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The tumor suppressor p16INK4a gene is a regulator of apoptosis induced by ultraviolet light and cisplatin

Oncogene volume 23, pages 201–212 (2004)Cite this article

Abstract

p16INK4a (hereafter referred to as p16), a major cyclin-dependent kinase (CDK) inhibitor, is the product of a tumor-suppressor gene that has been found inactivated in different cancer types. In the present study, we sought to investigate the role of p16 in apoptosis induced by ultraviolet light (the most important etiological cause of skin cancer) and cisplatin (an anticancer DNA damaging agent). It is clearly shown that p16-compromised osteosarcoma U2OS cell line and p16−/− mouse embryo fibroblasts are sensitive to UV-induced apoptosis, as compared to their respective isogenic p16-expressing cells (EH1, EH2) and p16 +/+, indicating that p16 protects cells from undergoing apoptosis in response to UV light. Importantly, this reduction in UV-mediated apoptosis was associated with downregulation of the proapoptotic Bax protein, with no effect on Bcl-2 expression, suggesting that this antiapoptotic role of p16 is mediated via the intrinsic-mitochondrial pathway. On the other hand, p16 sensitized cells to cisplatin-mediated apoptosis through Bcl-2 decline. Interestingly, only proliferating but not G1-arrested EH1 cells underwent apoptosis in response to the anticancer drug. These novel findings provide further insight into the role of p16 in carcinogenesis, and has potential implications for future therapy strategies.

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References

  • Abrahams PJ, Houweling A, Cornelissen-Steijger PD, Jaspers NG, Darroudi F, Meijers CM, Mullenders LH, Filon R, Arwert F, Pinedo HM, Natarajan AP, Terleth C, Van Zeeland AA and van der Eb AJ . (1998). Mutat. Res., 407, 189–201.

  • Adams JM, Harris AW, Strasser A, Ogilvy S and Cory S . (1999). Oncogene, 18, 5268–5277.

  • Allan LA and Fried M . (1999). Oncogene, 18, 5403–5412.

  • Al-Mohanna MA, Al-Khodairy FM, Krezolek Z, Bertilsson PA, Al-Houssein KA and Aboussekhra A . (2001). Carcinogenesis, 22, 573–578.

  • Amundson SA, Myers TG and Fornace Jr AJ . (1998). Oncogene, 17, 3287–3299.

  • Amundson SA, Myers TG, Scudiero D, Kitada S, Reed JC and Fornace Jr AJ . (2000). Cancer Res., 60, 6101–6110.

  • Bissonnette N and Hunting DJ . (1998). Oncogene, 16, 3461–3469.

  • Brash DE . (1997). Trends Genet., 13, 410–414.

  • Canman CE and Kastan MB . (1998). Oncogene, 16, 957–966.

  • Dunkern TR, Fritz G and Kaina B . (2001). Oncogene, 20, 6026–6038.

  • Evans DL, Tilby M and Dive C . (1994). Cancer Res., 54, 1596–1603.

  • Gonzalez VM, Fuertes MA, Alonso C and Perez JM . (2001). Mol. Pharmacol., 59, 657–663.

  • Gorospe M, Cirielli C, Wang X, Seth P, Capogrossi MC and Holbrook NJ . (1997). Oncogene, 14, 929–935.

  • Grim J, D'Amico A, Frizelle S, Zhou J, Kratzke RA and Curiel DT . (1997). Clin. Cancer Res., 3, 2415–2423.

  • Haluska FG and Hodi FS . (1998). J. Clin. Oncol., 16, 670–682.

  • Hanahan D and Weinberg RA . (2000). Cell, 100, 57–70.

  • Hussussian CJ, Struewing JP, Goldstein AM, Higgins PA, Ally DS, Sheahan MD, Clark Jr WH, Tucker MA and Dracopoli NC . (1994). Nat. Genet., 8, 15–21.

  • Johnstone RW, Ruefli AA and Lowe SW . (2002). Cell, 108, 153–164.

  • Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K, Tavtigian SV, Stockert E, Day III RS, Johnson BE and Skolnick MH . (1994). Science, 264, 436–440.

  • Kataoka M, Wiehle S, Spitz F, Schumacher G, Roth JA and Cristiano RJ . (2000). Oncogene, 19, 1589–1595.

  • Katsuda K, Kataoka M, Uno, Murakami T, Kondo T, Roth JA, Tanaka N and Fujiwara T . (2002). Oncogene, 21, 2108–2113.

  • Ljungman and Zhang F . (1996). Oncogene, 13, 823–831.

  • Lowe SW, Bodis S, McClatchey A, Remington L, Ruley HE, Fisher DE, Housman DE and Jacks T . (1994). Science, 266, 807–810.

  • Lowe SW, Ruley H, Jacks T and Housman DE . (1993). Cell, 74, 957–967.

  • McConnell BB, Gregory F, Stot F, Hara E and Peters G . (1999). Mol. Cell Biol., 19, 1981–1989.

  • McKay BC, Ljungman M and Rainbow AJ . (1998). Oncogene, 17, 545–555.

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

  • Miyashita T, Harigai M, Hanada M and Reed JC . (1994a). Cancer Res., 54, 3131–3135.

  • Miyashita T, Krajewski S, Krajewska M, Wang HG, Lin HK, Liebermann DA, Hoffman B and Reed JC . (1994b). Oncogene, 9, 1799–1805.

  • Moriwaki SI, Tarone RE, Tucker MA, Goldstein AM and Kraemer KH . (1997). Cancer Res., 57, 4637–4641.

  • Nobori T, Miura K, Wu DJ, Lois A, Takabayashi K and Carson DA . (1994). Nature, 368, 753–756.

  • Ortega S, Malumbres M and Barbacid M . (2002). Biochim. Biophys. Acta, 1602, 73–87.

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

  • Pavey S and Gabrielli B . (2002). Cancer Res., 62, 875–880.

  • Poluha W, Poluha DK, Chang B, Crosbie NE, Schonhoff CM, Kilpatrick DL and Ross AH . (1996). Mol. Cell Biol., 16, 1335–1341.

  • Polyak K, Waldman T, He TC, Kinzler KW and Vogelstein B . (1996). Genes Dev., 10, 1945–1952.

  • Reed JC . (1995). Curr. Opin. Oncol., 7, 541–546.

  • Ruas M and Peters G . (1998). Biochim. Biophys. Acta, 1378, F115–77.

  • Sandig V, Brand K, Herwig S, Lukas J, Bartek J and Strauss M . (1997). Nat. Med., 3, 313–319.

  • Selvakumaran M, Lin HK, Miyashita T, Wang HG, Krajewski S, Reed JC, Hoffman B and Liebermann D . (1994). Oncogene, 9, 1791–1798.

  • Serrano M, Hannon GJ and Beach D . (1993). Nature, 366, 704–707.

  • Sharpless NE, Bardeesy N, Lee KH, Carrasco D, Castrillon DH, Aguirre AJ, Wu EA, Horner JW and DePinho RA . (2001). Nature, 413, 86–91.

  • Sorenson CM and Eastman A . (1988a). Cancer Res., 48, 6703–6707.

  • Sorenson CM and Eastman A . (1988b). Cancer Res., 48, 4484–4488.

  • Stone S, Dayananth P and Kamb A . (1996). Cancer Res., 56, 3199–3202.

  • Tamm I, Schumacher A, Karawajew L, Ruppert V, Arnold W, Nussler AK, Neuhaus P, Dorken B and Wolff G . (2002). Cancer Gene Ther., 9, 641–650.

  • Wyllie AH, Kerr JF and Currie AR . (1980). Int. Rev. Cytol., 68, 251–306.

  • Zamble DB, Jacks T and Lippard SJ . (1998). Proc. Natl. Acad. Sci. USA, 95, 6163–6168.

  • Zornig M, Hueber A, Baum W and Evan G . (2001). Biochim. Biophys. Acta, 1551, F1–F37.

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Acknowledgements

We are very grateful to Dr G Peters for kindly providing U2OS, EH1 and EH2 cell lines. We are also very thankful to Dr NE Sharpless and RA DePinho for providing us with the MEFs. We also thank the research center administration at the KFSHandRC for their continuous support. This work was supported by the King Faisal Specialist Hospital and Research Center, under the RAC proposal # 990025.

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  1. King Faisal Specialist Hospital and Research Center, BMR, MBC # 03, PO Box 3354, Riyadh, 11211, Saudi Arabia

    Mai A Al-Mohanna, Pulicat S Manogaran, Zuha Al-Mukhalafi, Khaled A Al-Hussein & Abdelilah Aboussekhra

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  1. Mai A Al-Mohanna
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  2. Pulicat S Manogaran
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Correspondence to Abdelilah Aboussekhra.

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Al-Mohanna, M., Manogaran, P., Al-Mukhalafi, Z. et al. The tumor suppressor p16INK4a gene is a regulator of apoptosis induced by ultraviolet light and cisplatin. Oncogene 23, 201–212 (2004). https://doi.org/10.1038/sj.onc.1206927

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