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Lack of requirement of STAT1 for activation of nuclear factor-κB, c-Jun NH2-terminal protein kinase, and apoptosis by tumor necrosis factor-α

✍ Scribed by Asok Mukhopadhyay; Shishir Shishodia; Xin-Yuan Fu; Bharat B. Aggarwal

Publisher
John Wiley and Sons
Year
2002
Tongue
English
Weight
377 KB
Volume
84
Category
Article
ISSN
0730-2312

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✦ Synopsis

Abstract

Tumor necrosis factor (TNF) is one of the most potent activators of nuclear transcription factor NF‐κB, c‐Jun N‐terminal protein kinase (JNK), and apoptosis in a wide variety of cells. The biological effects of TNF are mediated through sequential interactions of various cytoplasmic proteins with intracellular domains of TNF receptors. Whether signal transducer and activator of transcription‐1 (STAT1), which mediates interferon (IFN) signaling, also plays any role in the TNF‐mediated activation of NF‐κB, JNK, and apoptosis has not been established. Here, we report our investigation of the role of STAT1 in TNF signaling using STAT1‐deficient U3A and STAT1‐stably transfected U3A‐PSG91 cells. IFNα inhibited the proliferation of STAT1‐expressing U3A‐PSG91 cells but had no effect on STAT1‐negative U3A cells. TNF alone, even up to 10 nM, had no effect on the proliferation of either U3A‐PSG91 or U3A cells. Irrespective of STAT1 status, TNF induced cytotoxic effects in the presence of cycloheximide (CHX) in both cell types. Additionally, TNF‐induced caspase‐3 and caspase‐8 activation and TNF‐induced PARP cleavage were unaffected by the presence or absence of STAT1. TNF activated NF‐κB, consisting of p50 and p65, in both U3A and U3A‐pSG91 cells in a dose‐ and time‐dependent manner, but the degree and rate of activation were slightly lower in U3A cells, as were IκBα degradation and NF‐κB‐dependent reporter gene expression. STAT1 was, however, required for IFNα‐mediated downregulation of TNF‐induced NF‐κB activation. TNF activated JNK in both cell types, but dose and time of exposure required for optimum activation differed slightly. Thus, overall our results indicate that STAT1 plays a minimal role in TNF‐mediated cellular responses. J. Cell. Biochem. 84: 803–815, 2002. © 2002 Wiley‐Liss, Inc.

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