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:

Mutation at p53 serine 389 does not rescue the embryonic lethality in mdm2 or mdm4 null mice

Oncogene volume 23, pages 7644–7650 (2004)Cite this article

Abstract

Mdm2 and its homolog Mdm4 inhibit the function of the tumor suppressor p53. Targeted disruption of either mdm2 or mdm4 genes in mice results in embryonic lethality that is completely rescued by concomitant deletion of p53, suggesting that deletion of negative regulators of p53 results in a constitutively active p53. Thus, these mouse models offer a unique in vivo system to assay the functional significance of different p53 modifications. Phosphorylation of serine 389 in murine p53 occurs specifically after ultraviolet-light-induced DNA damage, and phosphorylation of this site enhances p53 activity both in vitro and in vivo. Recently, mice with a serine to alanine substitution at serine 389 (p53S389A) in the endogenous p53 locus were generated. To examine the in vivo significance of serine 389 phosphorylation during embryogenesis, we crossed these mutant mice to mice lacking mdm2 or mdm4. The p53S389A allele did not alter the embryonic lethality of mdm2 or mdm4. Additional crosses to assay the effect of one p53S389A allele with a p53 null allele also did not rescue the lethal phenotypes. In conclusion, the phenotypes due to loss of mdm2 or mdm4 were not even partially rescued by p53S389A, suggesting that p53S389A is functionally wild type during embryogenesis.

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

References

  • Achison M and Hupp TR . (2003). Oncogene, 228, 3431–3440.

  • Appella E and Anderson CW . (2001). Eur. J. Biochem., 268, 2764–2772.

  • Ashcroft M, Kubbutat MH and Vousden KH . (1999). Mol. Cell. Biol., 19, 1751–1758.

  • Avantaggiati ML, Ogryzko V, Gardner K, Giordano A, Levine AS and Kelly K . (1997). Cell, 89, 1175–1184.

  • Blattner C, Tobiasch E, Litfen M, Rahmsdorf HJ and Herrlich P . (1999). Oncogene, 18, 1723–1732.

  • Bottger V, Bottger A, Garcia-Echeverria C, Ramos YF, van der Eb AJ, Jochemsen AG and Lane DP . (1999). Oncogene, 18, 189–199.

  • Bruins W, Zwart E, Attardi LD, Iwakuma T, Hoogervorst EM, Beems RB, Miranda B, van Oostrom CTM, van den Berg J, van den Aardweg GJ, Lozano G, van Steeg H, Jacks T and de Vries A . (2004). Mol. Cell. Biol. (in press).

  • Chao C, Saito S, Anderson CW, Appella E and Xu Y . (2000). Proc. Natl. Acad. Sci. USA, 97, 11936–11941.

  • Chavez-Reyes A, Parant JM, Amelse LL, Montes de Oca Luna R, Korsmeyer SJ and Lozano G . (2003). Cancer Res., 63, 8664–8669.

  • Chen J, Marechal V and Levine AJ . (1993). Mol. Cell. Biol., 13, 4107–4114.

  • Chen J, Wu X, Lin J and Levine AJ . (1996). Mol. Cell. Biol., 16, 2445–2452.

  • Cho Y, Gorina S, Jeffrey PD and Pavletich NP . (1994). Science, 265, 346–355.

  • Clarke AR, Purdie CA, Harrison DJ, Morris RG, Bird CC, Hooper ML and Wyllie AH . (1993). Nature, 362, 849–852.

  • de Rozieres S, Maya R, Oren M and Lozano G . (2000). Oncogene, 19, 1691–1697.

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

  • Finch RA, Donoviel DB, Potter D, Shi M, Fan A, Freed DD, Wang CY, Zambrowicz BP, Ramirez-Solis R, Sands AT and Zhang N . (2002). Cancer Res., 62, 3221–3225.

  • Fiscella M, Zambrano N, Ullrich SJ, Unger T, Lin D, Cho B, Mercer WE, Anderson CW and Appella E . (1994). Oncogene, 9, 3249–3257.

  • Furihata M, Kurabayashl A, Matsumoto M, Sonobe H, Ohtsuki Y, Terao N, Kuwahara M and Shuin T . (2002). J. Pathol., 197, 82–88.

  • Hao M, Kapoor M, Deffie A, Liu G and Lozano G . (1996). J. Biol. Chem., 271, 29380–29385.

  • Harvey M, Sands AT, Weiss RS, Hegi ME, Wiseman RW, Pantazis P, Giovanella BC, Tainsky MA, Bradley A and Donehower LA . (1993). Oncogene, 8, 2457–2467.

  • Hupp TR and Lane DP . (1994a). Curr. Biol., 4, 865–875.

  • Hupp TR and Lane DP . (1994b). Cold Spring Harb. Symp. Quant. Biol., 59, 195–206.

  • Hupp TR and Lane DP . (1995). J. Biol. Chem., 270, 18165–18174.

  • Itahana K, Dimri GP, Hara E, Itahana Y, Zou Y, Desprez PY and Campisi J . (2002). J. Biol. Chem., 277, 18206–18214.

  • Jacks T, Remington L, Williams BO, Schmitt EM, Halachmi S, Bronson RT and Weinberg RA . (1994). Curr. Biol., 4, 1–7.

  • Jones SN, Roe AE, Donehower LA and Bradley A . (1995). Nature, 378, 206–208.

  • Kapoor M and Lozano G . (1998). Proc. Natl. Acad. Sci. USA, 95, 2834–2837.

  • Keller DM, Zeng X, Wang Y, Zhang QH, Kapoor M, Shu H, Goodman R, Lozano G, Zhao Y and Lu H . (2001). Mol. Cell, 7, 283–292.

  • Lakin ND and Jackson SP . (1999). Oncogene, 18, 7644–7655.

  • Lee CW, Sorensen TS, Shikama N and La Thangue NB . (1998). Oncogene, 16, 2695–2710.

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

  • Lowe SW . (1999). Endocr. Relat. Cancer, 6, 45–48.

  • Lowe SW, Schmitt EM, Smith SW, Osborne BA and Jacks T . (1993). Nature, 362, 847–849.

  • Lu H, T Y, Ikeda M and Levine AJ . (1998). Proc. Natl. Acad. Sci. USA, 95, 6399–6402.

  • Migliorini D, Denchi EL, Danovi D, Jochemsen A, Capillo M, Gobbi A, Helin K, Pelicci PG and Marine JC . (2002). Mol. Cell. Biol., 22, 5527–5538.

  • Miller M, Lubkowski J, Rao JK, Danishefsky AT, Omichinski JG, Sakaguchi K, Sakamoto H, Appella E, Gronenborn AM and Clore GM . (1996). FEBS Lett., 399, 166–170.

  • Milne DM, Palmer RH and Meek DW . (1992). Nucleic Acids Res., 20, 5565–5570.

  • Montes de Oca Luna R, Wagner DS and Lozano G . (1995). Nature, 378, 203–206.

  • Parant J, Chavez-Reyes A, Little NA, Yan W, Reinke V, Jochemsen AG and Lozano G . (2001). Nat. Genet., 29, 92–95.

  • Parant JM and Lozano G . (2003). Hum. Mutat., 21, 321–326.

  • Pellegata NS, Cajot JF and Stanbridge EJ . (1995). Oncogene, 11, 337–349.

  • Pietenpol JA, Tokino T, Thiagalingam S, el-Deiry WS, Kinzler KW and Vogelstein B . (1994). Proc. Natl. Acad. Sci. USA, 91, 1998–2002.

  • Rolley N and Milner J . (1994). Oncogene, 9, 3067–3070.

  • Sakaguchi K, Sakamoto H, Lewis MS, Anderson CW, Erickson JW, Appella E and Xie D . (1997). Biochemistry, 36, 10117–10124.

  • Sayed M, Kim SO, Salh BS, Issinger OG and Pelech SL . (2000). J. Biol. Chem., 275, 16569–16573.

  • Shieh SY, Taya Y and Prives C . (1999). EMBO J., 18, 1815–1823.

  • Shikama N, Lee CW, France S, Delavaine L, Lyon J, Krstic-Demonacos M and La Thangue NB . (1999). Mol. Cell, 4, 365–376.

  • Shvarts A, Bazuine M, Dekker P, Ramos YF, Steegenga WT, Merckx G, van Ham RC, van der Houven van Oordt W, van der Eb AJ and Jochemsen AG . (1997). Genomics, 43, 34–42.

  • Shvarts A, Steegenga WT, Riteco N, van Laar T, Dekker P, Bazuine M, van Ham RC, van der Houven van Oordt W, Hateboer G, van der Eb AJ and Jochemsen AG . (1996). EMBO J., 15, 5349–5357.

  • Sluss HK, Armata H, Gallant J and Jones SN . (2004). Mol. Cell. Biol., 24, 976–984.

  • Unger T, Juven-Gershon T, Moallem E, Berger M, Vogt Sionov R, Lozano G, Oren M and Haupt Y . (1999). EMBO J., 18, 1805–1814.

  • Venkatachalam S, Shi YP, Jones SN, Vogel H, Bradley A, Pinkel D and Donehower LA . (1998). EMBO J., 17, 4657–4667.

  • Wiederschain D, Gu J and Yuan ZM . (2001). J. Biol. Chem., 276, 27999–28005.

  • Wu Z, Earle J, Saito S, Anderson CW, Appella E and Xu Y . (2002). Mol. Cell. Biol., 22, 2441–2449.

Download references

Acknowledgements

We thank Mini Kapoor and Brandon M Greenberg for helpful discussions, and Arlette Audiffred and Lisa C Caldwell for genotyping of mice. We also thank the department of scientific publications in MD Anderson Cancer Center for editing the manuscript. This work is supported by a grant from the NIH (CA47296) to GL.

Author information

Authors and Affiliations

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

    Tomoo Iwakuma, John M Parant, Mark Fasulo Jr & Guillermina Lozano

  2. Laboratory of Toxicology, Pathology and Genetics, National Institute of Public Health and The Environment, 3720 BA Bilthoven, The Netherlands

    Edwin Zwart & Annemieke de Vries

  3. Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, 02139, MA, USA

    Tyler Jacks

Authors
  1. Tomoo Iwakuma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John M Parant
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mark Fasulo Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Edwin Zwart
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tyler Jacks
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Annemieke de Vries
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Guillermina Lozano
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Guillermina Lozano.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Iwakuma, T., Parant, J., Fasulo, M. et al. Mutation at p53 serine 389 does not rescue the embryonic lethality in mdm2 or mdm4 null mice. Oncogene 23, 7644–7650 (2004). https://doi.org/10.1038/sj.onc.1207793

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207793

Keywords

This article is cited by

Search

Advanced search

Quick links