Deakin home > Deakin University Library > Deakin Research Online > Multiple pathways contribute to the hyperproliferative responses from truncated granulocyte colony-stimulating factor receptors

Multiple pathways contribute to the hyperproliferative responses from truncated granulocyte colony-stimulating factor receptors

Gits, J., van Leeuwen, D., Carroll, H. P., Touw, I. P. and Ward, Alister 2006, Multiple pathways contribute to the hyperproliferative responses from truncated granulocyte colony-stimulating factor receptors, Leukemia, vol. 20, pp. 2111-2118.

Attached Files (Some files may be inaccessible until you login with your Deakin Research Online credentials)
Name Description MIMEType Size Downloads

Title Multiple pathways contribute to the hyperproliferative responses from truncated granulocyte colony-stimulating factor receptors
Author(s) Gits, J.
van Leeuwen, D.
Carroll, H. P.
Touw, I. P.
Ward, Alister
Journal name Leukemia
Volume number 20
Start page 2111
End page 2118
Publisher Nature Publishing Group
Place of publication Houndmills, England
Publication date 2006-10-26
ISSN 0887-6924
Keyword(s) granulocyte colony-stimulating factor
hyperproliferation
STAT5
Summary Mutations in the granulocyte colony-stimulating factor receptor (G-CSF-R) gene leading to a truncated protein have been identified in a cohort of neutropenia patients highly predisposed to acute myeloid leukemia. Such mutations act in a dominant manner resulting in hyperproliferation but impaired differentiation in response to G-CSF. This is due, at least in part, to defective internalization and loss of binding sites for several negative regulators, leading to sustained receptor activation. However, those signaling pathways responsible for mediating the hyperproliferative function have remained unclear. In this study, analysis of an additional G-CSF-R mutant confirmed the importance of residues downstream of Box 2 as important contributors to the sustained proliferation. However, maximal proliferation correlated with the ability to robustly activate signal transducer and activator of transcription (STAT) 5 in a sustained manner, whereas co-expression of dominant-negative STAT5, but not dominant-negative STAT3, was able to inhibit G-CSF-stimulated proliferation from a truncated receptor. Furthermore, a Janus kinase (JAK) inhibitor also strongly reduced the proliferative response, whereas inhibitors of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) or phosphatidylinositol (PI) 3-kinase reduced proliferation to a lesser degree. These data suggest that sustained JAK2/STAT5 activation is a major contributor to the hyperproliferative function of truncated G-CSF receptors, with pathways involving MEK and PI 3-kinase playing a reduced role.
Language eng
Field of Research 110202 Haematology
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2006, Nature Publishing Group
Persistent URL http://hdl.handle.net/10536/DRO/DU:30006532

Document type: Journal Article
Collection: School of Medicine
Connect to link resolver
 
Unless expressly stated otherwise, the copyright for items in Deakin Research Online is owned by the author, with all rights reserved.

Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 9 times in TR Web of Science
Scopus Citation Count Cited 10 times in Scopus
Access Statistics: 548 Abstract Views, 2 File Downloads  -  Detailed Statistics
Created: Thu, 31 Jul 2008, 10:41:07 EST