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:

A comprehensive assessment of p53-responsive genes following adenoviral-p53 gene transfer in Bcl-2-expressing prostate cancer cells

Oncogene volume 23, pages 1712–1723 (2004)Cite this article

Abstract

The p53 protein can induce cell cycle arrest or apoptosis following activation in response to DNA damage. The function of p53 is largely mediated by regulating the expression of downstream target genes. Adenoviral-p53 gene transfer (Ad-p53) is currently being evaluated in clinical trials as a therapeutic intervention. Tumor response is likely to be influenced by context-dependent variables, such as expression of bcl-2. Bcl-2 is upregulated in a variety of neoplasms, and can inhibit p53-dependent apoptosis. It was therefore of interest to use a global genomic strategy to assess gene expression following Ad-p53 gene transfer and to determine if the expression of specific Ad-p53-responsive genes could be modulated in the context of bcl-2 gene deregulation. cDNA arrays were used to identify p53-responsive genes following Ad-p53 gene transfer in control and bcl-2-overexpressing PC3 prostate cancer cells. A total of 40 transcripts were significantly upregulated by Ad-p53 in both control and bcl-2-transfectant PC3 cells. Conversely, 19 transcripts were significantly repressed in both cell lines. These Ad-p53-responsive transcripts included previously identified p53 targets, known genes representing candidate p53 targets, and transcripts identified as expressed sequence tags. A subset of 15 transcripts was differentially modulated by Ad-p53 in the context of bcl-2. Some of these genes were also differentially modulated in LNCaP (wt p53) cells following DNA damage. These results document a number of potential p53 targets and mediators of therapeutically relevant genotoxic stress. The findings further suggest that bcl-2 may inhibit cell death at multiple points downstream of p53 activation.

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

Similar content being viewed by others

References

  • Adams JM and Cory S . (1998). Science, 281, 1322–1326.

  • Amstad PA, Liu H, Ichimiya M, Berezesky IK, Trump BF, Buhimschi IA and Gutierrez PL . (2001). Redox Rep., 6, 351–362.

  • Bartek J and Lukas J . (2001a). Curr. Opin. Cell Biol., 13, 738–747.

  • Bartek J and Lukas J . (2001b). Curr. Opin. Cell Biol., 13, 738–747.

  • Beham A, Marin MC, Fernandez A, Herrmann J, Brisbay S, Tari AM, Lopez-Berestein G, Lozano G, Sarkiss M and McDonnell TJ . (1997). Oncogene, 15, 2767–2772.

  • Beham AW, Sarkiss M, Brisbay S, Tu SM, von Eschenbach AC and McDonnell TJ . (1998). Int. J. Mol. Med., 1, 953–959.

  • Boldin MP, Mett IL and Wallach D . (1995). FEBS Lett., 367, 39–44.

  • Bradford MM . (1976). Anal. Biochem., 72, 248–254.

  • Bruckheimer EM, Brisbay S, Johnson DJ, Gingrich JR, Greenberg N and McDonnell TJ . (2000). Oncogene, 19, 5251–5258.

  • Buzek J, Latonen L, Kurki S, Peltonen K and Laiho M . (2002). Nucleic Acids Res., 30, 2340–2348.

  • Caelles C, Helmberg A and Karin M . (1994). Nature, 370, 220–223.

  • Carroll AG, Voeller HJ, Sugars L and Gelmann EP . (1993). Prostate, 23, 123–134.

  • Chen J, Wu W, Tahir SK, Kroeger PE, Rosenberg SH, Cowsert LM, Bennett F, Krajewski S, Krajewska M, Welsh K, Reed JC and Ng SC . (2000). Neoplasia, 2, 235–241.

  • Chen SR, Dunigan DD and Dickman MB . (2003). Free Radic. Biol. Med., 34, 1315–1325.

  • Clayman GL, el-Naggar AK, Lippman SM, Henderson YC, Frederick M, Merritt JA, Zumstein LA, Timmons TM, Liu TJ, Ginsberg L, Roth JA, Hong WK, Bruso P and Goepfert H . (1998). J. Clin. Oncol., 16, 2221–2232.

  • Clayman GL, Frank DK, Bruso PA and Goepfert H . (1999). Clin. Cancer Res., 5, 1715–1722.

  • Ding HF, Lin YL, McGill G, Juo P, Zhu H, Blenis J, Yuan J and Fisher DE . (2000). J. Biol. Chem., 275, 38905–38911.

  • Dummer R, Bergh J, Karlsson Y, Horowitz JA, Mulder NH, Huinink DTB, Burg G, Hofbauer G and Osanto S . (2000). Cancer Gene Ther., 7, 1069–1076.

  • el-Deiry WS, Harper JW, O'Connor PM, Velculescu VE, Canman CE, Jackman J, Pietenpol JA, Burrell M, Hill DE and Wang Y et al. (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.

  • Fridovich I . (1986). Adv. Enzymol. Relat. Areas Mol. Biol., 58, 61–97.

  • Friedlander P, Haupt Y, Prives C and Oren M . (1996). Mol. Cell. Biol., 16, 4961–4971.

  • Fritsche M, Haessler C and Brandner G . (1993). Oncogene, 8, 307–318.

  • Froesch BA, Aime-Sempe C, Leber B, Andrews D and Reed JC . (1999). J. Biol. Chem., 274, 6469–6475.

  • Hainaut P and Milner J . (1993). Cancer Res., 53, 4469–4473.

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

  • Haupt Y, Rowan S, Shaulian E, Vousden KH and Oren M . (1995). Genes Dev., 9, 2170–2183.

  • Herrmann JL, Beham AW, Sarkiss M, Chiao PJ, Rands MT, Bruckheimer EM, Brisbay S and McDonnell TJ . (1997). Exp. Cell. Res., 237, 101–109.

  • Herrmann JL, Briones Jr. F, Brisbay S, Logothetis CJ and McDonnell TJ . (1998). Oncogene, 17, 2889–2899.

  • Hoffman WH, Biade S, Zilfou JT, Chen J and Murphy M . (2002). J. Biol. Chem., 277, 3247–3257.

  • Hoh J, Jin S, Parrado T, Edington J, Levine AJ and Ott J . (2002). Proc. Natl. Acad. Sci. USA, 99, 8467–8472.

  • Hollstein M, Rice K, Greenblatt MS, Soussi T, Fuchs R, Sorlie T, Hovig E, Smith-Sorensen B, Montesano R and Harris CC . (1994). Nucleic Acids Res., 22, 3551–3555.

  • Hollstein M, Sidransky D, Vogelstein B and Harris CC . (1991). Science, 253, 49–53.

  • Honda R, Tanaka H and Yasuda H . (1997). FEBS Lett., 420, 25–27.

  • Honda T, Kagawa S, Spurgers KB, Gjertsen BT, Roth JA, Fang B, Lowe SL, Norris JS, Meyn RE and McDonnell TJ . (2002). Cancer Biol. Ther., 1, 163–167.

  • Horoszewicz JS, Leong SS, Kawinski E, Karr JP, Rosenthal H, Chu TM, Mirand EA and Murphy GP . (1983). Cancer Res., 43, 1809–1818.

  • Huang P, Feng L, Oldham EA, Keating MJ and Plunkett W . (2000). Nature, 407, 390–395.

  • Introgen. (2003). BioDrugs, 17, 216–222.

  • Isaacs WB, Carter BS and Ewing CM . (1991). Cancer Res., 51, 4716–4720.

  • Jayaraman L and Prives C . (1999). Cell. Mol. Life. Sci., 55, 76–87.

  • Kaighn ME, Narayan KS, Ohnuki Y, Lechner JF and Jones LW . (1979). Invest. Urol., 17, 16–23.

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

  • Kovach JS, Hartmann A, Blaszyk H, Cunningham J, Schaid D and Sommer SS . (1996). Proc. Natl. Acad. Sci. USA, 93, 1093–1096.

  • Lane DP . (1992). Nature, 358, 15–16.

  • Lang FF, Bruner JM, Fuller GN, Aldape K, Prados MD, Chang S, Berger MS, McDermott MW, Kunwar SM, Junck LR, Chandler W, Zwiebel JA, Kaplan RS and Yung WK . (2003). J. Clin. Oncol., 21, 2508–2518.

  • Lennon G, Auffray C, Polymeropoulos M and Soares MB . (1996). Genomics, 33, 151–152.

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

  • Levine AJ, Momand J and Finlay CA . (1991). Nature, 351, 453–456.

  • Lowe S . (1999). Apoptosis and Cancer Chemotherapy, Vol. 2: Cancer Drug Discovery and Development. Hickman, JADC (ed) Humana Press Inc: Totowa, NJ, pp. 21–36.

  • Ludwig RL, Bates S and Vousden KH . (1996). Mol. Cell. Biol., 16, 4952–4960.

  • MacCarthy-Morrogh L, Mouzakiti A, Townsend P, Brimmell M and Packham G . (1999). Biochem. Soc. Trans., 27, 785–789.

  • Mailand N, Falck J, Lukas C, Syljuasen RG, Welcker M, Bartek J and Lukas J . (2000). Science, 288, 1425–1429.

  • Maltzman W and Czyzyk L . (1984). Mol. Cell. Biol., 4, 1689–1694.

  • Mano Y, Kikuchi Y, Yamamoto K, Kita T, Hirata J, Tode T, Ishii K and Nagata I . (1999). Eur. J. Cancer., 35, 1214–1219.

  • McDonnell TJ and Korsmeyer SJ . (1991). Nature, 349, 254–256.

  • Michael D and Oren M . (2002). Curr. Opin. Genet. Dev., 12, 53–59.

  • Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P and Moll UM . (2003). Mol. Cell., 11, 577–590.

  • Mirkovic N, Voehringer DW, Story MD, McConkey DJ, McDonnell TJ and Meyn RE . (1997). Oncogene, 15, 1461–1470.

  • Mirza A, McGuirk M, Hockenberry TN, Wu Q, Ashar H, Black S, Wen SF, Wang L, Kirschmeier P, Bishop WR, Nielsen LL, Pickett CB and Liu S . (2002). Oncogene, 21, 2613–2622.

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

  • Miyashita T and Reed JC . (1995). Cell, 80, 293–299.

  • Momand J, Zambetti GP, Olson DC, George D and Levine AJ . (1992). Cell, 69, 1237–1245.

  • Moul JW . (1999). Eur. Urol., 35, 399–407.

  • Munshi A, Pappas G, Honda T, McDonnell TJ, Younes A, Li Y and Meyn RE . (2001). Oncogene, 20, 3757–3765.

  • Murphy M, Hinman A and Levine AJ . (1996). Genes Dev., 10, 2971–2980.

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

  • Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T, Tokino T, Taniguchi T and Tanaka N . (2000a). Science, 288, 1053–1058.

  • Oda K, Arakawa H, Tanaka T, Matsuda K, Tanikawa C, Mori T, Nishimori H, Tamai K, Tokino T, Nakamura Y and Taya Y . (2000b). Cell, 102, 849–862.

  • Olie RA, Simoes-Wust AP, Baumann B, Leech SH, Fabbro D, Stahel RA and Zangemeister-Wittke U . (2000). Cancer Res., 60, 2805–2809.

  • Pagliaro LC . (2000). World J. Urol., 18, 148–151.

  • Pearson GD and Merrill GF . (1998). J. Biol. Chem., 273, 5431–5434.

  • Pirollo KF, Bouker KB and Chang EH . (2000). Anticancer Drugs, 11, 419–432.

  • Pollack A, Cowen D, Troncoso P, Zagars GK, von Eschenbach AC, Meistrich ML and McDonnell T . (2003). Cancer, 97, 1630–1638.

  • Polyak K, Xia Y, Zweier JL, Kinzler KW and Vogelstein B . (1997). Nature, 389, 300–305.

  • Rainwater R, Parks D, Anderson ME, Tegtmeyer P and Mann K . (1995). Mol. Cell. Biol., 15, 3892–3903.

  • Robles AI, Bemmels NA, Foraker AB and Harris CC . (2001). Cancer Res., 61, 6660–6664.

  • Rodriguez-Villanueva J, Greenhalgh D, Wang XJ, Bundman D, Cho S, Delehedde M, Roop D and McDonnell TJ . (1998). Oncogene, 16, 853–863.

  • Rubin SJ, Hallahan DE, Ashman CR, Brachman DG, Beckett MA, Virudachalam S, Yandell DW and Weichselbaum RR . (1991). J. Surg. Oncol., 46, 31–36.

  • Schuler M, Bossy-Wetzel E, Goldstein JC, Fitzgerald P and Green DR . (2000). J. Biol. Chem., 275, 7337–7342.

  • Schuler M and Green DR . (2001). Biochem. Soc. Trans., 29, 684–688.

  • Schumacher G, Bruckheimer EM, Beham AW, Honda T, Brisbay S, Roth JA, Logothetis C and McDonnell TJ . (2001). Int. J. Cancer, 91, 159–166.

  • Sheikh MS and Fornace Jr. AJ . (2000). Leukemia, 14, 1509–1513.

  • Shen Y and Shenk T . (1994). Proc. Natl. Acad. Sci. USA, 91, 8940–8944.

  • Soengas MS, Alarcon RM, Yoshida H, Giaccia AJ, Hakem R, Mak TW and Lowe SW . (1999). Science, 284, 156–159.

  • Swisher SG and Roth JA . (2002). Surg. Oncol. Clin. N. Am., 11, 521–535.

  • Tanaka K and Tsurumi C . (1997). Mol. Biol. Rep., 24, 3–11.

  • Troy CM and Shelanski ML . (1994). Proc. Natl. Acad. Sci. USA, 91, 6384–6387.

  • Voehringer DW . (1999). Free Radic. Biol. Med., 27, 945–950.

  • Voehringer DW, McConkey DJ, McDonnell TJ, Brisbay S and Meyn RE . (1998). Proc. Natl. Acad. Sci. USA, 95, 2956–2960.

  • Voehringer DW and Meyn RE . (2000). Antioxid. Redox. Signal., 2, 537–550.

  • Vousden KH and Lu X . (2002). Nat. Rev. Cancer, 2, 594–604.

  • Wagner AJ, Kokontis JM and Hay N . (1994). Genes Dev., 8, 2817–2830.

  • Wang L, Wu Q, Qiu P, Mirza A, McGuirk M, Kirschmeier P, Greene JR, Wang Y, Pickett CB and Liu S . (2001). J. Biol. Chem., 276, 43604–43610.

  • Wen SF, Mahavni V, Quijano E, Shinoda J, Grace M, Musco-Hobkinson ML, Yang TY, Chen Y, Runnenbaum I, Horowitz J, Maneval D, Hutchins B and Buller R . (2003). Cancer Gene Ther., 10, 224–238.

  • Zhan Q, Kontny U, Iglesias M, Alamo Jr. I, Yu K, Hollander MC, Woodworth CD and Fornace Jr. AJ . (1999). Oncogene, 18, 297–304.

  • Zhang WW, Alemany R, Wang J, Koch PE, Ordonez NG and Roth JA . (1995). Hum. Gene. Ther., 6, 155–164.

  • Zhang WW, Fang X, Mazur W, French BA, Georges RN and Roth JA . (1994). Cancer Gene Ther., 1, 5–13.

  • Zhao R, Gish K, Murphy M, Yin Y, Notterman D, Hoffman WH, Tom E, Mack DH and Levine AJ . (2000). Genes Dev., 14, 981–993.

Download references

Acknowledgements

This work was supported by NIH PO1 CA78778, P50 CA90270 and RO1 CA69003. Kevin Spurgers is supported by NIH training grant CA60440 and the American Legion Auxiliary Fellowship in Cancer Research.

Author information

Authors and Affiliations

  1. Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, 77030, TX, USA

    Kevin B Spurgers, Terry J Johnson & Timothy J McDonnell

  2. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, 77030, TX, USA

    Kevin R Coombes & David L Gold

  3. Department of Experimental Radiation Oncology,

    Raymond E Meyn

  4. Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, 77030, TX, USA

    Christopher J Logothetis

Authors
  1. Kevin B Spurgers
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kevin R Coombes
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Raymond E Meyn
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David L Gold
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Christopher J Logothetis
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Terry J Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Timothy J McDonnell
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Timothy J McDonnell.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Spurgers, K., Coombes, K., Meyn, R. et al. A comprehensive assessment of p53-responsive genes following adenoviral-p53 gene transfer in Bcl-2-expressing prostate cancer cells. Oncogene 23, 1712–1723 (2004). https://doi.org/10.1038/sj.onc.1207293

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207293

Keywords

This article is cited by

Search

Advanced search

Quick links