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Molecular and Cellular Biology, May 2001, p. 3547-3557, Vol. 21, No. 10
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.10.3547-3557.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Socs-1 Inhibits TEL-JAK2-Mediated Transformation of
Hematopoietic Cells through Inhibition of JAK2 Kinase Activity and
Induction of Proteasome-Mediated Degradation
Julie
Frantsve,1,2
Juerg
Schwaller,1,
David W.
Sternberg,1
Jeffery
Kutok,3 and
D. Gary
Gilliland1,2,4,*
Division of Hematology, Department of
Medicine,1 and Department of
Pathology,3 Brigham and Women's
Hospital, Harvard Institutes of Medicine, Harvard Medical
School,2 and Howard Hughes Medical
Institute,4 Boston, Massachusetts 02115
Received 1 December 2000/Returned for modification 10 January
2001/Accepted 22 February 2001
TEL-JAK2 fusion proteins, which are a result of
t(9;12)(p24;p13) translocations associated with human
leukemia, activate Stat5 in vitro and in vivo and cause a myelo- and
lymphoproliferative disease in a murine bone marrow transplant model.
We report that Socs-1, a member of the SOCS family of endogenous
inhibitors of JAKs and STATs, inhibits transformation of Ba/F3 cells by
TEL-JAK2 but has no effect on Ba/F3 cells transformed by BCR-ABL,
TEL-ABL, or TEL-platelet-derived growth factor receptor beta.
TEL-JAK2, in addition to activating Stat5, associates with Shc and Grb2 and induces activation of Erk2, and expression of Socs-1 inhibits engagement of each of these signaling molecules. TEL-JAK2 kinase activity is inhibited by Socs-1, as assessed by in vitro kinase assays.
In addition, Socs-1 induces proteasomal degradation of TEL-JAK2.
Mutational analysis indicates that the SOCS box of Socs-1 is required
for proteasomal degradation and for abrogation of growth of
TEL-JAK2-transformed cells. Furthermore, murine bone marrow transplant
assays demonstrate that expression of Socs-1 prolongs latency of
TEL-JAK2-mediated disease in vivo. Collectively, these data indicate
that Socs-1 inhibits TEL-JAK2 in vitro and in vivo through inhibition
of kinase activity and induction of TEL-JAK2 protein degradation.
*
Corresponding author. Mailing address: Division of
Hematology, Brigham and Women's Hospital, Boston, MA 02115. Phone:
(617) 525-5525. Fax: (617) 525-5530. E-mail:
gilliland{at}calvin.bwh.harvard.edu.

Present address: Institute de Pathologie Clinique, Hôpital
Cantonale Univérsitaire de Genève, Geneva,
Switzerland.
Molecular and Cellular Biology, May 2001, p. 3547-3557, Vol. 21, No. 10
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.10.3547-3557.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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