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P16INK4A is implicated in both the immediate and adaptative response of human keratinocytes to UVB irradiation

Oncogene volume 21, pages 2652–2661 (2002)Cite this article

Abstract

The p16INK4A-ARF locus plays a crucial role in the control of cellular proliferation via both the Rb and P53 pathways. We previously demonstrated that this locus is altered in human skin carcinomas. In the present study we have studied the expression of the p16INK4A-ARF locus following UVB irradiation of normal human keratinocytes both at the mRNA (RT–PCR) and at the protein (Western blotting) levels. Our data confirmed that P16INK4A protein is induced by UVB at low (30 mJ cm2) and high (100 mJ cm2) doses and is observed after a single or repeated exposure implying that this response is involved in both the immediate and adaptative response to UVB. The apparent absence of induction p16INK4A mRNA suggested that P16INK4A protein is upregulated at the post-transcriptional level. Analysis by flow cytometry and BrdU staining indicated that the highest protein level of P16INK4A in the cells was associated with a G2 cell cycle arrest. Comparative analysis of P16INK4A and P53 showed that they were differentially modulated in keratinocytes according to the UVB dose and regimen. Low, acute or repeated UVB exposures led to accumulation of both P16INK4A and p53, whereas at high UVB doses, P53 and P53-dependent genes were not induced or even downregulated and only a slight but reproducible stabilization of P16INK4A protein was observed. In our conditions, P14ARF did not seem to participate in the UV response in these cells as P14ARF protein did not vary. These results infer that P16INK4A plays a role in cell cycle regulation of keratinocytes submitted to UVB irradiation. They also reinforce our previous demonstration of the importance of inactivation of this gene in UV-induced skin carcinogenesis.

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Abbreviations

ARF:

alternative reading frame

cDNA:

complementary DNA

DNA:

desoxyribonucleic acid

INK4A:

inhibitor of cyclin dependent kinase 4 (CDK4)

INK4A-ARF:

inhibitor of cyclin dependent kinase 4 (CDK4)-alternative reading frame

MDM2:

multiple murine double minute gene 2

mRNA:

messenger RNA

Rb:

retinoblastoma

RNA:

ribonucleic acid

RT–PCR:

reverse transcription polymerase chain reaction

UVB:

ultraviolet B

UVC:

ultraviolet C

References

  • Agarwal ML, Agarwal A, Taylor WR, Stark GR . 1995 Proc. Natl. Acad. Sci. USA 92: 8493–8497

  • Ahmed NU, Ueda M, Ichihashi M . 1999 J. Dermatol. Sci. 19: 175–181

  • Basset-Séguin N, Moles JP, Mils V, Dereure O, Guilhou JJ . 1994 J. Invest. Dermatol. 103: 102S–106S

  • Bradford MM . 1976 Anal. Biochem. 72: 248–254

  • Brugarolas J, Chandrasekaran C, Gordon JI, Beach D, Jacks T, Hannon GJ . 1995 Nature 377: 552–557

  • Chaturvedi V, Qin JZ, Denning MF, Choubey D, Diaz MO, Nickoloff BJ . 1999 J. Biol. Chem. 274: 23358–23367

  • Della Valle V, Duro D, Bernard O, Larsen CJ . 1997 Oncogene 15: 2475–2481

  • Dimri GP, Itahana K, Acosta M, Campisi J . 2000 Mol. Cell. Biol. 20: 273–285

  • el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B . 1993 Cell 75: 817–825

  • Enders GH, Koh J, Missero C, Rustgi AK, Harlow E . 1996 Oncogene 12: 1239–1245

  • Fritsche M, Haessler C, Brandner G . 1993 Oncogene 8: 307–318

  • Gabrielli BG, Sarcevic B, Sinnamon J, Walker G, Castellano M, Wang XQ, Ellem KA . 1999 J. Biol. Chem. 274: 13961–13969

  • Hall PA, McKee PH, Menage HD, Dover R, Lane DP . 1993 Oncogene 8: 203–207

  • Hara E, Smith R, Parry D, Tahara H, Stone S, Peters G . 1996 Mol. Cell. Biol. 16: 859–867

  • Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ . 1993 Cell 75: 805–816

  • Inohara S, Kitagawa K, Kitano Y . 1996 Br. J. Dermatol. 135: 717–720

  • Kallassy M, Martel N, Damour O, Yamasaki H, Nakazawa H . 1998 Mol. Carcinog. 21: 26–36

  • Kamijo T, Weber JD, Zambetti G, Zindy F, Roussel MF, Sherr CJ . 1998 Proc. Natl. Acad. Sci. USA 95: 8292–8297

  • Kamijo T, Zindy F, Roussel MF, Quelle DE, Downing JR, Ashmun RA, Grosveld G, Sherr CJ . 1997 Cell 91: 649–659

  • Kastan MB, Kuerbitz SJ . 1993 Environ. Health Perspect. 101: Suppl 5 55–58

  • Kastan MB, Onyekwere O, Sidransky D, Vogelstein B, Craig RW . 1991 Cancer Res. 51: 6304–6311

  • Larsen CJ . 1996 Oncogene 12: 2041–2044

  • Levine AJ . 1997 Cell 88: 323–331

  • Li G, Ho VC . 1998 Br. J. Dermatol. 139: 3–10

  • Liefer KM, Koster MI, Wang XJ, Yang A, McKeon F, Roop DR . 2000 Cancer Res. 60: 4016–4020

  • Loughran O, Malliri A, Owens D, Gallimore PH, Stanley MA, Ozanne B, Frame MC, Parkinson EK . 1996 Oncogene 13: 561–568

  • Lowe SW, Ruley HE, Jacks T, Housman DE . 1993 Cell 74: 957–967

  • Milligan A, Gabrielli BG, Clark JM, Hayward NK, Ellem KA . 1998 Mutat. Res. 422: 43–53

  • Miyashita T, Reed JC . 1995 Cell 80: 293–299

  • Nielsen GP, Stemmer-Rachamimov AO, Shaw J, Roy JE, Koh J, Louis DN . 1999 Lab. Invest. 79: 1137–1143

  • Ouhtit A, Muller HK, Davis DW, Ullrich SE, McConkey D, Ananthaswamy HN . 2000 Am. J. Pathol. 156: 201–207

  • Parker CA . 1968 Photoluminescence of solutions Amsterdam: Elsevier

    Google Scholar 

  • Pavey S, Conroy S, Russell T, Gabrielli B . 1999 Cancer Res. 59: 4185–4189

  • Piepkorn M . 2000 J. Am. Acad. Dermatol. 42: 741–745

  • Reznikoff CA, Yeager TR, Belair CD, Savelieva E, Puthenveettil JA, Stadler WM . 1996 Cancer Res. 56: 2886–2890

  • Schagger H, von Jagow G . 1987 Anal. Biochem. 166: 368–379

  • Serrano M, Lee H, Chin L, Cordon-Cardo C, Beach D, DePinho RA . 1996 Cell 85: 27–37

  • Shapiro GI, Edwards CD, Ewen ME, Rollins BJ . 1998 Mol. Cell. Biol. 18: 378–387

  • Sherr CJ . 1996 Science 274: 1672–1677

  • Soufir N, Daya-Grosjean L, de La Salmoniere P, Moles JP, Dubertret L, Sarasin A, Basset-Séguin N . 2000 J. Natl. Cancer Inst. 92: 1841–1847

  • Soufir N, Moles JP, Vilmer C, Moch C, Verola O, Rivet J, Tesniere A, Dubertret L, Basset-Séguin N . 1999 Oncogene 18: 5477–5481

  • Stone S, Jiang P, Dayananth P, Tavtigian SV, Katcher H, Parry D, Peters G, Kamb A . 1995 Cancer Res. 55: 2988–2994

  • Stott FJ, Bates S, James MC, McConnell BB, Starborg M, Brookes S, Palmero I, Ryan K, Hara E, Vousden KH, Peters G . 1998 EMBO J. 17: 5001–5014

  • Waldman T, Kinzler KW, Vogelstein B . 1995 Cancer Res. 55: 5187–5190

  • Wang JA, Fan S, Yuan RQ, Ma YX, Meng Q, Goldberg ID, Rosen EM . 1999 Int. J. Radiat. Biol. 75: 301–316

  • Wang XQ, Gabrielli BG, Milligan A, Dickinson JL, Antalis TM, Ellem KA . 1996 Cancer Res. 56: 2510–2514

  • Weinberg WC, Azzoli CG, Kadiwar N, Yuspa SH . 1994 Cancer Res. 54: 5584–5592

  • Wu L, Levine AJ . 1997 Mol. Med. 3: 441–451

  • Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D . 1993 Nature 366: 701–704

  • Zhang Y, Xiong Y, Yarbrough WG . 1998 Cell 92: 725–734

  • Ziegler A, Jonason AS, Leffell DJ, Simon JA, Sharma HW, Kimmelman J, Remington L, Jacks T, Brash DE . 1994 Nature 372: 773–776

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Acknowledgements

This work was supported by INSERM funds and a grant from ‘Ligue contre le Cancer’.

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Authors and Affiliations

  1. INSERM U532, Institut de Recherche sur la Peau, Pavillon Bazin, Hôpital SaintLouis, 1 avenue C Vellefaux, Paris, 75010, France

    Marjorie Chazal, Claire Marionnet, Laurence Michel, Karine Mollier, Marie-Pierre Gras & Nicole Basset-Séguin

  2. CNRS-UMR 5535, Institut de Génétique Moléculaire, Montpellier, 34090, France

    Jean-Eudes Dazard

  3. INSERM U434, Institut de Génétique Moléculaire, Paris, 75010, France

    Véronique Della Valle

  4. Laboratoire d'Oncologie Moléculaire, IBMIG, Poitiers, 86022, France

    Christian-Jacques Larsen

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  1. Marjorie Chazal
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Correspondence to Nicole Basset-Séguin.

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Chazal, M., Marionnet, C., Michel, L. et al. P16INK4A is implicated in both the immediate and adaptative response of human keratinocytes to UVB irradiation. Oncogene 21, 2652–2661 (2002). https://doi.org/10.1038/sj.onc.1205349

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