Regulation of Epidermal Growth

  • E. M. Saihan
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 87 / 1)


The epidermis is a classical example of a renewing tissue. There is constant shedding of horny cells, these being replaced by new cells. Continuous replacement is of major importance for the proper maintenance of the epidermis. Since skin is the largest organ in the body, this is one of the major cell renewal systems. Moreover, epidermal growth can be increased temporarily over a short period by local injury or over a longer term as in psoriasis. This control of epidermal proliferation and differentiation is a highly complex and integrated process, and it depends on a delicate balance between factors promoting proliferation and factors favouring differentiation. Various chemical regulators have been postulated, including epidermal growth factor, cyclic nucleotides, chalones, prostaglandins, histamines and calcium and calmodulin. In this chapter I shall briefly review these substances.


Epidermal Growth Factor Cholera Toxin Cyclic Nucleotide Mouse Epidermis Epidermal Growth Factor Level 
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  1. Adachi K, Yoshikawa K, Halprin K, Levine V (1975) Prostaglandins and cyclic AMP in epidermis. Br J Dermatol 92:381–388CrossRefPubMedGoogle Scholar
  2. Adachi K, Iizuka H, Halprin K, Levine V (1980) Epidermal cyclic AMP is not decreased in psoriatic lesions. J Invest Dermatol 74:74–76PubMedGoogle Scholar
  3. Angeletti PU, Salvi ML, Chesanow RL, Cohen S (1964) Azione dell epidermal growth factor — sulla sintesti di acidi nucleicic apriteine delFepithelio cutaneo. Experientia 20:1–6CrossRefGoogle Scholar
  4. Aoyagi T, Adachi K, Halprin K, Levine V (1980) The effects of epidermal growth factor on the cyclic nucleotide system in pig epidermis. J Invest Dermatol 74:238–241CrossRefPubMedGoogle Scholar
  5. Aoyagi T, Suya H, Kato N, Nemoto O, Kobayashi H, Miura Y (1985) Epidermal growth factor stimulates release of arachidinic acid in pig epidermis. J Invest Dermatol 84:168–171CrossRefPubMedGoogle Scholar
  6. Aso K, Orenberg EK, Farber EM (1975) Reduced epidermal cyclic AMP accumulation following prostaglandin stimulation:its possible role in the pathology of psoriasis. J Invest Dermatol 65:375–378CrossRefPubMedGoogle Scholar
  7. Bern JL, Greaves MW (1974) Prostaglandin Ex effects on epidermal cell growth “in vitro”. Arch Dermatol Forsch 251:35–41CrossRefGoogle Scholar
  8. Bentley-Phillips CB, Paulli-Jogensen H, Marks R (1977) The effects of prostaglandin E1 and F2a on epidermal growth. Arch Dermatol Res 257:233–237CrossRefPubMedGoogle Scholar
  9. Birbaum JE, Sapp TM, Moore JB (1976) Effects of reserpine, epidermal growth factor and cyclic nucleotide modulators in epidermal mitosis. J Invest Dermatol 66:313–318CrossRefGoogle Scholar
  10. Blosse PT, Fenton EL, Henningsson S, Kahlson G, Rogengren E (1974) Activities of de-carboxylase of histidine and ornithine in young male mice after injection of epidermal growth factor. Experientia 30:22–23CrossRefGoogle Scholar
  11. Bullough WS (1962) The control of mitotic activity in adult mammalian tissues. Biol Rev 37:307–342CrossRefPubMedGoogle Scholar
  12. Bullough WS, Lawrence EB (1964) Mitotic control by internal secretion:the role of chalone-adrenalin complex. Exp Cell Res 33:176–194CrossRefPubMedGoogle Scholar
  13. Byyny RL, Orth DN, Cohen S, Doyne ES (1974) Epidermal growth factor:effects on androgen and andrenergic agents. Endocrinology 95:776–782CrossRefPubMedGoogle Scholar
  14. Carpenter G, Cohen S (1979) Epidermal growth factor. Annu Rev Biochem 48:193–216CrossRefPubMedGoogle Scholar
  15. Chopra DP, Yu RJ, Flaxman BA (1972) Demonstration of a tissue-specific inhibitor of mitosis of human epidermal cells in vitro. J Invest Dermatol 59:207–210CrossRefPubMedGoogle Scholar
  16. Cohen S (1960) Purification of a nerve growth promoting protein from the mouse salivary gland and its neuro-cytotoxic antiserum. Proc Natl Acad Sci USA 46:302–311CrossRefPubMedGoogle Scholar
  17. Cohen S (1962) Isolation of a mouse submaxillary gland protein accelerating incisor eruption and eyelid opening in the new-born animal. J Biol Chem 237:1555–1562PubMedGoogle Scholar
  18. Cohen S, Carpenter G, Lembach KJ (1975) Interaction of epidermal growth factor with cultured fibroblasts. Adv Metab Disord 8:265–284PubMedGoogle Scholar
  19. Covelli I, Rossi R, Mozzi R, Frati L (1972) Synthesis of bioactive 131I-labelled epidermal growth factor and its distribution in rat tissues. Eur J Biochem 27:225–230CrossRefPubMedGoogle Scholar
  20. Dailey GE, Krana JW, Orth DN (1978) Homologans radioimmunoassay for human epidermal growth factor (urogastrone). J Clin Endocrinol Metab 46:929–936CrossRefPubMedGoogle Scholar
  21. Daniele S, Frati L, Fiore C, Santoni G (1979) The effect of the epidermal growth factor (EGF) on the corneal epithelium. Graefes Arch Clin Exp Opthalmol 210:159–165CrossRefGoogle Scholar
  22. Dedman JR, Brinkley BR, Means AR (1979) Regulation of microfilaments and microtubules by calcium and cyclic AMP. Adv Cyclic Nucleotide Res 11:131–174PubMedGoogle Scholar
  23. Delescluse C, Colburn NH, Duell EA, Voorhees JJ (1974) Cyclic AMP elevating agents inhibit proliferation of keratinizing guine pig epidermal cells. Differentiation 2:343–350CrossRefPubMedGoogle Scholar
  24. Dewey DL (1973) The melanocytic chalone. In:Forscher BK, Houck JC (eds) Chalones:concepts and current researches. Nat Cancer Inst Monogr 38:213–216Google Scholar
  25. Duell E (1980) Identification of a beta2-adrenergic receptor in mammalian epidermis. Biochem Pharmacol 29:97–101CrossRefPubMedGoogle Scholar
  26. Eaglstein WH, Weinstein GD (1975) Prostaglandin and DNA synthesis in human skin. Possible relationship to ultraviolet light effects. J Invest Dermatol 64:386–389CrossRefPubMedGoogle Scholar
  27. Elgjo K, Henning SH, Edgehill W (1971) Epidermal mitotic rate and DNA synthesis after infection of water extracts made from mouse skin treated with actinomycin D:two or more growth-regulating substances? Virchows Arch [B] 7:342–347Google Scholar
  28. Fairley JA, Marcelo CL, Hogan VA, Voorhees JJ (1985) Increased calmodulin levels in psoriasis and low Ca+ + regulated mouse epidermal keratinocyte cultures. J Invest Dermatol 84:195–198CrossRefPubMedGoogle Scholar
  29. Flaxman BA, Harper RA (1975) In vitro analysis of the control of keratinocyte proliferation in human epidermis by physiologic and pharmacologic agents. J Invest Dermatol 65:52–59CrossRefPubMedGoogle Scholar
  30. Frati C, Covelli I, Mozzi R, Frati L (1972a) Mechanism of action of epidermal growth factor:effect on thfc sulfhydryl and disulfide group content of mouse epidermis during keratinization. Cell Differ 1:239–244CrossRefGoogle Scholar
  31. Garte SJ, Belman S (1983) Prostaglandins fail to elevate cyclic AMP levels in mouse epidermis in vivo and in vitro. J Invest Dermatol 81:422–423CrossRefPubMedGoogle Scholar
  32. Gordon P, Carpenter J, Cohen S, Orci L (1978) Epidermal growth factor:morphological demonstration of binding internalization and lysosomal association in a human fibroblast. Proc Natl Acad Sci USA 75:5025–5029CrossRefGoogle Scholar
  33. Greaves MW (1980) Lack of effect of topically applied epidermal growth factor (EGF) on epidermal growth in man in vivo. Clin Exp Dermatol 5:101–103CrossRefPubMedGoogle Scholar
  34. Green H (1978) Cyclic AMP in relation to proliferation of the epidermal cell:a new view. Cell 15:801–811CrossRefPubMedGoogle Scholar
  35. Gregory H (1975) Isolation and structure of urogastrone and its relationship to epidermal growth factor. Nature 257:325–327CrossRefPubMedGoogle Scholar
  36. Gregory H, Bower JM, Willshire IR (1977) Urogastone and epidermal growth factor. In:Kastrup KW, Nielsen JH (eds) Growth factors. Pergamon, Elmsford, pp 75–84Google Scholar
  37. Haigler HT, Ash JF, Singer SJ, Cohen S (1978) Visualization by fluorescence of the binding and internalization of epidermal growth factor in human carcinoma cell A-431. Proc Natl Acad Sci USA 75:3317–3321CrossRefPubMedGoogle Scholar
  38. Haigler HT, McKanna JA, Cohen S (1979) Direct visualization of the binding and internalization of a ferritin conjugate of epidermal growth factor in a human carcinoma cell A-431. J Cell Biol 81:382–395CrossRefPubMedGoogle Scholar
  39. Harper RA (1976) Effect of prostaglandins on 3H-thymidine uptake into human epidermal cells in vitro. Prostaglandins 12:1019–1025CrossRefPubMedGoogle Scholar
  40. Harper RA, Flaxman A, Chopra D (1974a) Effect of pharmacological agents on human keratinocyte mitosis in vitro. 1. Inhibition by adenine nucleotides. Proc Soc Exp Biol Med 146:1032–1036Google Scholar
  41. Harper RA, Flaxman B, Chopra D (1974b) Mitotic response of normal and psoriatic keratinoeytes in vitro to compounds known to effect intracellular cyclic AMP. J Invest Dermatol 62:384–387CrossRefGoogle Scholar
  42. Hirata Y, Orth DN (1979a) Concentrations of epidermal growth factor, nerve growth factor, and submandibular gland renin in male and female mouse tissue and fluids. Endocrinology 105:1382–1387CrossRefGoogle Scholar
  43. Hirata Y, Orth DN (1979b) Epidermal growth factor (urogastrone) in human tissues. J Clin Endocrinol Metab 48:667–672CrossRefPubMedGoogle Scholar
  44. Hirata Y, Moore GM, Bertagna C, Orth DN (1980) Plasma concentration of immunon-reactive human epidermal growth factor (urogastrone) in man. J Clin Endocrinol Metab 50:440–444CrossRefPubMedGoogle Scholar
  45. Hollenberg MD, Cuatrecasas P (1973) Epidermal growth factor:receptors in human fibroblasts and modulation by cholera toxin. Proc Natl Acad Sci USA 70:2964–2968CrossRefPubMedGoogle Scholar
  46. Hopkins CR, Boothroyd B, Gregory H (1981) Early events following the binding of epidermal growth factor to surface receptors on ovarian granulosa cells. Eur J Cell Biol 24:259–265PubMedGoogle Scholar
  47. Iizuka H, Adachi K, Halprin K, Levine V (1976a) Histamine H2 receptor-adenylate cyclase system in pig skin (epidermis). Biochim Biophys Acta 437:150–157CrossRefGoogle Scholar
  48. Iizuka A, Adachi K, Halprin K, Levine V (1976b) Adenosine and adenine nucleotides stimulation of skin (epidermis) adenylate cyclase. Biochim Biophys Acta 444:685–693CrossRefGoogle Scholar
  49. Iizuka H, Adachi K, Aoyagi T, Halprin K, Levine V (1979) Cyclic GMP system in epidermis II histamine stimulates cyclic GMP formation. J Invest Dermatol 73:313–316CrossRefPubMedGoogle Scholar
  50. Iizuka H, Ischizawa H, Koizumi H, Aoyagi T, Miura Y (1982) Pig skin epidermal calmodulin:effect of calmodulin deficient phosphodiesterase. J Invest Dermatol 78:230–233CrossRefPubMedGoogle Scholar
  51. Iversen OH (1969) Chalones of the skin in homeostatis regulators. In:Wolstenholme GE, Knight J (eds) Ciba Foundation symposium on homeostatic regulators. Churchill, London, pp 29–53CrossRefGoogle Scholar
  52. Iversen OH (1976) The history of chalones in chalones. In:Houck JC (ed) North-Holland, pp 37–69Google Scholar
  53. Kischer CW (1967) Effects of specific prostaglandins on development of chick embryo skin and down feather organ in vitro. Dev Biol 16:203–215CrossRefPubMedGoogle Scholar
  54. Kragballe K, Desjarlais L, Voorhees JJ (1985) Leukotrienes B4, C4, and D4 stimulate DNA synthesis in cultured human epidermal keratinoeytes. Br J Dermatol 113:43–52CrossRefPubMedGoogle Scholar
  55. Liu S, Karasek M (1978) Isolation and growth of adult human epidermal keratinoeytes in cell culture. J Invest Dermatol 71:157–162CrossRefPubMedGoogle Scholar
  56. Lowe NJ, DeQuoy P (1978) Linoleic acid effects on epidermal DNA synthesis and cutaneous prostaglandin levels in essential fatty acid deficiency. J Invest Dermatol 70:200–203CrossRefPubMedGoogle Scholar
  57. Lowe NJ, Stoughton R (1977) Effects of topical prostaglandins E2 analogue on normal hairless mouse epidermal DNA synthesis. J Invest Dermatol 68:134–137 Marcelo C (1979) Differential effects of cyclic AMP and cyclic GMP on in vitro epidermal cell growth. Exp Cell Res 120:201–210Google Scholar
  58. Marcelo C, Duell EA (1979) Cyclic AMP stimulates and inhibits adult human epidermal cell growth. J Invest Dermatol 72:279CrossRefGoogle Scholar
  59. Marcelo CL, Tomich J (1983) Cyclic AMP, glucocorticoid and retinoid modulation of in vitro keratinocyte growth. J Invest Dermatol 81:64s–68sCrossRefPubMedGoogle Scholar
  60. Marcelo C, Duell E, Stawiski M, Anderson T, Voorhees J (1979) Cyclic nucleotide levels in psoriatic and normal keratomed epidermis. J Invest Dermatol 72:20–24CrossRefPubMedGoogle Scholar
  61. Marks F (1971) Direct evidence of two tissue-specific chalone-like factors regulating mitosis and DNA synthesis in mouse epidermis. Hoppe-Seylers Z Physiol Chem 353:1273–1274Google Scholar
  62. Marks F (1973) A tissue specific factor inhibiting DNA synthesis in mouse epidermis. Natl Cancer Inst Monogr 38:79–90 Marks F, Rebien W (1972a) Cyclic 3–5 AMP and theophylline inhibit epidermal mitosis in G2 phase. Naturwissenschaften 59:41–42CrossRefGoogle Scholar
  63. Marks F, Rebien W (1972b) The second messenger system of mouse epidermis. 1. Properties and beta adrenergic activation of adenylate cyclase in vitro. Biochim Biophys Acta 284:556–567Google Scholar
  64. Means AR, Dedman JR (1980) Calmodulin and intracellular calcium receptor. Nature 285:73–77CrossRefPubMedGoogle Scholar
  65. Mizumoto T, Hashimoto Y, Hirokawa M, Ohkuma N, Iizuka H, Ohkawara A (1985) Calmodulin activities are significantly increased in both uninvolved and involved epidermis in psoriasis. J Invest Dermatol 85:450–452CrossRefPubMedGoogle Scholar
  66. Mohr U, Hondius Boldingh W, Althoff J (1972) Identification of contaminating Clostridium spores as the oncholytic agent in some chalone preparations. Cancer Res 32:1117–1121PubMedGoogle Scholar
  67. Murray AW, Rogers A (1978) Calcium dependent protein modulator of cyclic nucleotide phosphodiasterases from mouse epidermis. Biochem J 176:727–732PubMedGoogle Scholar
  68. Nanney LB, McKanna J A, Stoscheck CM, Carpenter G, King LE (1984) Visualization of epidermal growth factor receptors in human epidermis. J Invest Dermatol 82:165–169CrossRefPubMedGoogle Scholar
  69. Okada N, Kitano Y, Ischihara K (1982) Effect of cholera toxin on proliferation of cultured human keratinoeytes in relation to intracellular cyclic AMP levels. J Invest Dermatol 79:42–47CrossRefPubMedGoogle Scholar
  70. Pentland A, Needleman P (1986) Modulation of keratinocyte proliferation in vitro by endogenous prostaglandin synthesis. J Clin Invest 77:246–251 Peterson LL, Wuepper KD (1983) Purification of human epidermal calmodulin. J Invest Dermatol 81:68–70Google Scholar
  71. Powell JA, Duell EA, Voorhees JJ (1971) Beta adrenergic stimulation of endogenous epidermal cyclic AMP formation. Arch Dermatol 104:359–365CrossRefPubMedGoogle Scholar
  72. Rasmussen H, Jensen P, Goodman DB (1976) Interactions between calcium and cyclic nucleotides in control of secretion. In:Case RM, Goebell H (eds) Stimulus-secretion coupling in the gastrointestinal tract. Baltimore University Park Press, Baltimore, pp 33–47Google Scholar
  73. Riley J, West GB (1953) The presence of histamine in tissue mast cells. J Physiol (Lond) 120:528–537Google Scholar
  74. Rothman S (1954) Physiology and biochemistry of skin. The University of Chicago Press, ChicagoGoogle Scholar
  75. Saihan EM, Albano J, Burton J (1980) The effect of steroid and dithranol therapy on cyclic nucleotides in psoriatic epidermis. Br J Dermatol 102:565–569CrossRefPubMedGoogle Scholar
  76. Salisbury JL, Condelis JS, Maihle NJ, Satir P (1981) Calmodulin localisation during capping and receptor-mediated endocytosis. Nature 294:163–166CrossRefPubMedGoogle Scholar
  77. Savage CR Jr, Cohen S (1973) Proliferation of corneal epithelium induced by epidermal growth factor. Exp Eye Res 15:361–366CrossRefPubMedGoogle Scholar
  78. Schlessinger J, Schechter Y, Willingham MC, Pastan I (1978a) Direct visualisation of binding aggegation and internalization of insulin and epidermal growth factor on living fibroblastic cells. Proc Natl Acad Sci USA 75:2659–2663CrossRefGoogle Scholar
  79. Schlessinger J, Schechter Y, Cuatrecasas P, Willingham MC, Pastan I (1978b) Quantitative determination of the lateral diffusion coefficients of the hormone-receptor complexes of insulin and epidermal growth factor on the plasma membrane of cultured fibroblasts. Proc Natl Acad Sci USA 75:5353–5357CrossRefGoogle Scholar
  80. Starkey RH, Orth DN (1977) Radioimmunoassay of human epidermal growth factor (urogastrone). J Clin Endocrinol Metab 45:1144–1153CrossRefPubMedGoogle Scholar
  81. Starkey RH, Cohen S, Orth DN (1975) Epidermal growth factor:identification of a new hormone in human urine. Science 189:800–802CrossRefPubMedGoogle Scholar
  82. Stastny M, Cohen S (1970) Epidermal growth factor IV. The induction of ornithine decarboxylase. Biochim Biophys Acta 204:578–589PubMedGoogle Scholar
  83. Steiner AL, Ferrendelli JA, Kipuis DM (1972) Radioimmunoassay for cyclic nucleotides III. Effect of ischaemia, changes during development and regional distribution of adenosine 3/,5’-monophosphate and guanosine 3’,5’-monophosphate in mouse brain. J Biol Chem 247:1121–1124PubMedGoogle Scholar
  84. Taylor JM, Cohen S, Michell WM (1970) Epidermal growth factor:high and low molecular weight forms. Proc Natl Acad Sci USA 67:164–171CrossRefPubMedGoogle Scholar
  85. Taylor JM, Mitchell WM, Cohen S (1972) Epidermal growth factor:physical and chemical properties. J Biol Chem 247:5928–5934PubMedGoogle Scholar
  86. Taylor JM, Mitchell WM, Cohen S (1974) Characterization of the high molecular weight form of epidermal growth factor. J Biol Chem 249:3198–3203PubMedGoogle Scholar
  87. Tucker WFG, MacNeil S, Bleehen SS, Tomlinson S (1984) Biological active calmodulin levels are elevated in both involved and uninvolved epidermis in psoriasis. J Invest Dermatol 82:298–299CrossRefPubMedGoogle Scholar
  88. Van de Kerkhof PCM, Van Erp PEJ (1983) Calmodulin levels are grossly elevated in psoriatic lesions. Br J Dermatol 108:217–218CrossRefPubMedGoogle Scholar
  89. Voorhees J J, Duell EA (1971) Psoriasis as a possible defect of the adenyl cyclase-cyclic AMP cascade. Arch Dermatol 104:352–358CrossRefPubMedGoogle Scholar
  90. Voorhees J J, Duell EA, Kelsey WH (1972) Dibutyryl cyclic AMP inhibition of epidermal cell division. Arch Dermatol 105:384–386CrossRefPubMedGoogle Scholar
  91. Voorhees J, Stawiski M, Duell E (1973) Increased cyclic GMP and decreased cyclic AMP levels in the hyperplastic, abnormally differentiated epidermis of psoriasis. Life Sci 13:639–653CrossRefGoogle Scholar
  92. Wightman PD, Dahlgren ME, Bonney RJ (1982) Protein kinase activation of phospholipase A2 in sonicates of mouse peritoneal macrophages. J Biol Chem 257:6650–6652PubMedGoogle Scholar
  93. Wilkinson DI, Orenberg EK (1979) Effect of prostaglandins on cyclic nucleotide levels in cultured keratinoeytes. Prostaglandins 17:419–429CrossRefPubMedGoogle Scholar
  94. Wolf D J, Siegel F (1972) Purification of a calcium-binding phosphoprotein from pig brain. J Biol Chem 247:4180–4185Google Scholar
  95. Yoshikawa K, Adachi K, Halprin KM, Levine V (1975a) Cyclic AMP in skin: effects of acute ischaemia. Br J Dermatol 92:249–254CrossRefGoogle Scholar
  96. Yoshikawa K, Adachi K, Halprin K, Levine V (1975b) The effect of catecholamine and related compounds on the adenyl cyclase system in epidermis. Br J Dermatol 93:29–36CrossRefGoogle Scholar
  97. Ziboh V, Hsia S (1972) Effects of prostaglandin E2 on rat skin:inhibition of sterol ester-biosynthesis and clearing of scaly lesions in essential fatty acid deficiency. J Lipid Res 13:458–467PubMedGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 1989

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  • E. M. Saihan

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