HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kirken, R. A. Articles by Farrar, W. L. Search for Related Content PubMed PubMed Citation Articles by Kirken, R. A. Articles by Farrar, W. L.

Functional Uncoupling of the Janus Kinase 3-Stat5 Pathway in Malignant Growth of Human T Cell Leukemia Virus Type 1-Transformed Human T Cells¹

Robert A. Kirken^2,3,*,, Rebecca A. Erwin^2,*,, Lihua Wang, Yuling Wang^*, Hallgeir Rui^§ and William L. Farrar

^* Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, TX 77030; IRSP, Science Applications International Corporation Frederick, and Division of Basic Sciences, Cytokine Molecular Mechanisms Section, Laboratory of Molecular Immunoregulation, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, MD 21702; and ^§ Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814

Human T cell leukemia virus type 1 (HTLV-1) transforms cytokine-dependent T lymphocytes and causes adult T cell leukemia. Janus tyrosine kinase (Jak)3 and transcription factors Stat5a and Stat5b are essential for the proliferation of normal T cells and are constitutively hyperactivated in both HTLV-1-transformed human T cell lines and lymphocytes isolated from HTLV-1-infected patients; therefore, a critical role for the Jak3-Stat5 pathway in the progression of this disease has been postulated. We recently reported that tyrphostin AG-490 selectively blocked IL-2 activation of Jak3/Stat5 and growth of murine T cell lines. Here we demonstrate that disruption of Jak3/Stat5a/b signaling with AG-490 (50 µM) blocked the proliferation of primary human T lymphocytes, but paradoxically failed to inhibit the proliferation of HTLV-1-transformed human T cell lines, HuT-102 and MT-2. Structural homologues of AG-490 also inhibited the proliferation of primary human T cells, but not HTLV-1-infected cells. Disruption of constitutive Jak3/Stat5 activation by AG-490 was demonstrated by inhibition of 1) tyrosine phosphorylation of Jak3, Stat5a (Tyr⁶⁹⁴), and Stat5b (Tyr⁶⁹⁹); 2) serine phosphorylation of Stat5a (Ser⁷²⁶) as determined by a novel phosphospecific Ab; and 3) Stat5a/b DNA binding to the Stat5-responsive ß-casein promoter. In contrast, AG-490 had no effect on DNA binding by p50/p65 components of NF-B, a transcription factor activated by the HTLV-1-encoded phosphoprotein, Tax. Collectively, these data suggest that the Jak3-Stat5 pathway in HTLV-1-transformed T cells has become functionally redundant for proliferation. Reversal of this functional uncoupling may be required before Jak3/Stat5 inhibitors will be useful in the treatment of this malignancy.

This article has been cited by other articles:

				J. R. Cortes, M. Perez-G, M. D. Rivas, and J. Zamorano Kaempferol Inhibits IL-4-Induced STAT6 Activation by Specifically Targeting JAK3 J. Immunol., September 15, 2007; 179(6): 3881 - 3887. [Abstract] [Full Text] [PDF]

				A. Crotti, M. Lusic, R. Lupo, P. M. J. Lievens, E. Liboi, G. D. Chiara, M. Tinelli, A. Lazzarin, B. K. Patterson, M. Giacca, et al. Naturally occurring C-terminally truncated STAT5 is a negative regulator of HIV-1 expression Blood, June 15, 2007; 109(12): 5380 - 5389. [Abstract] [Full Text] [PDF]

				Z. S. Nagy, H. Rui, S. M. Stepkowski, J. Karras, and R. A. Kirken A Preferential Role for STAT5, not Constitutively Active STAT3, in Promoting Survival of a Human Lymphoid Tumor J. Immunol., October 15, 2006; 177(8): 5032 - 5040. [Abstract] [Full Text] [PDF]

				S. Mohapatra, B. Chu, S. Wei, J. Djeu, P. K. Epling-Burnette, T. Loughran, R. Jove, and W. J. Pledger Roscovitine Inhibits STAT5 Activity and Induces Apoptosis in the Human Leukemia Virus Type 1-Transformed Cell Line MT-2 Cancer Res., December 1, 2003; 63(23): 8523 - 8530. [Abstract] [Full Text] [PDF]

				M. Benekli, M. R. Baer, H. Baumann, and M. Wetzler Signal transducer and activator of transcription proteins in leukemias Blood, April 15, 2003; 101(8): 2940 - 2954. [Abstract] [Full Text] [PDF]

				Z. S. Nagy, Y. Wang, R. A. Erwin-Cohen, J. Aradi, B. Monia, L. H. Wang, S. M. Stepkowski, H. Rui, and R. A. Kirken Interleukin-2 family cytokines stimulate phosphorylation of the Pro-Ser-Pro motif of Stat5 transcription factors in human T cells: resistance to suppression of multiple serine kinase pathways J. Leukoc. Biol., October 1, 2002; 72(4): 819 - 828. [Abstract] [Full Text] [PDF]