A preferential role for STAT5, not constitutively active STAT3, in promoting survival of a human lymphoid tumor.
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-kappaB 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.
Nagy
Zsuzsanna S
ZS
Department of Biological Sciences, University of Texas, El Paso, TX 79968, USA. znagy@utep.edu
Rui
Hallgeir
H
Stepkowski
Stanislaw M
SM
Karras
James
J
Kirken
Robert A
RA
D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007376:Interleukin-2; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D050796:STAT3 Transcription Factor / Q000172:deficiency / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000172:deficiency / Q000502:physiology*
D007376:Interleukin-2; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor