Letter | Published:

Gigantism in mice lacking suppressor of cytokine signalling-2

Nature volume 405, pages 10691073 (29 June 2000) | Download Citation

Subjects

Abstract

Suppressor of cytokine signalling-2 (SOCS-2) is a member of the suppressor of cytokine signalling family, a group of related proteins implicated in the negative regulation of cytokine action through inhibition of the Janus kinase (JAK) signal transducers and activators of transcription (STAT) signal-transduction pathway1. Here we use mice unable to express SOCS-2 to examine its function in vivo. SOCS-2-/- mice grew significantly larger than their wild-type littermates. Increased body weight became evident after weaning and was associated with significantly increased long bone lengths and the proportionate enlargement of most organs. Characteristics of deregulated growth hormone and insulin-like growth factor-I (IGF-I) signalling, including decreased production of major urinary protein, increased local IGF-I production, and collagen accumulation in the dermis, were observed in SOCS-2-deficient mice, indicating that SOCS-2 may have an essential negative regulatory role in the growth hormone/IGF-I pathway.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    et al. A family of cytokine-inducible inhibitors of signalling. Nature 387, 917–921 ( 1997).

  2. 2.

    Negative regulators of cytokine signal transduction. Cell. Mol. Life Sci. 55, 1568–1577 (1999).

  3. 3.

    , , & Insulin-like growth factor I stimulates growth in hypophysectomized rats. Nature 296, 252–253 ( 1982).

  4. 4.

    & Insulin-like growth factors and their binding proteins: biological actions. Endocrine Rev. 16, 3–34 (1995 ).

  5. 5.

    , , & Developmental regulation of insulin-like growth factor-I and growth hormone receptor gene expression. Mol. Cell. Endocrinol. 152, 125–136 (1999).

  6. 6.

    , & Regulation of rat growth hormone receptor gene expression. J. Biol. Chem. 264, 9905– 9910 (1989).

  7. 7.

    , & Transgenic models of growth hormone action. Annu. Rev. Nutrition 19, 437–461 (1999).

  8. 8.

    in Endocrinology (ed. DeGroot, L. J.) 303– 329 (W. B. Saunders Company, Philidelphia, 1995).

  9. 9.

    et al. Histopathology associated with elevated levels of growth hormone and insulin-like growth factor I in transgenic mice. Endocrinology 124, 40–48 ( 1989).

  10. 10.

    et al. Overgrowth of skin in growth hormone transgenic mice depends on the presence of male gonads. J. Invest. Dermatol. 113, 967–971 (1999).

  11. 11.

    & Secretory rhythm of growth hormone regulates sexual differentiation of mouse liver. Cell 36, 805–812 (1984).

  12. 12.

    et al. Normal growth and development in the absence of hepatic insulin-like growth factor I. Proc. Natl Acad. Sci. USA 96, 7324–7329 (1999).

  13. 13.

    et al. Liver-derived insulin-like growth factor I (IGF-I) is the principal source of IGF-I in blood but is not required for postnatal body growth in mice. Proc. Natl Acad. Sci. USA 96, 7088–7092 (1999).

  14. 14.

    et al. Growth hormone preferentially induces the rapid, transient expression of SOCS-3, a novel inhibitor of cytokine receptor signaling. J. Biol. Chem. 273, 1285–1287 (1998).

  15. 15.

    , , , & Dual effects of suppressor of cytokine signaling (SOCS-2) on growth hormone signal transduction. FEBS Lett. 453, 63–66 ( 1999).

  16. 16.

    , , , & Growth hormone regulation of SOCS-2, SOCS-3, and CIS messenger ribonucleic acid expression in the rat. Endocrinology 140, 3693–3704 (1999).

  17. 17.

    , , , & STAT5b mediates the growth hormone-induced expression of SOCS-2 and SOCS-3 mRNA in the liver. Mol. Cell. Endocrinol. 158, 111–116 ( 1999).

  18. 18.

    & SOCS/CIS protein inhibition of growth hormone-stimulated STAT5 signaling by multiple mechanisms. J. Biol. Chem. 274, 35553–35561 (1999).

  19. 19.

    , , , & Mechanism of inhibition of growth hormone receptor signaling by suppressor of cytokine signaling proteins. Mol. Endocrinol. 13, 1832–1843 (1999).

  20. 20.

    et al. Suppression of STAT5 functions in liver, mammary glands, and T cells in cytokine-inducible SH2-containing protein 1 transgenic mice. Mol. Cell. Biol. 19, 6396–6407 (1999).

  21. 21.

    , , & Interaction of human suppressor of cytokine signaling (SOCS)-2 with the insulin-like growth factor-I receptor. J. Biol. Chem. 273, 24095–24101 (1998).

  22. 22.

    Differential regulation of signaling pathways for insulin and insulin- like growth factor I. Acta Biochim. Pol. 46, 51–60 (1999).

  23. 23.

    et al. Liver degeneration and lymphoid deficiencies in mice lacking suppressor of cytokine signalling-1. Proc. Natl Acad. Sci. USA 95, 14395–14399 ( 1998).

  24. 24.

    , & Point mutations within a dimer interface homolgy domain of c-mpl induce constitutive receptor activity and tumorigenesis. EMBO J. 14, 5569–5578 ( 1995).

  25. 25.

    , , , & Deficiencies in progenitor cells of multiple hematopoietic lineages and defective megakaryocytopoiesis in mice lacking the thrombopoietic receptor c-Mpl. Blood 87 , 2162–2170 (1996).

Download references

Acknowledgements

We thank N. Sprigg, J. Mighall, S. Mifsud and L. DiRago for technical assistance; K. Hanzinikolas for animal care; S. Mihajlovic for histology; and F. Koentgen, L. Barnett, J. DeWinter and M. Swift of the Walter and Eliza Hall Institute Genetically Modified Mouse Facility and T. Adams for discussions and critical assessment of the manuscript. This work was supported by the National Health and Medical Research Council, Canberra, the Anti-Cancer Council of Victoria, an Australian Government Cooperative Research Centres Program Grant, the National Institutes of Health, Bethesda, the J. D. and L. Harris Trust and AMRAD Operations Pty Ltd, Melbourne.

Author information

Affiliations

  1. The Walter and Eliza Hall Institute of Medical Research and The Cooperative Research Centre for Cellular Growth Factors, Post Office, Royal Melbourne Hospital, Victoria 3050, Australia

    • Donald Metcalf
    • , Christopher J. Greenhalgh
    • , Elizabeth Viney
    • , Tracy A. Willson
    • , Robyn Starr
    • , Nicos A. Nicola
    • , Douglas J. Hilton
    •  & Warren S. Alexander

Authors

  1. Search for Donald Metcalf in:

  2. Search for Christopher J. Greenhalgh in:

  3. Search for Elizabeth Viney in:

  4. Search for Tracy A. Willson in:

  5. Search for Robyn Starr in:

  6. Search for Nicos A. Nicola in:

  7. Search for Douglas J. Hilton in:

  8. Search for Warren S. Alexander in:

Corresponding author

Correspondence to Warren S. Alexander.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/35016611

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.