Nuclear targeting of the growth hormone receptor results in dysregulation of cell proliferation and tumorigenesis

doi:10.1073/pnas.0600181104

Nuclear targeting of the growth hormone receptor results in dysregulation of cell proliferation and tumorigenesis

*Institute for Molecular Bioscience and School of Biomedical Sciences, University of Queensland, Brisbane 4072, Australia;
^†Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia; and
^‡Queensland Institute of Medical Research, Queensland 4029, Australia

Edited by William H. Daughaday, University of California, Irvine, CA, and approved June 29, 2007 (received for review January 9, 2006)

Abstract

Growth hormone receptor (GHR) has been demonstrated to be nuclear localized both in vivo and in vitro, but the significance of this observation has remained elusive. Here we show that nuclear GHR is strongly correlated with proliferative status in vivo by using a liver regeneration model. In vitro, nuclear translocation of the GH receptor is GH-dependent and appears to be mediated by the Importin system. Constitutive nuclear targeting of GHR in murine pro-B cells is associated with constitutive activation of STAT5, a transforming agent in lymphoma and other cell types. This activation is abrogated by inhibition of JAK2 and appears to be driven by autocrine murine GH action coupled with enhanced nuclear uptake of phospho-STAT5. Nuclear targeting induces dysregulated cell cycle progression in the pro-B cell line, associated with constitutive up-regulation of the proliferation inducers Survivin and Mybbp, the metastasis related Dysadherin, and other tumor markers. GHR nuclear-targeted cells generate aggressive metastatic tumors when injected into nude mice, which display nuclear localized GHR strikingly similar to that seen in human lymphomas. We conclude that aberrant nuclear localization of GHR is a marker of high proliferative status and is sufficient to induce tumorigenesis and tumor progression.

Footnotes

^§To whom correspondence should be addressed. E-mail: m.waters{at}imb.uq.edu.au
Author contributions: B.L.C-C. and J.W.W. contributed equally to this work; B.L.C.-C., A.M.L., D.A.J., and M.J.W. designed research; B.L.C.-C., J.W.W., A.J.B., R.J.B., A.M.L., D.G., H.S.C., C.L.B., and G.M.B. performed research; B.L.C.-C., J.W.W., A.J.B., R.J.B., A.M.L., D.G., H.S.C., C.L.B., G.M.B., P.G.P., D.A.J., and M.J.W. analyzed data; and B.L.C.-C. and M.J.W. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The sequence reported in this paper has been deposited in the GEO Database, www.ncbi.nlm.nih.gov/geo (accession no. GSE2898).
This article contains supporting information online at www.pnas.org/cgi/content/full/0600181104/DC1.
Abbreviations:

GH,

growth hormone;

GHR,

GH receptor;

PCNA,

proliferating cell nuclear antigen;

GHR NLS,

canonical T-Ag NLS at the N terminus of the mature GHR extracellular domain;

IMP,

Importin;

T-ag,

tumor antigen;

IAF,

iodoacetamido-fluorescein;

NLS,

nuclear localization sequence.