Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Low p21Waf1/Cip1 protein level sensitizes testicular germ cell tumor cells to Fas-mediated apoptosis

Oncogene volume 23, pages 4862–4872 (2004)Cite this article

Abstract

In the present study, we investigated the relation between p21 expression and the sensitivity of testicular germ cell tumor (TGCT) cells to apoptotic stimuli. Despite similar cisplatin-induced wild-type p53 accumulation, the TGCT cell lines Tera and Scha expressed low p21 protein and mRNA levels in comparison to A2780 ovarian cancer cells. Inhibition of the proteasome complex with MG-132 increased p21 protein levels in TGCT cells but much more in A2780 cells, whereas cisplatin had no additional effect on p21 protein levels. Inhibition of caspase-3 activity in TGCT cells with the broad-spectrum caspase inhibitor zVAD-fmk had no effect on p21 levels and also not upon cisplatin treatment. A similar induction of p53 irradiation, in contrast to cisplatin, substantially increased both p21 mRNA and protein expression in Tera cells. Cisplatin-treated Tera cells expressing low p21 protein levels were Fas-sensitive, while irradiation-induced p21, which was mainly localized in the cytosol, rendered irradiated Tera cells resistant to Fas-induced apoptosis. Sensitivity of irradiated Tera cells to Fas-induced apoptosis was restored by short interfering RNA-specific suppression of p21 expression. These results strongly indicate that the low p21 protein levels are caused by reduced p21 gene transcription and sensitize cisplatin-treated TGCT cells to the Fas death pathway.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  • Agami R, Blandino G, Oren M and Shaul Y . (1999). Nature, 399, 809–813.

  • Agarwal ML, Taylor WR, Chernov MV, Chernova OB and Stark GR . (1998). J. Biol. Chem., 273, 1–4.

  • Arriola EL, Rodriguez-Lopez AM, Hickman JA and Chresta CM . (1999). Oncogene, 18, 1457–1464.

  • Asada M, Yamada T, Ichijo H, Delia D, Miyazono K, Fukumuro K and Mizutani S . (1999). EMBO J., 18, 1223–1234.

  • Bartkova J, Thullberg M, Rajpert-de Meyts E, Skakkebaek NE and Bartek J . (2000). Int. J. Cancer, 85, 370–375.

  • Burger H, Nooter K, Boersma AW, Kortland CJ and Stoter G . (1997). Int. J. Cancer, 73, 592–599.

  • Burger H, Nooter K, Boersma AW, Kortland CJ and Stoter G . (1998a). Br. J. Cancer, 77, 1562–1567.

  • Burger H, Nooter K, Boersma AW, Kortland CJ, van den Berg AP and Stoter G . (1998b). Int. J. Radiat. Oncol. Biol. Phys., 41, 415–424.

  • Burger H, Nooter K, Boersma AW, van Wingerden KE, Looijenga LH, Jochemsen AG and Stoter G . (1999). Int. J. Cancer, 81, 620–628.

  • Butz K, Geisen C, Ullmann A, Zentgraf H and Hoppe-Seyler F . (1998). Oncogene, 17, 781–787.

  • Chang HY, Nishitoh H, Yang X, Ichijo H and Baltimore D . (1998). Science, 281, 1860–1863.

  • Charette SJ, Lavoie JN, Lambert H and Landry J . (2000). Mol. Cell Biol., 20, 7602–7612.

  • Chresta CM, Masters JR and Hickman JA . (1996). Cancer Res., 56, 1834–1841.

  • Cram EJ, Ramos RA, Wang EC, Cha HH, Nishio Y and Firestone GL . (1998). J. Biol. Chem., 273, 2008–2014.

  • Datta MW, Macri E, Signoretti S, Renshaw AA and Loda M . (2001). Mod. Pathol., 14, 437–442.

  • De Jong S, Timmer-Bosscha H, de Vries EG and Mulder NH . (1993). Int. J. Cancer, 53, 110–117.

  • De Jong S, van Zanten J, Dam WA, Mulder NH and de Vries EG . (1999). Proc. Am. Assoc. Cancer Res., 40, 4588.

  • Deveraux QL, Leo E, Stennicke HR, Welsh K, Salvesen GS and Reed JC . (1999). EMBO J., 18, 5242–5251.

  • Deverman BE, Cook BL, Manson SR, Niederhoff RA, Langer EM, Rosova I, Kulans LA, Fu X, Weinberg JS, Heinecke JW, Roth KA and Weintraub SJ . (2002). Cell, 111, 51–62.

  • Dijkhuizen T, Van den Berg E, Van den Berg A, Storkel S, De Jong B, Seitz G and Henn W . (1996). Int. J. Cancer, 68, 47–50.

  • Einhorn LH . (2002). Proc. Natl. Acad. Sci. USA, 99, 4592–4595.

  • El-Deiry WS, Harper JW, O’Connor PM, Velculescu VE, Canman CE, Jackman J, Pietenpol JA, Burrell M, Hill DE, Wang Y, Wiman KG, Mercer WE, Kastan MB, Kohn KW, Elledge SJ, Kinzler KW and Vogelstein B . (1994). Cancer Res., 54, 1169–1174.

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

  • Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K and Tuschl T . (2001a). Nature, 411, 494–498.

  • Elbashir SM, Lendeckel W and Tuschl T . (2001b). Genes Dev., 15, 188–200.

  • Fillippovich I, Sorokina N, Gatei M, Haupt Y, Hobson K, Moallem E, Spring K, Mould M, McGuckin MA, Lavin MF and Khanna KK . (2001). Oncogene, 20, 514–522.

  • Fulda S, Scaffidi C, Pietsch T, Krammer PH, Peter ME and Debatin KM . (1998). Cell Death Differ., 5, 884–893.

  • Gervais JL, Seth P and Zhang H . (1998). J. Biol. Chem., 273, 19207–19212.

  • Glaser T, Wagenknecht B and Weller M . (2001). Oncogene, 20, 4757–4767.

  • Gong JG, Costanzo A, Yang HQ, Melino G, Kaelin Jr WG, Levrero M and Wang JY . (1999). Nature, 399, 806–809.

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

  • Greenblatt MS, Bennett WP, Hollstein M and Harris CC . (1994). Cancer Res., 54, 4855–4878.

  • Grob TJ, Novak U, Maisse C, Barcaroli D, Luthi AU, Pirnia F, Hugli B, Graber HU, De LV, Fey MF, Melino G and Tobler A . (2001). Cell Death Differ., 8, 1213–1223.

  • Guillou L, Estreicher A, Chaubert P, Hurlimann J, Kurt AM, Metthez G, Iggo R, Gray AC, Jichlinski P, Leisinger HJ and Benhattar J . (1996). Am. J. Pathol., 149, 1221–1228.

  • Hara S, Miyake H, Nakamura I, Arakawa S, Kamidono S and Hara I . (2001). Urology, 58, 471–476.

  • Hiyama H, Iavarone A and Reeves SA . (1998). Oncogene, 16, 1513–1523.

  • Houldsworth J, Xiao H, Murty VV, Chen W, Ray B, Reuter VE, Bosl GJ and Chaganti RS . (1998). Oncogene, 16, 2345–2349.

  • Huddart RA, Titley J, Robertson D, Williams GT, Horwich A and Cooper CS . (1995). Eur. J. Cancer, 31A, 739–746.

  • Johnstone RW . (2002). Mol. Cell, 10, 695–697.

  • Kersemaekers AM, Mayer F, Molier M, van Weeren PC, Oosterhuis JW, Bokemeyer C and Looijenga LH . (2002a). J. Clin. Oncol., 20, 1551–1561.

  • Kersemaekers AM, van Weeren PC, Oosterhuis JW and Looijenga LH . (2002b). J. Pathol., 196, 423–429.

  • Kimura K and Gelmann EP . (2000). J. Biol. Chem., 275, 8610–8617.

  • Ko YG, Kang YS, Park H, Seol W, Kim J, Kim T, Park HS, Choi EJ and Kim S . (2001). J. Biol. Chem., 276, 39103–39106.

  • Levine AJ . (1997). Cell, 88, 323–331.

  • Levkau B, Koyama H, Raines EW, Clurman BE, Herren B, Orth K, Roberts JM and Ross R . (1998). Mol. Cell, 1, 553–563.

  • Levrero M, De LV, Costanzo A, Gong J, Wang JY and Melino G . (2000). J. Cell Sci., 113 (Part 10), 1661–1670.

  • Lundberg AS and Weinberg RA . (1999). Eur. J. Cancer, 35, 1886–1894.

  • Lutzker SG . (1998). APMIS, 106, 85–89.

  • Lutzker SG, Mathew R and Taller DR . (2001). Oncogene, 20, 2982–2986.

  • Malashicheva AB, Kislyakova TV, Aksenov ND, Osipov KA and Pospelov VA . (2000). Oncogene, 19, 3858–3865.

  • Masters JR, Osborne EJ, Walker MC and Parris CN . (1993). Int. J. Cancer, 53, 340–346.

  • Michieli P, Chedid M, Lin D, Pierce JH, Mercer WE and Givol D . (1994). Cancer Res., 54, 3391–3395.

  • Naujokat C and Hoffmann S . (2002). Lab. Invest., 82, 965–980.

  • Ogawa Y, Nishioka A, Kubonishi II, Inomata T, Yoshida S and Kataoka S . (1998). Int. J. Mol. Med., 2, 435–436.

  • Prives C and Hall PA . (1999). J. Pathol., 187, 112–126.

  • Riou G, Barrois M, Prost S, Terrier MJ, Theodore C and Levine AJ . (1995). Mol. Carcinog., 12, 124–131.

  • Sark MW, Timmer-Bosscha H, Meijer C, Uges DR, Sluiter WJ, Peters WH, Mulder NH and de Vries EG . (1995). Br. J. Cancer, 71, 684–690.

  • Scaffidi C, Schmitz I, Krammer PH and Peter ME . (1999). J. Biol. Chem., 274, 1541–1548.

  • Schepers H, Geugien M, Eggen BJL and Vellenga E . (2003). Leukemia, 17, 2113–2121.

  • Sheard MA, Krammer PH and Zaloudik J . (1999). Br. J. Cancer, 80, 1689–1696.

  • Shen Y and White E . (2001). Adv. Cancer Res., 82, 55–84.

  • Skilling JS, Squatrito RC, Connor JP, Niemann T and Buller RE . (1996). Gynecol. Oncol., 60, 72–80.

  • Snowden AW, Anderson LA, Webster GA and Perkins ND . (2000). Mol. Cell. Biol., 20, 2676–2686.

  • Somasundaram K, Zhang H, Zeng YX, Houvras Y, Peng Y, Zhang H, Wu GS, Licht JD, Weber BL and El-Deiry WS . (1997). Nature, 389, 187–190.

  • Spierings DCJ, de Vries EGE, Vellenga E and de Jong S . (2003a). Cell Death Differ., 10, 808–822.

  • Spierings DCJ, de Vries EGE, Vellenga E and de Jong S . (2003b). J. Pathol., 200, 137–148.

  • Stiewe T, Theseling CC and Putzer BM . (2002). J. Biol. Chem., 277, 14177–14185.

  • Sugihara A, Saiki S, Tsuji M, Tsujimura T, Nakata Y, Kubota A, Kotake T and Terada N . (1997). Anticancer Res., 17, 3861–3865.

  • Suzuki A, Ito T, Kawano H, Hayashida M, Hayasaki Y, Tsutomi Y, Akahane K, Nakano T, Miura M and Shiraki K . (2000a). Oncogene, 19, 1346–1353.

  • Suzuki A, Kawano H, Hayashida M, Hayasaki Y, Tsutomi Y and Akahane K . (2000b). Cell Death Differ., 7, 721–728.

  • Suzuki A, Tsutomi Y, Yamamoto N, Shibutani T and Akahane K . (1999). Mol. Cell Biol., 19, 3842–3847.

  • Tsai KKC and Yuan ZM . (2003). Cancer Res., 63, 3418–3424.

  • Vikhanskaya F, D’Incalci M and Broggini M . (2000). Nucleic Acids Res., 28, 513–519.

  • Xiang H, Fox JA, Totpal K, Aikawa M, Dupree K, Sinicropi D, Lowe J and Escandon E . (2002). Oncogene, 21, 3611–3619.

  • Xu SQ and El-Deiry WS . (2000). Biochem. Biophys. Res. Commun., 269, 179–190.

  • Zaika AI, Slade N, Erster SH, Sansome C, Joseph TW, Pearl M, Chalas E and Moll UM . (2002). J. Exp. Med., 196, 765–780.

  • Zeng YX, Somasundaram K and El-Deiry WS . (1997). Nat. Genet., 15, 78–82.

  • Zhang Y, Fujita N and Tsuruo T . (1999). Oncogene, 18, 1131–1138.

Download references

Acknowledgements

This study was supported by a grant from the Therapeutic Proteins for Chronic Diseases program of the University of Groningen, and by Grant RUG 99-1880 from the Dutch Cancer Society.

Author information

Authors and Affiliations

  1. Department of Medical Oncology, University Hospzital Groningen, Groningen, 9713 GZ, The Netherlands

    Diana C J Spierings, Elisabeth G E de Vries, Alja J Stel, Nelina te Rietstap & Steven de Jong

  2. Department of Hematology, University Hospital Groningen, Groningen, 9713 GZ, The Netherlands

    Diana C J Spierings & Edo Vellenga

Authors
  1. Diana C J Spierings
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elisabeth G E de Vries
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alja J Stel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nelina te Rietstap
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Edo Vellenga
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Steven de Jong
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Steven de Jong.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Spierings, D., de Vries, E., Stel, A. et al. Low p21Waf1/Cip1 protein level sensitizes testicular germ cell tumor cells to Fas-mediated apoptosis. Oncogene 23, 4862–4872 (2004). https://doi.org/10.1038/sj.onc.1207617

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207617

Keywords

This article is cited by

Search

Advanced search

Quick links