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Rescue of Mdm4-deficient mice by Mdm2 reveals functional overlap of Mdm2 and Mdm4 in development

Oncogene volume 24, pages 7935–7940 (2005)Cite this article

Abstract

The Mdm2 and Mdm4 genes are amplified and overexpressed in a variety of human cancers and encode structurally related oncoproteins that bind to the p53 tumor suppressor protein and inhibit p53 activity. Mice deleted for either Mdm2 or Mdm4 die during embryogenesis, and the developmental lethality of either mouse model can be rescued by concomitant deletion of p53. However, the phenotypes of Mdm2 and Mdm4-deficient mice suggest that Mdm2 and Mdm4 play nonoverlapping roles in regulating p53 activity during development, with Mdm2 regulating p53-mediated cell death and Mdm4 regulating p53-mediated inhibition of cell growth. Here, we describe complete rescue of Mdm4-deficient mice by expression of an Mdm2 transgene, and demonstrate that Mdm2 can regulate both p53-mediated apoptosis and inhibition of cell growth in the absence of Mdm4 in primary cells. Furthermore, deletion of Mdm4 enhances the ability of Mdm2 to promote cell growth and tumor formation, indicating that Mdm4 has antioncogenic properties when Mdm2 is overexpressed.

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References

  • Attardi LD, Reczek EE, Cosmas C, Demicco EG, McCurrach ME, Lowe SW and Jacks T . (2000). Genes Dev., 14, 704–718.

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

  • Danovi D, Meulmeester E, Pasini D, Migliorini D, Capra M, Frenk R, de Graaf P, Francoz S, Gasparini P, Gobbi A, Helin K, Pelicci PG, Jochemsen AG and Marine JC . (2004). Mol. Cell. Biol., 24, 5835–5843.

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

  • Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery Jr CA, Butell JS and Bradley A . (1992). Nature, 356, 215–221.

  • 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.

  • Gu J, Kawai H, Nie L, Kitao H, Wiederschain D, Jochemsen AG, Parant J, Lozano G and Yuan ZM . (2002). J. Biol. Chem., 277, 19251–19254.

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

  • Jackson MW and Berberich SJ . (2000). Mol. Cell. Biol., 20, 1001–1007.

  • Jones SN, Hancock AR, Vogel H, Donehower LA and Bradley A . (1998). Proc. Natl. Acad. Sci. USA, 95, 15608–15612.

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

  • Jones SN, Sands AT, Hancock AR, Vogel H, Donehower LA, Linke SP, Wahl GM and Bradley A . (1996). Proc. Natl. Acad. Sci. USA, 93, 14106–14111.

  • Mancini F, Gentiletti F, D'Angelo M, Giglio S, Nanni S, D'Angelo C, Farsetti A, Citro G, Sacchi A, Pontecorvi A and Moretti F . (2004). J. Biol. Chem., 279, 8169–8180.

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

  • 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.

  • Montes de Oca Luna R, Amelse LL, Chavez-Reyes A, Evans SC, Brugarolas J, Jacks T and Lozano G . (1997). Nat. Genet., 16, 336–337.

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

  • Oliner JD, Kinzler KW, Meltzer PS, George DL and Vogelstein B . (1992). Nature, 358, 15–16.

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

  • Sharp DA, Kratowicz SA, Sank MJ and George DL . (1999). J. Biol. Chem., 274, 38189–38196.

  • 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.

  • Stad R, Little NA, Xirodimas DP, Frenk R, van der Eb AJ, Lane DP, Saville MK and Jochemsen AG . (2001). EMBO Rep., 2, 1029–1034.

  • Stad R, Ramos YF, Little N, Grivell S, Attema J, van Der Eb AJ and Jochemsen AG . (2000). J. Biol. Chem., 275, 28039–28044.

  • Steinman HA and Jones SN . (2002). Genesis, 32, 142–144.

  • Steinman HA, Sluss HK, Sands AT, Pihan G and Jones SN . (2004). Oncogene, 23, 303–306.

  • Vousden KH . (2000). Cell, 103, 691–694.

  • Woods DB and Vousden KH . (2001). Exp. Cell Res., 264, 56–66.

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Acknowledgements

We thank Scott Lowe for providing the pLPC-12sE1A vector, Christopher Lengner for technical assistance with real-time PCR, and Charlene Baron for assistance with manuscript preparation. This work was supported by a grant (CA77735) from the National Institutes of Health to SNJ.

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Authors and Affiliations

  1. Department of Cell Biology, University of Massachusetts Medical School, S3-123, 55 Lake Avenue North, Worcester, 01655, MA, USA

    Heather A Steinman, Kathleen M Hoover, Marilyn L Keeler & Stephen N Jones

  2. Department of Cancer Biology, University of Massachusetts Medical School, S3-123, 55 Lake Avenue North, Worcester, 01655, MA, USA

    Heather A Steinman, Kathleen M Hoover, Marilyn L Keeler & Stephen N Jones

  3. Lexicon Genetics, The Woodlands, 77381, TX, USA

    Arthur T Sands

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  1. Heather A Steinman
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  2. Kathleen M Hoover
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Correspondence to Stephen N Jones.

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Steinman, H., Hoover, K., Keeler, M. et al. Rescue of Mdm4-deficient mice by Mdm2 reveals functional overlap of Mdm2 and Mdm4 in development. Oncogene 24, 7935–7940 (2005). https://doi.org/10.1038/sj.onc.1208930

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