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Article

  • The EMBO Journal (2006) 25, 5805 - 5815
  • doi:10.1038/sj.emboj.7601455

Published online: 30 November 2006

c-myc as a mediator of accelerated apoptosis and involution in mammary glands lacking Socs3

Kate D Sutherland1,2, François Vaillant1, Warren S Alexander3, Tim M Wintermantel4, Natasha C Forrest1, Sheridan L Holroyd1, Edward J McManus3, Gunther Schutz4, Christine J Watson5, Lewis A Chodosh6, Geoffrey J Lindeman1 and Jane E Visvader1

  1. VBCRC Laboratory, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
  2. Department of Medical Biology, University of Melbourne, Victoria, Australia
  3. Cancer & Haematology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
  4. Molecular Biology of the Cell I, German Cancer Research Centre, Heidelberg, Germany
  5. Mammary Apoptosis and Development Group, Department of Pathology, University of Cambridge, Cambridge, UK
  6. Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

Correspondence to:

Jane E Visvader, VBCRC Laboratory, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia. Tel.: +61 3 9345 2494; Fax: 61 3 9347 0852; E-mail: visvader@wehi.edu.au

Received 3 May 2006; Accepted 31 October 2006

Suppressor of cytokine signalling (SOCS) proteins are critical attenuators of cytokine-mediated signalling in diverse tissues. To determine the importance of Socs3 in mammary development, we generated mice in which Socs3 was deleted in mammary epithelial cells. No overt phenotype was evident during pregnancy and lactation, indicating that Socs3 is not a key physiological regulator of prolactin signalling. However, Socs3-deficient mammary glands exhibited a profound increase in epithelial apoptosis and tissue remodelling, resulting in precocious involution. This phenotype was accompanied by augmented Stat3 activation and a marked increase in the level of c-myc. Moreover, induction of c-myc before weaning using an inducible transgenic model recapitulated the Socs3 phenotype, and elevated expression of likely c-myc target genes, E2F-1, Bax and p53, was observed. Our data establish Socs3 as a critical attenuator of pro-apoptotic pathways that act in the developing mammary gland and provide evidence that c-myc regulates apoptosis during involution.

  • Keywords:

    • apoptosis,
    • c-myc,
    • mammary,
    • Socs3,
    • Stat3