Nevogenesis pp 117-126 | Cite as

Nevus Senescence: An Update

  • Andrew L. Ross
  • Margaret I. Sanchez
  • James M. GrichnikEmail author


Nevi and melanomas share the many of the same growth-promoting mutations. However, benign nevi eventually undergo growth arrest and stabilize while melanomas grow relentlessly. The difference in their long-term growth potential can in part be attributed to activation of cellular senescence pathways. The primary mediator of senescence in nevi appears to be p16. Redundant, secondary senescence systems are also present and include the p14-p53-p21 pathway, the IGFBP7 pathway, the FBXO31 pathway, and the PI3K-mediated stress-induced endoplasmic reticulum unfolded protein response. It is evident that these senescence pathways result in an irreversible arrest in most instances; however, they can clearly be overcome in melanoma. Circumvention of these pathways is most frequently associated with gene deletion or transcriptional repression. Reactivation of senescence mechanisms could serve to inhibit melanoma tumor progression.


Unfold Protein Response Senescent Cell Primary Mediator BRAFV600E Mutation Molecular Mediator 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Conflict of Interest

DigitalDerm, Inc – major shareholder. Spectral Image, Inc – past grants and consulting. MELA Sciences – past grants and consulting. Genentech – ­consultant. Archives of Dermatology, skINsight – section editor.


  1. 1.
    Ross AL, Sanchez MI, Grichnik JM. Nevus senescence. ISRN Dermatol. 2011;2011:642157.PubMedGoogle Scholar
  2. 2.
    Zeff RA, Freitag A, Grin CM, Grant-Kels JM. The immune response in halo nevi. J Am Acad Dermatol. 1997;37(4):620–4.PubMedCrossRefGoogle Scholar
  3. 3.
    Kageshita T, Inoue Y, Ono T. Spontaneous regression of congenital melanocytic nevi without evidence of the halo phenomenon. Dermatology. 2003;207(2):193–5.PubMedCrossRefGoogle Scholar
  4. 4.
    Lee HJ, Ha SJ, Lee SJ, Kim JW. Melanocytic nevus with pregnancy-related changes in size accompanied by apoptosis of nevus cells: a case report. J Am Acad Dermatol. 2000;42(5 Pt 2):936–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Banky JP, Kelly JW, English DR, Yeatman JM, Dowling JP. Incidence of new and changed nevi and melanomas detected using baseline images and dermoscopy in patients at high risk for melanoma. Arch Dermatol. 2005;141(8):998–1006.PubMedCrossRefGoogle Scholar
  6. 6.
    Medrano EE, Yang F, Boissy R, et al. Terminal differentiation and senescence in the human melanocyte: repression of tyrosine-phosphorylation of the extracellular signal-regulated kinase 2 selectively defines the two phenotypes. Mol Biol Cell. 1994;5(4):497–509.PubMedGoogle Scholar
  7. 7.
    Dimri GP, Lee X, Basile G, et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA. 1995;92(20):9363–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Haddad MM, Xu W, Schwahn DJ, Liao F, Medrano EE. Activation of a cAMP pathway and induction of melanogenesis correlate with association of p16(INK4) and p27(KIP1) to CDKs, loss of E2F-binding activity, and premature senescence of human melanocytes. Exp Cell Res. 1999;253(2):561–72.PubMedCrossRefGoogle Scholar
  9. 9.
    Shay JW, Wright WE. Senescence and immortalization: role of telomeres and telomerase. Carcinogenesis. 2005;26(5):867–74.PubMedCrossRefGoogle Scholar
  10. 10.
    Bandyopadhyay D, Curry JL, Lin Q, et al. Dynamic assembly of chromatin complexes during cellular senescence: implications for the growth arrest of human melanocytic nevi. Aging Cell. 2007;6(4):577–91.PubMedCrossRefGoogle Scholar
  11. 11.
    Dimri GP, Hara E, Campisi J. Regulation of two E2F-related genes in presenescent and senescent human fibroblasts. J Biol Chem. 1994;269(23):16180–6.PubMedGoogle Scholar
  12. 12.
    Dimri GP, Testori A, Acosta M, Campisi J. Replicative senescence, aging and growth-regulatory transcription factors. Biol Signals. 1996;5(3):154–62.PubMedCrossRefGoogle Scholar
  13. 13.
    Takahashi Y, Rayman JB, Dynlacht BD. Analysis of promoter binding by the E2F and pRB families in vivo: distinct E2F proteins mediate activation and repression. Genes Dev. 2000;14(7):804–16.PubMedGoogle Scholar
  14. 14.
    Narita M, Nunez S, Heard E, et al. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell. 2003;113(6):703–16.PubMedCrossRefGoogle Scholar
  15. 15.
    Dimauro T, David G. Chromatin modifications: the driving force of senescence and aging? Aging (Albany NY). 2009;1(2):182–90.Google Scholar
  16. 16.
    Blackburn EH, Greider CW, Henderson E, et al. Recognition and elongation of telomeres by telomerase. Genome. 1989;31(2):553–60.PubMedCrossRefGoogle Scholar
  17. 17.
    Harley CB. Telomere loss: mitotic clock or genetic time bomb? Mutat Res. 1991;256(2–6):271–82.PubMedGoogle Scholar
  18. 18.
    Bandyopadhyay D, Timchenko N, Suwa T, et al. The human melanocyte: a model system to study the complexity of cellular aging and transformation in non-fibroblastic cells. Exp Gerontol. 2001;36(8):1265–75.PubMedCrossRefGoogle Scholar
  19. 19.
    Glaessl A, Bosserhoff AK, Buettner R, et al. Increase in telomerase activity during progression of melanocytic cells from melanocytic naevi to malignant melanomas. Arch Dermatol Res. 1999;291(2–3):81–7.PubMedCrossRefGoogle Scholar
  20. 20.
    Bataille V, Kato BS, Falchi M, et al. Nevus size and number are associated with telomere length and represent potential markers of a decreased senescence in vivo. Cancer Epidemiol Biomarkers Prev. 2007;16(7):1499–502.PubMedCrossRefGoogle Scholar
  21. 21.
    Alarcon-Vargas D, Ronai Z. p53-Mdm2 – the affair that never ends. Carcinogenesis. 2002;23(4):541–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Wright WE, Shay JW. Historical claims and current interpretations of replicative aging. Nat Biotechnol. 2002;20(7):682–8.PubMedCrossRefGoogle Scholar
  23. 23.
    de Lange T. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev. 2005;19(18):2100–10.PubMedCrossRefGoogle Scholar
  24. 24.
    von Zglinicki T, Saretzki G, Ladhoff J, d’Adda di Fagagna F, Jackson SP. Human cell senescence as a DNA damage response. Mech Ageing Dev. 2005;126(1):111–7.CrossRefGoogle Scholar
  25. 25.
    Stein GH, Drullinger LF, Soulard A, Dulic V. Differential roles for cyclin-dependent kinase inhibitors p21 and p16 in the mechanisms of senescence and differentiation in human fibroblasts. Mol Cell Biol. 1999;19(3):2109–17.PubMedGoogle Scholar
  26. 26.
    Beausejour CM, Krtolica A, Galimi F, et al. Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J. 2003;22(16):4212–22.PubMedCrossRefGoogle Scholar
  27. 27.
    Jacobs JJ, de Lange T. Significant role for p16INK4a in p53-independent telomere-directed senescence. Curr Biol. 2004;14(24):2302–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Bond J, Jones C, Haughton M, et al. Direct evidence from siRNA-directed “knock down” that p16(INK4a) is required for human fibroblast senescence and for limiting ras-induced epithelial cell proliferation. Exp Cell Res. 2004;292(1):151–6.PubMedCrossRefGoogle Scholar
  29. 29.
    Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997;88(5):593–602.PubMedCrossRefGoogle Scholar
  30. 30.
    Kiyono T, Foster SA, Koop JI, et al. Both Rb/p16INK4a inactivation and telomerase activity are required to immortalize human epithelial cells. Nature. 1998;396(6706):84–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Serrano M, Lee H, Chin L, et al. Role of the INK4a locus in tumor suppression and cell mortality. Cell. 1996;85(1):27–37.PubMedCrossRefGoogle Scholar
  32. 32.
    Dimri GP, Itahana K, Acosta M, Campisi J. Regulation of a senescence checkpoint response by the E2F1 transcription factor and p14(ARF) tumor suppressor. Mol Cell Biol. 2000;20(1):273–85.PubMedCrossRefGoogle Scholar
  33. 33.
    Haferkamp S, Tran SL, Becker TM. The relative contributions of the p53 and pRb pathways in oncogene-induced melanocyte senescence. Aging (Albany NY). 2009;1(6):542–56.Google Scholar
  34. 34.
    Collado M, Serrano M. The power and the promise of oncogene-induced senescence markers. Nat Rev Cancer. 2006;6(6):472–6.PubMedCrossRefGoogle Scholar
  35. 35.
    Ramirez RD, Morales CP, Herbert BS, et al. Putative telomere-independent mechanisms of replicative aging reflect inadequate growth conditions. Genes Dev. 2001;15(4):398–403.PubMedCrossRefGoogle Scholar
  36. 36.
    Kim WY, Sharpless NE. The regulation of INK4/ARF in cancer and aging. Cell. 2006;127(2):265–75.PubMedCrossRefGoogle Scholar
  37. 37.
    Ross AL, Sanchez MI, Grichnik JM. Molecular nevogenesis. Dermatol Res Pract. 2011;2011:9.Google Scholar
  38. 38.
    Michaloglou C, Vredeveld LC, Soengas MS, et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature. 2005;436(7051):720–4.PubMedCrossRefGoogle Scholar
  39. 39.
    Venesio T, Chiorino G, Balsamo A, et al. In melanocytic lesions the fraction of BRAF V600E alleles is associated with sun exposure but unrelated to ERK phosphorylation. Mod Pathol. 2008;21(6):716–26.PubMedCrossRefGoogle Scholar
  40. 40.
    Dhomen N, Reis-Filho JS, da Rocha Dias S, et al. Oncogenic Braf induces melanocyte senescence and melanoma in mice. Cancer Cell. 2009;15(4):294–303.PubMedCrossRefGoogle Scholar
  41. 41.
    Wajapeyee N, Serra RW, Zhu X, Mahalingam M, Green MR. Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. Cell. 2008;132(3):363–74.PubMedCrossRefGoogle Scholar
  42. 42.
    Uribe P, Andrade L, Gonzalez S. Lack of association between BRAF mutation and MAPK ERK activation in melanocytic nevi. J Invest Dermatol. 2006;126(1):161–6.PubMedCrossRefGoogle Scholar
  43. 43.
    Di Micco R, Fumagalli M, Cicalese A, et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature. 2006;444(7119):638–42.PubMedCrossRefGoogle Scholar
  44. 44.
    Mallette FA, Gaumont-Leclerc MF, Ferbeyre G. The DNA damage signaling pathway is a critical mediator of oncogene-induced senescence. Genes Dev. 2007;21(1):43–8.PubMedCrossRefGoogle Scholar
  45. 45.
    Santra MK, Wajapeyee N, Green MR. F-box protein FBXO31 mediates cyclin D1 degradation to induce G1 arrest after DNA damage. Nature. 2009;459(7247):722–5.PubMedCrossRefGoogle Scholar
  46. 46.
    Denoyelle C, Abou-Rjaily G, Bezrookove V, et al. Anti-oncogenic role of the endoplasmic reticulum differentially activated by mutations in the MAPK pathway. Nat Cell Biol. 2006;8(10):1053–63.PubMedCrossRefGoogle Scholar
  47. 47.
    Yan J, Roy S, Apolloni A, Lane A, Hancock JF. Ras isoforms vary in their ability to activate Raf-1 and phosphoinositide 3-kinase. J Biol Chem. 1998;273(37):24052–6.PubMedCrossRefGoogle Scholar
  48. 48.
    Chin L, Pomerantz J, Polsky D, et al. Cooperative effects of INK4a and ras in melanoma susceptibility in vivo. Genes Dev. 1997;11(21):2822–34.PubMedCrossRefGoogle Scholar
  49. 49.
    Haferkamp S, Scurr LL, Becker TM, et al. Oncogene-induced senescence does not require the p16(INK4a) or p14ARF melanoma tumor suppressors. J Invest Dermatol. 2009;129(8):1983–91.PubMedCrossRefGoogle Scholar
  50. 50.
    Leikam C, Hufnagel A, Schartl M, Meierjohann S. Oncogene activation in melanocytes links reactive oxygen to multinucleated phenotype and senescence. Oncogene. 2008;27(56):7070–82.PubMedCrossRefGoogle Scholar
  51. 51.
    Finkel T. Intracellular redox regulation by the family of small GTPases. Antioxid Redox Signal. 2006;8(9–10):1857–63.PubMedCrossRefGoogle Scholar
  52. 52.
    Busuttil RA, Rubio M, Dolle ME, Campisi J, Vijg J. Mutant frequencies and spectra depend on growth state and passage number in cells cultured from transgenic lacZ-plasmid reporter mice. DNA Repair (Amst). 2006;5(1):52–60.CrossRefGoogle Scholar
  53. 53.
    Vijg J, Busuttil RA, Bahar R, Dolle ME. Aging and genome maintenance. Ann N Y Acad Sci. 2005;1055: 35–47.PubMedCrossRefGoogle Scholar
  54. 54.
    Gire V, Wynford-Thomas D. Reinitiation of DNA synthesis and cell division in senescent human fibroblasts by microinjection of anti-p53 antibodies. Mol Cell Biol. 1998;18(3):1611–21.PubMedGoogle Scholar
  55. 55.
    Sage J, Miller AL, Perez-Mancera PA, Wysocki JM, Jacks T. Acute mutation of retinoblastoma gene function is sufficient for cell cycle re-entry. Nature. 2003;424(6945):223–8.PubMedCrossRefGoogle Scholar
  56. 56.
    Saab R. Senescence and pre-malignancy: how do tumors progress? Semin Cancer Biol. 2011;21(6):385–91.PubMedCrossRefGoogle Scholar
  57. 57.
    Quelle DE, Zindy F, Ashmun RA, Sherr CJ. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell. 1995;83(6):993–1000.PubMedCrossRefGoogle Scholar
  58. 58.
    Rutter JL, Goldstein AM, Davila MR, Tucker MA, Struewing JP. CDKN2A point mutations D153spl(c.457 G  >  T) and IVS2  +  1 G  >  T result in aberrant splice products affecting both p16INK4a and p14ARF. Oncogene. 2003;22(28):4444–8.PubMedCrossRefGoogle Scholar
  59. 59.
    Florell SR, Meyer LJ, Boucher KM, et al. Increased melanocytic nevi and nevus density in a G-34T CDKN2A/p16 melanoma-prone pedigree. J Invest Dermatol. 2008;128(8):2122–5.PubMedGoogle Scholar
  60. 60.
    Florell SR, Meyer LJ, Boucher KM, et al. Longitudinal assessment of the nevus phenotype in a melanoma kindred. J Invest Dermatol. 2004;123(3):576–82.PubMedCrossRefGoogle Scholar
  61. 61.
    Florell SR, Meyer LJ, Boucher KM, et al. Nevus distribution in a Utah melanoma kindred with a temperature-sensitive CDKN2A mutation. J Invest Dermatol. 2005;125(6):1310–2.PubMedCrossRefGoogle Scholar
  62. 62.
    Karim RZ, Li W, Sanki A, et al. Reduced p16 and increased cyclin D1 and pRb expression are correlated with progression in cutaneous melanocytic tumors. Int J Surg Pathol. 2009;17(5):361–7.PubMedCrossRefGoogle Scholar
  63. 63.
    Straume O, Sviland L, Akslen LA. Loss of nuclear p16 protein expression correlates with increased tumor cell proliferation (Ki-67) and poor prognosis in patients with vertical growth phase melanoma. Clin Cancer Res. 2000;6(5):1845–53.PubMedGoogle Scholar
  64. 64.
    Goldstein AM, Chan M, Harland M, et al. High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL. Cancer Res. 2006;66(20):9818–28.PubMedCrossRefGoogle Scholar
  65. 65.
    Binni F, Antigoni I, De Simone P, et al. Novel and recurrent p14 mutations in Italian familial melanoma. Clin Genet. 2010;77(6):581–6.PubMedCrossRefGoogle Scholar
  66. 66.
    Garcia-Casado Z, Nagore E, Fernandez-Serra A, Botella-Estrada R, Lopez-Guerrero JA. A germline mutation of p14/ARF in a melanoma kindred. Melanoma Res. 2009;19(5):335–7.PubMedCrossRefGoogle Scholar
  67. 67.
    Vidal MJ, Loganzo Jr F, de Oliveira AR, Hayward NK, Albino AP. Mutations and defective expression of the WAF1 p21 tumour-suppressor gene in malignant melanomas. Melanoma Res. 1995;5(4):243–50.PubMedCrossRefGoogle Scholar
  68. 68.
    Sparrow LE, Eldon MJ, English DR, Heenan PJ. p16 and p21WAF1 protein expression in melanocytic tumors by immunohistochemistry. Am J Dermatopathol. 1998;20(3):255–61.PubMedCrossRefGoogle Scholar
  69. 69.
    Papp T, Jafari M, Schiffmann D. Lack of p53 mutations and loss of heterozygosity in non-cultured human melanocytic lesions. J Cancer Res Clin Oncol. 1996;122(9):541–8.PubMedCrossRefGoogle Scholar
  70. 70.
    Zerp SF, van Elsas A, Peltenburg LT, Schrier PI. p53 mutations in human cutaneous melanoma correlate with sun exposure but are not always involved in melanomagenesis. Br J Cancer. 1999;79(5–6):921–6.PubMedCrossRefGoogle Scholar
  71. 71.
    Terzian T, Torchia EC, Dai D, et al. p53 prevents progression of nevi to melanoma predominantly through cell cycle regulation. Pigment Cell Melanoma Res. 2010;23(6):781–94.PubMedCrossRefGoogle Scholar
  72. 72.
    Bennett DC, Medrano EE. Molecular regulation of melanocyte senescence. Pigment Cell Res. 2002;15(4):242–50.PubMedCrossRefGoogle Scholar
  73. 73.
    Peeper DS. Oncogene-induced senescence and melanoma: where do we stand? Pigment Cell Melanoma Res. 2011;24(6):1107–11.PubMedCrossRefGoogle Scholar
  74. 74.
    Semple TU, Moore GE, Morgan RT, Woods LK, Quinn LA. Multiple cell lines from patients with malignant melanoma: morphology, karyology, and biochemical analysis. J Natl Cancer Inst. 1982;68(3):365–80.PubMedGoogle Scholar
  75. 75.
    Pope JH, Morrison L, Moss DJ, Parsons PG, Regius Mary S. Human malignant melanoma cell lines. Pathology. 1979;11(2):191–5.PubMedCrossRefGoogle Scholar
  76. 76.
    Soo JK, Mackenzie Ross AD, Kallenberg DM, et al. Malignancy without immortality? Cellular immortalization as a possible late event in melanoma progression. Pigment Cell Melanoma Res. 2011;24(3):490–503.PubMedCrossRefGoogle Scholar

Copyright information

© Springer- Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Andrew L. Ross
    • 1
  • Margaret I. Sanchez
    • 1
  • James M. Grichnik
    • 1
    • 2
    • 3
    Email author
  1. 1.Department of Dermatology and Cutaneous SurgeryUniversity of Miami Miller School of MedicineMiamiUSA
  2. 2.Melanoma Program, Department of Dermatology and Cutaneous SurgerySylvester Comprehensive Cancer CenterMiamiUSA
  3. 3.Interdisciplinary Stem Cell Institute, Miller School of MedicineUniversity of MiamiMiamiUSA

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