al.PKC-delta and -eta, MEKK-1, MEK-6, MEK-3, and p38-delta are essential mediators of the response of normal human epidermal keratinocytes to differentiating agents.J Invest Dermatol. 2010; 130: 2017-2030Crossref PubMed Scopus (50) Google Scholar. For calcium-induced keratinocyte differentiation, the G-protein–coupled CaR and PLC-γ1 are involved, and mechanisms beyond raising intracellular calcium may contribute to the pro-differentiation response and PKC signaling (Tu et al., 2004Tu C.L. Oda Y. Komuves L. et al.The role of the calcium-sensing receptor in epidermal differentiation.Cell Calcium. 2004; 35: 265-273Crossref PubMed Scopus (102) Google Scholar; Xie and Bikle, 2007Xie Z. Bikle D.D. The recruitment of phosphatidylinositol 3-kinase to the E-cadherin-catenin complex at the plasma membrane is required for calcium-induced phospholipase C-gamma1 activation and human keratinocyte differentiation.J Biol Chem. 2007; 282: 8695-8703Crossref PubMed Scopus (91) Google Scholar. PKC is also linked to differentiation functions of the pigment-producing melanocyte (Park et al., 1999Park H.Y. Perez J.M. Laursen R. et al.Protein kinase C-beta activates tyrosinase by phosphorylating serine residues in its cytoplasmic domain.J Biol Chem. 1999; 274: 16470-16478Crossref PubMed Scopus (120) Google Scholar, Park et al., 2004Park H.Y. Lee J. Gonzalez S. et al.Topical application of a protein kinase C inhibitor reduces skin and hair pigmentation.J Invest Dermatol. 2004; 122: 159-166Crossref PubMed Scopus (53) Google Scholar. PKCβ is able to phosphorylate and activate tyrosinase, the rate-limiting enzyme in melanin biosynthesis, and is thus implicated in melanogenesis. The heterogeneic PKC signaling landscape has required cancer biologists to integrate PKC signaling into the larger cellular and tissue framework to understand how phorbol esters promote tumor development. In mouse skin chemical carcinogenesis, initiating H-Ras mutations result in increased phosphatidylinositol hydrolysis, thus elevating DAG levels and activating PKCα (Lee and Yuspa, 1991Lee E. Yuspa S.H. Changes in inositol phosphate metabolism are associated with terminal differentiation and neoplasia in mouse keratinocytes.Carcinogenesis. 1991; 12: 1651-1658Crossref PubMed Scopus (60) Google Scholar; Denning et al., 1995Denning M.F. Dlugosz A.A. Williams E.K. et al.Specific protein kinase C isozymes mediate the induction of keratinocyte differentiation markers by calcium.Cell Growth Differ. 1995; 6: 149-157PubMed Google Scholar. H-Ras activation also elevates Src family kinase signaling, resulting in inactivation of the pro-apoptotic PKCδ through tyrosine phosphorylation and/or transcriptional silencing (Denning et al., 1993Denning M.F. Dlugosz A.A. Howett M.K. et al.Expression of an oncogenic ras Ha gene in murine keratinoctyes induces tyrosine phosphorylation and reduced activity of protein kinase C delta.J Biol Chem. 1993; 268: 26079-26081Abstract Full Text PDF PubMed Google Scholar; Geiges et al., 1995Geiges D. Marks F. Gschwendt M. Loss of protein kinase C delta from human HaCaT keratinocytes upon ras transfection is mediated by TGF alpha.Exp Cell Res. 1995; 219: 299-303Crossref PubMed Scopus (40) Google Scholar; D’Costa et al., 2006D’Costa A.M. Robinson J.K. Maududi T. et al.The proapoptotic tumor suppressor protein kinase C-delta is lost in human squamous cell carcinomas.Oncogene. 2006; 25: 378-386PubMed Google Scholar. Chronic TPA treatment results in selective survival and proliferation of H-Ras mutant keratinocytes, but this occurs in the context of general epidermal hyperplasia and cytokine release by keratinocytes in response to TPA. PKCα, PKCε, and NF-κB have been implicated in this cytokine and inflammatory response, but precisely how the combined effects of H-Ras activation and chronic PKC activation result in squamous skin cancers is still unclear (Cataisson et al., 2005Cataisson C. Pearson A.J. Torgerson S. et al.Protein kinase C alpha-mediated chemotaxis of neutrophils requires NF-kappa B activity but is independent of TNF alpha signaling in mouse skin in vivo.J Immunol. 2005; 174: 1686-1692Crossref PubMed Scopus (60) Google Scholar; Wheeler et al., 2005Wheeler D.L. Reddig P.J. Ness K.J. et al.Overexpression of protein kinase C-{epsilon} in the mouse epidermis leads to a spontaneous myeloproliferative-like disease.Am J Pathol. 2005; 166: 117-126Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar. A similar scenario exists for UV skin carcinogenesis as UV elevates DAG levels, pro-apoptotic PKCδ expression is repressed, and chronic activation of PKCε promotes regenerative hyperplasia (Punnonen and Yuspa, 1992Punnonen K. Yuspa S.H. Ultraviolet light irradiation increases cellular diacylglycerol and induces translocation of diacylglycerol kinase in murine keratinocytes.J Invest Dermatol. 1992; 99: 221-226Abstract Full Text PDF PubMed Scopus (44) Google Scholar; Jansen et al., 2001Jansen A.P. Verwiebe E.G. Dreckschmidt N.E. et al.Protein kinase C-epsilon transgenic mice: a unique model for metastatic squamous cell carcinoma.Cancer Res. 2001; 61: 808-812PubMed Google Scholar; Aziz et al., 2007Aziz M.H. Manoharan H.T. Verma A.K. Protein kinase C epsilon, which sensitizes skin to sun's UV radiation-induced cutaneous damage and development of squamous cell carcinomas, associates with Stat3.Cancer Res. 2007; 67: 1385-1394Crossref PubMed Scopus (64) Google Scholar. One reasonable model for the role of PKC isoforms in skin carcinogenesis is selective activation of PKCα driving inflammation, whereas PKCε drives cell proliferation. In association, inactivation/repression of pro-apoptotic PKCδ promotes cell survival. This model is supported by studies in transgenic mice in which PKCε transgenic mice are highly susceptible to both chemical and UV skin carcinogenesis, whereas PKCδ mice are resistant to skin carcinogenesis (Reddig et al., 1999Reddig P.J. Dreckschmidt N.E. Ahrens H. et al.Transgenic mice overexpressing protein kinase Cdelta in the epidermis are resistant to skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate.Cancer Res. 1999; 59: 5710-5718PubMed Google Scholar, Reddig et al., 2000Reddig P.J. Dreckschmidt N.E. Zou J. et al.Transgenic mice overexpressing protein kinase C epsilon in their epidermis exhibit reduced papilloma burden but enhanced carcinoma formation after tumor promotion.Cancer Res. 2000; 60: 595-602PubMed Google Scholar; Jansen et al., 2001Jansen A.P. Verwiebe E.G. Dreckschmidt N.E. et al.Protein kinase C-epsilon transgenic mice: a unique model for metastatic squamous cell carcinoma.Cancer Res. 2001; 61: 808-812PubMed Google Scholar. Several of the fundamental signaling molecules related to PLC/PKC signaling function very differently in epidermal keratinocytes compared with most other cell types. Central among these is calcium, which is abbreviated as “C” in PKC despite most PKC isoforms lacking a canonical C2 domain and being calcium independent. As discussed previously, most cells bathed in serum in vivo or grown in tissue culture proliferate normally in >1mM calcium. In contrast, epidermal keratinocytes proliferate well in <0.1mM calcium and are induced to undergo squamous differentiation by >1mM Ca2+ in association with PLC/PKC activation (Hennings et al., 1980Hennings H. Michael D. Cheng C. et al.Calcium regulation of growth and differentiation of mouse epidermal cells in culture.Cell. 1980; 19: 245-254Abstract Full Text PDF PubMed Scopus (1502) Google Scholar; Denning et al., 1995Denning M.F. Dlugosz A.A. Williams E.K. et al.Specific protein kinase C isozymes mediate the induction of keratinocyte differentiation markers by calcium.Cell Growth Differ. 1995; 6: 149-157PubMed Google Scholar. Keratinocytes also express PKCη, a PKC isoform unique to squamous differentiation tissues (Kashiwagi et al., 2002Kashiwagi M. Ohba M. Chida K. et al.Protein kinase C eta (PKC eta): its involvement in keratinocyte differentiation.J Biochem. 2002; 132: 853-857Crossref PubMed Scopus (53) Google Scholar. The function of the PKC effector NF-κB in keratinocytes is also unusual. NF-κB is pro-survival and thus promotes cancer development in most cell types; however, the NF-κB upstream activating kinase IKKα promotes keratinocyte differentiation, and blockade of NF-κB activation with a dominant/negative IκB is a potent oncogene in human keratinocytes (Hu et al., 2001Hu Y. Baud V. Oga T. et al.IKKalpha controls formation of the epidermis independently of NF-kappaB.Nature. 2001; 410: 710-714Crossref PubMed Scopus (301) Google Scholar; Dajee et al., 2003Dajee M. Lazarov M. Zhang J.Y. et al.NF-kappaB blockade and oncogenic Ras trigger invasive human epidermal neoplasia.Nature. 2003; 421: 639-643Crossref PubMed Scopus (483) Google Scholar. The signaling responsible for these unusual keratinocyte responses is still enigmatic, but is an area of active investigation. Despite the complexity of PLC/PKC signaling and lack of isoform-selective small-molecule activators/inhibitors, the diverse and significant effects of PLC/PKC modulation on skin biology have attracted much interest from drug developers. Ingenol-3-angelate (ingenol mebutate, PEP005), which a" @default.
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• W2020671917 date "2012-03-01" @default.
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• W2020671917 title "The Black Box Illuminated: Signals and Signaling" @default.
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