Abstract:

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.

Open in

PUBMED | DOI | PMC | Google Scholar | Wikipedia

Relations:

Content

Citations

(22)

References

(61)

Chemicals

(10)

Genes

(3)

Organisms

(2)

Processes

(4)

Anatomy

(2)

Affiliates

(1)

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

Christine Watson+3 authors

^{VBCRC Laboratory, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia}

^{Department of Medical Biology, University of Melbourne, Victoria, Australia}

^{Cancer & Haematology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia}

^{Molecular Biology of the Cell I, German Cancer Research Centre, Heidelberg, Germany}

^{Mammary Apoptosis and Development Group, Department of Pathology, University of Cambridge, Cambridge, UK}

^{Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA}

^{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:}ua.ude.ihew@redavsiv

Received 2006 May 3; Accepted 2006 Oct 31.

Abstract

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

Abstract

Click here to view.^{(276K, pdf)}Click here to view.^{(32K, doc)}

Acknowledgments

We are grateful to D Smith for invaluable advice, D Krebs for expert help with AKT Western blots, B Duscio for excellent assistance, M Le Fleur for advice on zymography, M-L Asselin-Labat and H Barker for discussions and S Mihajlovic for histology. We also wish to thank M Ernst for critical review of the manuscript, as well as B Croker, C Ormandy, D Huang, D Smith, K-U Wagner, D Galloway and P Humbert for generous gifts of mice, antibodies and plasmids. This work was supported by the Victorian Breast Cancer Research Consortium Inc., The Cancer Council Victoria and the National Health and Medical Research Council (Australia).

Acknowledgments

Collaboration tool especially designed for Life Science professionals.Drag-and-drop any entity to your messages.

Learn More