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* Department of Biological Sciences, University of Texas, El Paso, TX 79968;
Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107;
Department of Surgery, Division of Organ Transplantation, University of Texas Health Science Center at Houston, Medical School, Houston, TX 77030; and
Molecular and Cellular Pharmacology, ISIS Pharmaceuticals, Carlsbad, CA 92008
STATs are believed to play key roles in normal and abnormal cell function. In the present work, we investigated the role of STATs in an IL-2-responsive human lymphoblastic lymphoma-derived cell line, YT. Only STAT3 was found constitutively tyrosine phosphorylated, but not other STATs. Hyperactive STAT3 was not attributable to a pre-existing intermediate affinity IL-2R complex and/or hyperactive Jak activity. Depletion of STAT3 protein expression reduced tumor cell viability with protracted kinetics (72–96 h), while TUNEL assays demonstrated cell death occurred via apoptosis. Interestingly, depletion of STAT5 in this same tumor induced more pronounced cell death compared with STAT3 depletion (24 h). Although IL-2 was able to rescue STAT3-depleted cells from death, it could not compensate for the loss of STAT5. To determine the prosurvival function of STAT3 vs STAT5 within the same tumor model, genes were profiled in STAT3- or STAT5-depleted YT cells by apoptosis-specific microarrays. Several differentially expressed genes were identified. Interestingly, those genes involved in NF-
B regulation, such as TNFR-associated factors 2 and 5 and B cell leukemia/lymphoma 10, were readily decreased upon STAT5, but not STAT3, depletion as validated by quantitative RT-PCR. These results suggest that STAT5 and, to a lesser extent, hyperactive STAT3 provide preferential and critical cell survival signals for certain human lymphoid tumors, indicating that nonhyperactive STATs should be considered as therapeutic targets for abrogating tumorigenesis.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants AI053566 (to R.A.K.) and AI061052 (to S.M.S.), and made possible by Grant 5G12RR008124 from the National Center for Research Resources, a component of the National Institutes of Health.
2 Address correspondence and reprint requests to Dr. Zsuzsanna S. Nagy, University of Texas, Department of Biological Sciences, 500 West University Avenue B226, El Paso, TX 79902. E-mail address: znagy{at}utep.edu
3 Abbreviations used in this paper: HTLV, human T cell leukemia virus; Bcl, B cell leukemia; Bcl10, B cell leukemia/lymphoma 10; LMP, latent membrane protein; MTS, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt; NEPHGE, nonequilibrium pH gradient electrofocusing; nrs, normal rabbit serum; ODN, oligodeoxynucleotide; Q-RT-PCR, quantitative real-time RT-PCR; SIE, sis-inducible element; Traf, TNFR-associated factor.
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  K. M. Mohankumar, J. K. Perry, N. Kannan, K. Kohno, P. D. Gluckman, B. S. Emerald, and P. E. Lobie Transcriptional Activation of Signal Transducer and Activator of Transcription (STAT) 3 and STAT5B Partially Mediate Homeobox A1-Stimulated Oncogenic Transformation of the Immortalized Human Mammary Epithelial Cell Endocrinology, May 1, 2008; 149(5): 2219 - 2229. [Abstract] [Full Text] [PDF]
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