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.

  • Oncogenomics
  • Published:

Global transcriptional program of p53 target genes during the process of apoptosis and cell cycle progression

Oncogene volume 22, pages 3645–3654 (2003)Cite this article

Abstract

The temporal gene expression profile during the entire process of apoptosis and cell cycle progression in response to p53 in human ovarian cancer cells was explored with cDNA microarrays representing 33 615 individual human genes. A total of 1501 genes (4.4%) were found to respond to p53 (approximately 80% of these were repressed by p53) using 2.5-fold change as a cutoff. It was anticipated that most of p53 responsive genes resulted from the secondary effect of p53 expression at late stage of apoptosis. To delineate potential p53 direct and indirect target genes during the process of apoptosis and cell cycle progression, microarray data were combined with global p53 DNA-binding site analysis. Here we showed that 361 out of 1501 p53 responsive genes contained p53 consensus DNA-binding sequence(s) in their regulatory region, approximately 80% of which were repressed by p53. This is the first time that a large number of p53-repressed genes have been identified to contain p53 consensus DNA-binding sequence(s) in their regulatory region. Hierarchical cluster analysis of these genes revealed distinct temporal expression patterns of transcriptional activation and repression by p53. More genes were activated at early time points, while more repressed genes were found after the onset of apoptosis. A small-scale quantitative chromatin immunoprecipitation analysis indicated that in vivo p53–DNA interaction was detected in eight out of 10 genes, most of which were repressed by p53 at the early onset of apoptosis, suggesting that a portion of p53 target genes in the human genome could be negatively regulated by p53 via sequence-specific DNA binding. The approaches and genes described here should aid the understanding of global gene regulatory network of p53.

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

Similar content being viewed by others

Abbreviations

rAd-p53:

adenovirus expressing p53

rAd-p21:

adenovirus expressing p21WAF1/Cip1

rAd-empty vector:

adenovirus containing an empty vector

ChIP:

chromatin immunoprecipitation

RT–PCR:

reverse transcription PCR

EF:

enrichment factor

References

  • Agoff SN, Hou J, Linzer DI and Wu B . (1993). Science, 259, 84–87.

  • Borellini F and Glazer R . (1993). J. Biol. Chem., 268, 7923–7928.

  • Buckbinder I, Talbott R, Velasco-Miguel S, Takenaka I, Faha B, Selzinger BR and Kley N . (1995). Nature, 377, 646–649.

  • Budhram-Mahadeo V, Morris PJ, Smith MD, Midgley CA, Boxer LM and Latchman DS . (1999). J. Biol. Chem., 274, 15237–15244.

  • DeRisi JL, Iyer VR and Brown PO . (1997). Science, 278, 680.

  • Desdouets C, Ory C, Matesic G, Soussi T, Brechot C and Sobczak-Thepot J . (1996). FEBS Lett, 385, 34–38.

  • Eisen MB, Spellman PT, Brown PO and Botstein D . (1998). Proc. Nat. Acad. Sci. USA, 95, 14863–14868.

  • El-Deiry WS, Kern SE, Pietenpol JA, Kinzler KW and Vogelstein B . (1992). Nat Genet, 1, 45–49.

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

  • Gerke V and Moss SE . (2002). Physiol. Rev., 82, 331–371.

  • Gopalkrishnan RV, Lam EW-F and Kedinger C . (1998). J. Biol. Chem., 273, 10972–10978.

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

  • Hollander MC, Alamo I, Jackman J, Wang MG, McBride OW and Fornace Jr AJ . (1993). J. Biol. Chem., 268, 24385–24393.

  • Johnson RA, Ince TA and Scotto KW . (2001). J. Biol. Chem., 276, 27716–27720.

  • Juven T, Barak Y, Zauberman A, George DL and Oren M . (1993). Oncogene, 8, 3411–3416.

  • Kaluzova M, Pastorekova S, Pastorek J and Kaluz S . (2000). Biochim. Biophys. Acta, 1491, 20–26.

  • Krause K, Wasner M, Reinhard W, Haugwitz U, Dohna CL, Mossner J and Engeland K . (2000). Nucleic Acid Res., 28, 4410–4418.

  • Lee KC, Crowe AJ and Barton MC . (1999). Mol. Cell. Biol., 19, 1279–1288.

  • Liu X, Miller CW, Koeffler PH and Berk AJ . (1993). Mol. Cell. Biol., 13, 3291–3300.

  • Lu H and Levine AJ . (1995). Proc. Natl. Acad. Sci. USA, 92, 5154–5158.

  • Ludes-Meyers JH, Subler MA, Shivakumar CV, Munoz RM, Jiang P, Bigger JE, Brown DR, Deb SP and Deb S . (1996). Mol. Cell. Biol., 16, 6009–6019.

  • Madden SL, Galella EA, Zhu J, Bertelsen AH and Beaudry GA . (1997). Oncogene, 15, 1079–1085.

  • Maiyar AC, Phu PT, Huang AJ and Firestone GL . (1997). Mol. Endocrinol., 11, 312–329.

  • Maxwell S and Davis GE . (2000). Proc. Natl. Acad. Sci. USA, 97, 13009–13014.

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

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

  • Morris GF, Bischoff JR and Mathews MB . (1996). Proc. Natl. Acad. Sci., 93, 895–899.

  • Murphy M, Ahn J, Walker KK, Hoffman WH, Evans RM, Levine AJ and George DL . (1999). Genes Dev., 13, 2490–2501.

  • Ori A, Zauberman A, Doitsh G, Paran N, Oren M and Shaul Y . (1998). EMBO J., 17, 544–553.

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

  • Seto E, Usheva A, Zambetti GP, Momand J, Horikoshi N, Weinmann R, Levine AJ and Shenk T . (1992). Proc. Natl. Acad. Sci. USA, 89, 12028–12032.

  • Thompson EB . (1998). Ann. Rev. Physiol., 60, 525–532.

  • Tokino T, Thiagalingam S, El-Deiry WS, Waldman T, Kinzler KW and Vogelstein B . (1994). Hum. Mol. Genet., 3, 1537–1542.

  • Vogelstein B and Levine AJ . (2000). Nature, 408, 307–310.

  • 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, Xie L, McDonald M, DiGiacomo R, Chang A, Gurnani M, Shi B, Liu S, Indelicato SR, Hutchins B and Nielsen LL . (2000). Cancer Gene Ther., 7, 1469–1479.

  • Wu Q, Kirschmeier P, Hockenberry T, Yang T-Y, Brassard DL, Wang L, McClanahan T, Black S, Rizzi G, Musco-Hobkinson ML, Mirza A and Liu S . (2002). J. Biol. Chem., 277, 36329–36337.

  • Yu J, Zhang L, Hwang PM, Rago C, Kinzer KW and Vogelstein B . (1999). Proc. Natl. Acad. Sci. USA, 96, 14517–14522.

  • Yue H, Eastman PS, Wang BB, Minor J, Doctolero MH, Nuttall RL, Stack R, Becker JW, Montgomery JR, Vainer M and Johnston R . (2001). Nulceic Acid Res., 29, E41–1.

  • 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

Author information

Author notes

  1. Asra Mirza and Qun Wu: These authors equally contributed to this work

Authors and Affiliations

  1. Tumor Biology Department, Schering-Plough Research Institute, 2015 Galloping Hill Road, K-15-4 (4600), Kenilworth, 07033, NJ, USA

    Asra Mirza, Qun Wu, W Robert Bishop, Tish Hockenberry, Paul Kirschmeier & Suxing Liu

  2. Human Genomic Research Department, Schering-Plough Research Institute, 2015 Galloping Hill Road, K-15-4 (4600), Kenilworth, 07033, NJ, USA

    Luquan Wang, Wei Ding & Jonathan R Greene

  3. DNAX Research Institute, 901 California Ave, Palo Alto, 94304, CA, USA

    Terri McClanahan

  4. Biostatistics Group, Schering-Plough Research Institute, 2015 Galloping Hill Road, K-15-4 (4600), Kenilworth, 07033, NJ, USA

    Ferdous Gheyas

  5. Canji Inc., 3525 Johns Hopkins Court, San Diego, 92121, CA, USA

    Beth Hutchins

Authors
  1. Asra Mirza
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qun Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Luquan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Terri McClanahan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. W Robert Bishop
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ferdous Gheyas
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wei Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Beth Hutchins
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tish Hockenberry
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Paul Kirschmeier
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jonathan R Greene
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Suxing Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Suxing Liu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mirza, A., Wu, Q., Wang, L. et al. Global transcriptional program of p53 target genes during the process of apoptosis and cell cycle progression. Oncogene 22, 3645–3654 (2003). https://doi.org/10.1038/sj.onc.1206477

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1206477

Keywords

This article is cited by

Search

Advanced search

Quick links