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c-MYC-Induced Sebaceous Gland Differentiation Is Controlled by an Androgen Receptor/p53 Axis

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Cottle, Denny L., Kretzschmar, Kai, Schweiger, Pawel J., Quist, Sven R., Gollnick, Harald P., Natsuga, Ken, Aoyagi, Satoru, Watt, Fiona M.·2013·Cell Reports
DOI 10.1016/j.celrep.2013.01.013PMC PMC3778892
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Abstract

Although the sebaceous gland (SG) plays an important role in skin function, the mechanisms regulating SG differentiation and carcinoma formation are poorly understood. We previously reported that c-MYC overexpression stimulates SG differentiation. We now demonstrate roles for the androgen receptor (AR) and p53. MYC-induced SG differentiation was reduced in mice lacking a functional AR. High levels of MYC triggered a p53-dependent DNA damage response, leading to accumulation of proliferative SG progenitors and inhibition of AR signaling. Conversely, testosterone treatment or p53 deletion activated AR signaling and restored MYC-induced differentiation. Poorly differentiated human sebaceous carcinomas exhibited high p53 and low AR expression. Thus, the consequences of overactivating MYC in the SG depend on whether AR or p53 is activated, as they form a regulatory axis controlling proliferation and differentiation.

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  1. Akamatsu H. Zouboulis C.C. Orfanos C.E. Control of human sebocyte proliferation in vitro by testosterone and 5-alpha-dihydrotestosterone is dependent on the localization of the sebaceous glands J. Invest. Dermatol. 99 1992 509 511 1402009
  2. Alimirah F. Panchanathan R. Chen J. Zhang X. Ho S.M. Choubey D. Expression of androgen receptor is negatively regulated by p53 Neoplasia 9 2007 1152 1159 18084622 PMC2134911
  3. Arnold I. Watt F.M. c-Myc activation in transgenic mouse epidermis results in mobilization of stem cells and differentiation of their progeny Curr. Biol. 11 2001 558 568 11369200
  4. Azzi L. El-Alfy M. Labrie F. Gender differences and effects of sex steroids and dehydroepiandrosterone on androgen and oestrogen alpha receptors in mouse sebaceous glands Br. J. Dermatol. 154 2006 21 27 16403089
  5. Bayer-Garner I.B. Givens V. Smoller B. Immunohistochemical staining for androgen receptors: a sensitive marker of sebaceous differentiation Am. J. Dermatopathol. 21 1999 426 431 10535570
  6. Bernard D. Pourtier-Manzanedo A. Gil J. Beach D.H. Myc confers androgen-independent prostate cancer cell growth J. Clin. Invest. 112 2003 1724 1731 14660748 PMC281646
  7. Berta M.A. Baker C.M. Cottle D.L. Watt F.M. Dose and context dependent effects of Myc on epidermal stem cell proliferation and differentiation EMBO Mol. Med. 2 2010 16 25 20043278 PMC2929372
  8. Buitrago W. Joseph A.K. Sebaceous carcinoma: the great masquerader: emgerging concepts in diagnosis and treatment Dermatol. Ther. 21 2008 459 466 19076624
  9. Ceballos E. Delgado M.D. Gutierrez P. Richard C. Müller D. Eilers M. Ehinger M. Gullberg U. León J. c-Myc antagonizes the effect of p53 on apoptosis and p21WAF1 transactivation in K562 leukemia cells Oncogene 19 2000 2194 2204 10822369
  10. Chang D.H. Cattoretti G. Calame K.L. The dynamic expression pattern of B lymphocyte induced maturation protein-1 (Blimp-1) during mouse embryonic development Mech. Dev. 117 2002 305 309 12204275
  11. Chen W. Tsai S.J. Liao C.Y. Tsai R.Y. Chen Y.J. Pan B.J. Hung C.L. Zouboulis C.C. Higher levels of steroidogenic acute regulatory protein and type I 3beta-hydroxysteroid dehydrogenase in the scalp of men with androgenetic alopecia J. Invest. Dermatol. 126 2006 2332 2335 16778788
  12. Chen W. Tsai S.J. Sheu H.M. Tsai J.C. Zouboulis C.C. Testosterone synthesized in cultured human SZ95 sebocytes derives mainly from dehydroepiandrosterone Exp. Dermatol. 19 2010 470 472 20337700
  13. Cui C.Y. Durmowicz M. Ottolenghi C. Hashimoto T. Griggs B. Srivastava A.K. Schlessinger D. Inducible mEDA-A1 transgene mediates sebaceous gland hyperplasia and differential formation of two types of mouse hair follicles Hum. Mol. Genet. 12 2003 2931 2940 14506134
  14. Deplewski D. Rosenfield R.L. Growth hormone and insulin-like growth factors have different effects on sebaceous cell growth and differentiation Endocrinology 140 1999 4089 4094 10465280
  15. Driskell I. Oda H. Blanco S. Nascimento E. Humphreys P. Frye M. The histone methyltransferase Setd8 acts in concert with c-Myc and is required to maintain skin EMBO J. 31 2011 616 629 22117221 PMC3273381
  16. Gaspar M.L. Meo T. Bourgarel P. Guenet J.L. Tosi M. A single base deletion in the Tfm androgen receptor gene creates a short-lived messenger RNA that directs internal translation initiation Proc. Natl. Acad. Sci. USA 88 1991 8606 8610 1924321 PMC52558
  17. Greenhalgh D.A. Wang X.J. Donehower L.A. Roop D.R. Paradoxical tumor inhibitory effect of p53 loss in transgenic mice expressing epidermal-targeted v-rasHa, v-fos, or human transforming growth factor alpha Cancer Res. 56 1996 4413 4423 8813135
  18. Hallenborg P. Feddersen S. Madsen L. Kristiansen K. The tumor suppressors pRB and p53 as regulators of adipocyte differentiation and function Expert Opin. Ther. Targets 13 2009 235 246 19236241
  19. Hasebe T. Mukai K. Yamaguchi N. Ishihara K. Kaneko A. Takasaki Y. Shimosato Y. Prognostic value of immunohistochemical staining for proliferating cell nuclear antigen, p53, and c-erbB-2 in sebaceous gland carcinoma and sweat gland carcinoma: comparison with histopathological parameter Mod. Pathol. 7 1994 37 43 7909154
  20. Hayashi N. Furihata M. Ohtsuki Y. Ueno H. Search for accumulation of p53 protein and detection of human papillomavirus genomes in sebaceous gland carcinoma of the eyelid Virchows Arch. 424 1994 503 509 8032531
  21. Hayward W.S. Neel B.G. Astrin S.M. Activation of a cellular onc gene by promoter insertion in ALV-induced lymphoid leukosis Nature 290 1981 475 480 6261142
  22. Honeycutt K.A. Roop D.R. c-Myc and epidermal stem cell fate determination J. Dermatol. 31 2004 368 375 15187303
  23. Hong S. Pusapati R.V. Powers J.T. Johnson D.G. Oncogenes and the DNA damage response: Myc and E2F1 engage the ATM signaling pathway to activate p53 and induce apoptosis Cell Cycle 5 2006 801 803 16582589
  24. Horsley V. O’Carroll D. Tooze R. Ohinata Y. Saitou M. Obukhanych T. Nussenzweig M. Tarakhovsky A. Fuchs E. Blimp1 defines a progenitor population that governs cellular input to the sebaceous gland Cell 126 2006 597 609 16901790 PMC2424190
  25. Imperato-McGinley J. Gautier T. Cai L.Q. Yee B. Epstein J. Pochi P. The androgen control of sebum production. Studies of subjects with dihydrotestosterone deficiency and complete androgen insensitivity J. Clin. Endocrinol. Metab. 76 1993 524 528 8381804
  26. Izumi M. Mukai K. Nagai T. Matsubayashi J. Iwaya K. Chiu C.S. Goto H. Sebaceous carcinoma of the eyelids: thirty cases from Japan Pathol. Int. 58 2008 483 488 18705767
  27. Jensen K.B. Collins C.A. Nascimento E. Tan D.W. Frye M. Itami S. Watt F.M. Lrig1 expression defines a distinct multipotent stem cell population in mammalian epidermis Cell Stem Cell 4 2009 427 439 19427292 PMC2698066
  28. Ju Q. Fimmel S. Hinz N. Stahlmann R. Xia L. Zouboulis C.C. 2,3,7,8-Tetrachlorodibenzo-p-dioxin alters sebaceous gland cell differentiation in vitro Exp. Dermatol. 20 2011 320 325 21410761
  29. Kiyosaki K. Nakada C. Hijiya N. Tsukamoto Y. Matsuura K. Nakatsuka K. Daa T. Yokoyama S. Imaizumi M. Moriyama M. Analysis of p53 mutations and the expression of p53 and p21WAF1/CIP1 protein in 15 cases of sebaceous carcinoma of the eyelid Invest. Ophthalmol. Vis. Sci. 51 2010 7 11 19628749
  30. Kulikov R. Letienne J. Kaur M. Grossman S.R. Arts J. Blattner C. Mdm2 facilitates the association of p53 with the proteasome Proc. Natl. Acad. Sci. USA 107 2010 10038 10043 20479273 PMC2890462
  31. Latham J.A. Redfern C.P. Thody A.J. De Kretser T.A. Immunohistochemical markers of human sebaceous gland differentiation Histochem J. Cytochem. 37 1989 729 734 2467930
  32. Laurent S.J. Mednieks M.I. Rosenfield R.L. Growth of sebaceous cells in monolayer culture In Vitro Cell. Dev. Biol. 28A 1992 83 89 1371506
  33. Lin H.K. Wang L. Hu Y.C. Altuwaijri S. Chang C. Phosphorylation-dependent ubiquitylation and degradation of androgen receptor by Akt require Mdm2 E3 ligase EMBO J. 21 2002 4037 4048 12145204 PMC126152
  34. Lo Celso C. Berta M.A. Braun K.M. Frye M. Lyle S. Zouboulis C.C. Watt F.M. Characterization of bipotential epidermal progenitors derived from human sebaceous gland: contrasting roles of c-Myc and beta-catenin Stem Cells 26 2008 1241 1252 18308950
  35. Markova M.S. Zeskand J. McEntee B. Rothstein J. Jimenez S.A. Siracusa L.D. A role for the androgen receptor in collagen content of the skin J. Invest. Dermatol. 123 2004 1052 1056 15610513
  36. McCulley J.P. Shine W.E. The lipid layer of tears: dependent on meibomian gland function Exp. Eye Res. 78 2004 361 365 15106913
  37. Montagna W. Ellis R.A. Silver A.F. Advances in Biology of Skin. The Sebaceous Glands Volume 4 1963 Oxford Pergamon
  38. Murphy D.J. Junttila M.R. Pouyet L. Karnezis A. Shchors K. Bui D.A. Brown-Swigart L. Johnson L. Evan G.I. Distinct thresholds govern Myc’s biological output in vivo Cancer Cell 14 2008 447 457 19061836 PMC2723751
  39. Nadiminty N. Tummala R. Lou W. Zhu Y. Zhang J. Chen X. eVere White R.W. Kung H.J. Evans C.P. Gao A.C. MicroRNA let-7c suppresses androgen receptor expression and activity via regulation of Myc expression in prostate cancer cells J. Biol. Chem. 287 2012 1527 1537 22128178 PMC3256915
  40. Nantermet P.V. Xu J. Yu Y. Hodor P. Holder D. Adamski S. Gentile M.A. Kimmel D.B. Harada S. Gerhold D. Identification of genetic pathways activated by the androgen receptor during the induction of proliferation in the ventral prostate gland J. Biol. Chem. 279 2004 1310 1322 14576152
  41. Nascimento E.M. Cox C.L. MacArthur S. Hussain S. Trotter M. Blanco S. Suraj M. Nichols J. Kübler B. Benitah S.A. The opposing transcriptional functions of Sin3a and c-Myc are required to maintain tissue homeostasis Nat. Cell Biol. 13 2011 1395 1405 22101514 PMC3242072
  42. Nesslinger N.J. Shi X.B. deVere White R.W. Androgen-independent growth of LNCaP prostate cancer cells is mediated by gain-of-function mutant p53 Cancer Res. 63 2003 2228 2233 12727844
  43. Petersson M. Brylka H. Kraus A. John S. Rappl G. Schettina P. Niemann C. TCF/Lef1 activity controls establishment of diverse stem and progenitor cell compartments in mouse epidermis EMBO J. 30 2011 3004 3018 21694721 PMC3160179
  44. Pusapati R.V. Rounbehler R.J. Hong S. Powers J.T. Yan M. Kiguchi K. McArthur M.J. Wong P.K. Johnson D.G. ATM promotes apoptosis and suppresses tumorigenesis in response to Myc Proc. Natl. Acad. Sci. USA 103 2006 1446 1451 16432227 PMC1345703
  45. Rahl P.B. Lin C.Y. Seila A.C. Flynn R.A. McCuine S. Burge C.B. Sharp P.A. Young R.A. c-Myc regulates transcriptional pause release Cell 141 2010 432 445 20434984 PMC2864022
  46. Reichelt J. Breiden B. Sandhoff K. Magin T.M. Loss of keratin 10 is accompanied by increased sebocyte proliferation and differentiation Eur. J. Cell Biol. 83 2004 747 759 15679119
  47. Rokhlin O.W. Taghiyev A.F. Guseva N.V. Glover R.A. Chumakov P.M. Kravchenko J.E. Cohen M.B. Androgen regulates apoptosis induced by TNFR family ligands via multiple signaling pathways in LNCaP Oncogene 24 2005 6773 6784 16007156 PMC1361275
  48. Rosenfield R.L. Relationship of sebaceous cell stage to growth in culture J. Invest. Dermatol. 92 1989 751 754 2715646
  49. Rosenfield R.L. Deplewski D. Kentsis A. Ciletti N. Mechanisms of androgen induction of sebocyte differentiation Dermatology (Basel) 196 1998 43 46 9557223
  50. Rosenfield R.L. Kentsis A. Deplewski D. Ciletti N. Rat preputial sebocyte differentiation involves peroxisome proliferator-activated receptors J. Invest. Dermatol. 112 1999 226 232 9989800
  51. Rudolf E. Rudolf K. Cervinka M. Camptothecin induces p53-dependent and -independent apoptogenic signaling in melanoma cells Apoptosis 16 2011 1165 1176 21809047
  52. Schirra F. Suzuki T. Richards S.M. Jensen R.V. Liu M. Lombardi M.J. Rowley P. Treister N.S. Sullivan D.A. Androgen control of gene expression in the mouse meibomian gland Invest. Ophthalmol. Vis. Sci. 46 2005 3666 3675 16186348
  53. Schirra F. Richards S.M. Liu M. Suzuki T. Yamagami H. Sullivan D.A. Androgen regulation of lipogenic pathways in the mouse meibomian gland Exp. Eye Res. 83 2006 291 296 16579987
  54. Schneider M.R. Paus R. Sebocytes, multifaceted epithelial cells: lipid production and holocrine secretion Int. J. Biochem. Cell Biol. 42 2010 181 185 19944183
  55. Sellheyer K. Krahl D. Blimp-1: a marker of terminal differentiation but not of sebocytic progenitor cells J. Cutan. Pathol. 37 2010 362 370 19788443
  56. Shah N.M. Pisapia D.J. Maniatis S. Mendelsohn M.M. Nemes A. Axel R. Visualizing sexual dimorphism in the brain Neuron 43 2004 313 319 15294140
  57. Sheiness D.K. Hughes S.H. Varmus H.E. Stubblefield E. Bishop J.M. The vertebrate homolog of the putative transforming gene of avian myelocytomatosis virus: characteristics of the DNA locus and its RNA transcript Virology 105 1980 415 424 6158786
  58. Shenk J.L. Fisher C.J. Chen S.Y. Zhou X.F. Tillman K. Shemshedini L. p53 represses androgen-induced transactivation of prostate-specific antigen by disrupting hAR amino- to carboxyl-terminal interaction J. Biol. Chem. 276 2001 38472 38479 11504717
  59. Snippert H.J. Haegebarth A. Kasper M. Jaks V. van Es J.H. Barker N. van de Wetering M. van den Born M. Begthel H. Vries R.G. Lgr6 marks stem cells in the hair follicle that generate all cell lineages of the skin Science 327 2010 1385 1389 20223988
  60. Sundberg J.P. Boggess D. Sundberg B.A. Eilertsen K. Parimoo S. Filippi M. Stenn K. Asebia-2J (Scd1(ab2J)): a new allele and a model for scarring alopecia Am. J. Pathol. 156 2000 2067 2075 10854228 PMC1850069
  61. Zouboulis C.C. [The sebaceous gland] Hautarzt 61 2010 467 468 4704, 476–477 20512305
  62. Zouboulis C.C. Xia L. Akamatsu H. Seltmann H. Fritsch M. Hornemann S. Rühl R. Chen W. Nau H. Orfanos C.E. The human sebocyte culture model provides new insights into development and management of seborrhoea and acne Dermatology (Basel) 196 1998 21 31 9557220
  63. Zouboulis C.C. Seltmann H. Neitzel H. Orfanos C.E. Establishment and characterization of an immortalized human sebaceous gland cell line (SZ95) J. Invest. Dermatol. 113 1999 1011 1020 10594745
  64. Blanchere M. Berthaut I. Portois M.C. Mestayer C. Mowszowicz I. Hormonal regulation of the androgen receptor expression in human prostatic cells in culture J. Steroid Biochem. Mol. Biol. 66 1998 319 326 9749837
  65. Driskell R.R. Juneja V.R. Connelly J.T. Kretzschmar K. Tan D.W. Watt F.M. Clonal growth of dermal papilla cells in hydrogels reveals intrinsic differences between Sox2-positive and -negative cells in vitro and in vivo J. Invest. Dermatol. 132 2011 1084 1093 22189784 PMC3306894
  66. Gao X.M. Perchellet E.M. Davis A.W. Newell S.W. Chen G. Hua D.H. Perchellet J.P. Camptothecin post-treatments inhibit the biochemical events linked to the tumor-promoting component of carcinogenesis in mouse epidermis in vivo Int. J. Cancer 66 1996 496 505 8635865
  67. Gao X.M. Perchellet E.M. Davis A.W. Newell S.W. Hua D.H. Perchellet J.P. Characterization of the antitumor-promoting activity of camptothecin in SENCAR mouse skin Carcinogenesis 17 1996 1141 1148 8640925
  68. Kao J. Patterson F.K. Hall J. Skin penetration and metabolism of topically applied chemicals in six mammalian species, including man: an in vitro study with benzo[a]pyrene and testosterone Toxicol. Appl. Pharmacol. 81 1985 502 516 3936234
  69. Littlewood T.D. Hancock D.C. Danielian P.S. Parker M.G. Evan G.I. A modified oestrogen receptor ligand-binding domain as an improved switch for the regulation of heterologous proteins Nucleic Acids Res. 23 1995 1686 1690 7784172 PMC306922
  70. Masiello D. Cheng S. Bubley G.J. Lu M.L. Balk S.P. Bicalutamide functions as an androgen receptor antagonist by assembly of a transcriptionally inactive receptor J. Biol. Chem. 277 2002 26321 26326 12015321
  71. Moguilewsky M. Bouton M.M. How the study of the biological activities of antiandrogens can be oriented towards the clinic J. Steroid Biochem. 31 4B 1988 699 710 3059062
  72. Müller-Röver S. Handjiski B. van der Veen C. Eichmüller S. Foitzik K. McKay I.A. Stenn K.S. Paus R. A comprehensive guide for the accurate classification of murine hair follicles in distinct hair cycle stages J. Invest. Dermatol. 117 2001 3 15 11442744
  73. Naito A. Sato T. Matsumoto T. Takeyama K. Yoshino T. Kato S. Ohdera M. Dihydrotestosterone inhibits murine hair growth via the androgen receptor Br. J. Dermatol. 159 2008 300 305 18547308
  74. Plewig G. Kligman A.M. Proliferative activity of the sebaceous glands of the aged J. Invest. Dermatol. 70 1978 314 317 649977
  75. Pochi P.E. Strauss J.S. Downing D.T. Age-related changes in sebaceous gland activity J. Invest. Dermatol. 73 1979 108 111 448169
  76. Tagliolatto S. Alchorne M.M. Enokihara M. Sebaceous hyperplasia: a pilot study to correlate this skin disease with circulating androgen levels An. Bras. Dermatol. 86 2011 917 923 22147031

Cited by

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Authors
Cottle, D. L., Kretzschmar, K., Schweiger, P. J., Quist, S. R., Gollnick, H. P., Natsuga, K., Aoyagi, S., & Watt, F. M.
Affiliations
  • Wellcome/MRC Cambridge Stem Cell Institute (GB)
  • Cancer Research UK (GB)
  • Otto-von-Guericke-Universität Magdeburg (DE)
  • Hokkaido University (JP)
Corresponding author
Watt, Fiona M.
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2013-02
Volume
3
Issue
2
Pages
427-441
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2013.01.013
PMC
PMC3778892
OpenAlex
W2099386293
Cited by
80
References
2
Citations by year
2026: 3 · 2025: 6 · 2024: 13 · 2023: 6 · 2022: 7 · 2021: 3 · 2020: 7 · 2019: 8 · 2018: 2 · 2017: 5 · 2016: 3 · 2015: 3 · 2014: 7 · 2013: 7
FWCI
7.83
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Research Portal (King's College London) (submittedVersion)
Funders
  • Wellcome Trust (EU-FP7-, 079249, 096540)
  • Cancer Research UK
  • University of Cambridge
  • Medical Research Council (EU FP7)
  • Japan Society for the Promotion of Science (25670494)
  • Cancer Research UK Cambridge Institute, University of Cambridge
Topics
  • Health Sciences › Medicine › Dermatology › Cancer and Skin Lesions
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and rare skin diseases.
Keywords
c-Myc, sebaceous gland differentiation, androgen receptor, p53, sebaceous carcinoma, DNA damage response, testosterone, cell proliferation
MeSH terms
Animals, Antineoplastic Agents, Cell Differentiation, Cells, Cultured, Humans, Mice, Inbred C57BL, Mice, Transgenic, Receptors, Androgen, RNA, Messenger, Sebaceous Gland Neoplasms, Sebaceous Glands, Tamoxifen, Testosterone, Signal Transduction, Tumor Suppressor Protein p53, Proto-Oncogene Proteins c-myc, Mice

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