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Targeted expression of c-Myc in the epidermis alters normal proliferation, differentiation and UV-B induced apoptosis

Oncogene volume 18, pages 4870–4878 (1999)Cite this article

Abstract

c-Myc overexpression has been associated with several types of human cancers. To study the role of c-myc in epidermal differentiation and carcinogenesis, a transgenic mouse model was created to overexpress c-Myc in the epidermis. Human c-myc 2 cDNA was subcloned into a 6.5 kb mouse loricrin expression vector, ML.myc2. This loricrin promoter primarily directs expression in the epidermis in both proliferating and differentiated keratinocytes. On day 4, ML.myc2 transgenic pups develop a hyperkeratotic phenotype, which progressively worsens until day 7. Upon histological analysis, both hyperplasia and hyperkeratosis were evident. Bromodeoxyuridine (BrdU) incorporation revealed that transgenic mice had a threefold increase in the number of proliferating cells as compared with a normal littermate. Proliferative cells in the ML.myc2 epidermis were also found to be suprabasal, suggesting an inhibition of terminal differentiation in keratinocytes. Inhibition of terminal differentiation by c-Myc overexpression was further suggested by aberrant expression of differentiation markers, keratin 1, keratin 6, loricrin, and filaggrin in ML.myc2 transgenic mice. Interestingly, ML.myc2 keratinocytes exhibit a reduced sensitivity to UV-B induced apoptosis, in vivo. In vitro studies reveal the reduced sensitivity of ML.myc2 keratinocytes to UV-B irradiation is growth factor dependent. These findings provide evidence that overexpression of c-Myc in the epidermis induces proliferation, inhibits terminal differentiation and decreases the sensitivity of keratinocytes to UV-B induced apoptosis.

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Abbreviations

ML.myc2:

human myc2 expressed from a mouse 6.5 kb loricrin promoter

TPA:

12-O-tetradecanoylphorbol-13-acetate

BrdU:

bromodeoxyuridine

References

  • Amati B and Land H. . 1994 Curr. Opin. Genet. Dev. 4: 102–108.

  • Ariizumi K, Bergstresser PR and Takashima A. . 1996 J. Dermatol. Sci. 12: 147–155.

  • Askew DS, Ashmun RA, Simmons BC and Cleveland DL. . 1991 Oncogene 6: 1915–1922.

  • Ayer DE and Eisenman RN. . 1993 Genes Dev. 7: 2110–2119.

  • Bello-Fernandez C, Packham G and Cleveland JL. . 1993 Proc. Natl. Acad. Sci. USA 90: 7804–7808.

  • Bentley DL and Groudine M. . 1988 Cell 53: 245–256.

  • Beijersbergen RL and Bernards R. . 1996 Biochim. Biophys. Acta 1287: 103–120.

  • Berns K, Hijmans EM and Bernards R. . 1997 Oncogene 15: 1347–1356.

  • Bertsch S and Marks F. . 1982 Cell Tiss. Kinet. 15: 81–87.

  • Biro S, Fu YM, Yu ZX and Epstein SE. . 1993 Proc. Natl. Acad. Sci. USA 90: 654–658.

  • Bissonnette RP, Echeverri F, Mahboubi A and Green DR. . 1992 Nature 359: 552–554.

  • Chin L, Schreiber-Agus N, Pellicer I, Chen K, Lee HW, Dudast M, Cordon-Cardo C and DePinho RA. . 1995 Proc. Natl. Acad. Sci. USA 92: 8488–8492.

  • Coppola JA and Cole MD. . 1986 Nature 320: 760–763.

  • Cotter FE. . 1993 Cancer Surv. 16: 157–174.

  • Eilers M, Schirm S and Bishop JM. . 1991 EMBO J. 10: 133–141.

  • Evan GI, Wyllie AH, Gilbert CS, Littlewood TD, Land H, Brooks M, Waters CM, Penn LZ and Hancock DC. . 1992 Cell 69: 119–128.

  • Foley KP, McArthur GA, Queva C, Hurlin PJ, Soriano P and Eisenman RN. . 1998 EMBO J. 17: 774–785.

  • Galaktionov K, Chen X and Beach D. . 1996 Nature 382: 511–517.

  • Gandarillas A and Watt FM. . 1997 Genes Dev. 11: 2869–2882.

  • Garmyn M, Yaar M, Boileau N, Backendorf C and Gilcherest BA. . 1991 J. Invest. Dermatol. 99: 743–748.

  • Gazdar AF. . 1994 Anticancer Res. 14: 261–267.

  • Greenhalgh DA, Wang XJ, Dominey AM, Rothnagel JA and Roop DR. . 1995 Skin Cancer: Mechanisms and Human Relevance. H. Mukhtar (ed.). CRC Press Inc: Boca Raton. pp. 317–330.

    Google Scholar 

  • Greenhalgh DA, Rothnagel JA, Wang X-J, Quintanilla MI, Orengo CC, Gagne TA, Bundman DS, Longley MA, Fisher C and Roop DR. . 1993 Oncogene 8: 2145–2157.

  • Hogan B, Constantini F and Lacey E. . 1986 Manipulating the Mouse Embryo: A Laboratory Manual. Cold Spring Harbor Lab Press, Plainview, NY.

    Google Scholar 

  • Hurlin PJ, Foley KP, Ayer DE, Eisenman RN, Hanahan D and Arbeit JM. . 1995a Oncogene 11: 2487–2501.

  • Hurlin PJ, Queva C, Koskinen P, Steingrimsson E, Ayer DE, Copeland NG, Jenkins NA and Eisenman RN. . 1995b EMBO J. 14: 5646–5659.

  • Hurlin PJ, Ayer DE, Grandori C and Eisenman RN. . 1994 Cold Spring Harbor Symp. Quant. Biol. 59: 109–116.

  • Jager R, Herzer U, Schenkel J and Weiher H. . 1997 Oncogene 15: 1787–1795.

  • Jin Y, Burns FJ and Garte SJ. . 1992 Radiat. Res. 132: 193–199.

  • Kato GJ and Dang CV. . 1992 FASEB J. 6: 3065–3072.

  • Kopan R and Fuchs E. . 1989 Genes Dev. 5: 1–15.

  • Kopnin B. . 1993 Tumori. 79: 235–243.

  • Larsson LG, Ivhed I, Gidlund M, Pettersson U, Vennstrom B and Nilsson K. . 1988 Proc. Natl. Acad. Sci. USA 85: 2638–2642.

  • Mehrel T, Hohl D, Rothnagal JA, Longley MA, Bundman D, Cheng C, Litchti U, Bisher ME, Steven AC, Steinert PM, Yuspa SH and Roop DR. . 1990 Cell 61: 1103–1112.

  • Muller D, Bouchard C, Rudolph B, Steiner P, Stuckmann I, Saffrich R, Ansorge W, Huttner W and Eilers M. . 1997 Oncogene 15: 2561–2576.

  • Nass SJ and Dickson RB. . 1997 Breast Cancer Res. Treat. 44: 1–22.

  • Packham G and Cleveland JL. . 1994 Mol. Cell. Biol. 9: 5741–5747.

  • Pietenpol JA, Holt JT, Stein RW and Moses HL. . 1990 Proc. Natl. Acad. Sci. USA 87: 3758–3762.

  • Pusch O, Bernaschek G, Eilers M and Hengstschlager M. . 1997 Oncogene 15: 649–656.

  • Rodriguez-Puebla ML, Robles AI, Johnson DJ, LaCava M and Conti CJ. . 1998 Cell Growth Differ. 9: 31–39.

  • Roop DR, Huitfeldt H, Kilkenny A and Yuspa SH. . 1987 Differentiation 35: 143–150.

  • Rosenwald IB, Rhoads DB, Callanan LD, Isselbacher KJ and Schmidt EV. . 1993 Proc. Natl. Acad. Sci. USA 90: 6175–6178.

  • Rothnagel JA, Mehrel T, Idler WW and Roop DR. . 1987 J. Biol. Chem. 262: 15643–15648.

  • Rothnagel JA and Roop DR. . 1995 J. Invest. Dermatol. 104: S42–S43.

  • Sato H, Suzuki JS, Tanaka M, Ogiso M, Tohyama C and Kobayashi S. . 1997 Photochem. Photobiol. 65: 908–914.

  • Schoenenberger CA, Andres AC, Groner B, van der Valk M, LeMeur M and Gerlinger P. . 1988 EMBO J. 7: 169–175.

  • Thompson EB. . 1998 Annu. Rev. Physiol. 60: 575–600.

  • Trudel M, Barisoni L, Lanoix J and D'Agati V. . 1998 Am. J. Pathol. 152: 219–229.

  • Wang XJ, Greenhalgh DA, Eckhardt JN, Rothnagal J and Roop DR. . 1994 Mol. Carcinog. 10: 15–22.

  • Wang XJ, Greenhalgh DA, Bickenbach JR, Jiang A, Bundman DS, Krieg T, Derynck R and Roop DR. . 1997 Proc. Natl. Acad. Sci. USA 94: 2386–2391.

  • Wu M, Arsura M, Bellas RE, Fitzgerald MJ, Lee H, Schauer SL, Sherr DH and Sonenshein GE. . 1996 Mol. Cell. Biol. 16: 5015–5025.

  • Yuspa SH, Kilkenny AE, Steinert PM, Roop DR. . 1989 J. Cell Biol. 109: 1207–1217.

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Acknowledgements

We would like to thank CV Dang for providing the SP65mycII construct. We would like to thank Tim McDonnell for discussions during the course of these experiments and critical comments on this manuscript. We would also like to thank Ping Li and Donnie Bundman for their excellent technical assistance. This work was funded by the National Institutes of Health Grant CA52607 (DR Roop) and Molecular Oncology Training Grant CA09197 (RL Waikel).

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Authors and Affiliations

  1. Department of Cell Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, Texas, USA

    Rebekah L Waikel, Xiao-Jing Wang & Dennis R Roop

  2. Department of Dermatology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, Texas, USA

    Xiao-Jing Wang & Dennis R Roop

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  1. Rebekah L Waikel
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Waikel, R., Wang, XJ. & Roop, D. Targeted expression of c-Myc in the epidermis alters normal proliferation, differentiation and UV-B induced apoptosis. Oncogene 18, 4870–4878 (1999). https://doi.org/10.1038/sj.onc.1203040

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