Tumor suppressor MMAC/PTEN inhibits cytokine-induced NFkappaB activation without interfering with the IkappaB degradation pathway.
The phosphoinositide 3-kinase (PI 3-kinase) pathway has been implicated in the activation of the proinflammatory transcription factor nuclear factor kappaB (NFkappaB). To investigate the role of this pathway in NFkappaB activation, we employed mutated in multiple advanced cancers/phosphatase and tensin homologue (MMAC/PTEN), a natural antagonist of PI 3-kinase activity. Our results show that cytokine-induced DNA binding and transcriptional activities of NFkappaB were both inhibited in a glioma cell line that was stably transfected with MMAC/PTEN. The ability of interleukin-1 (IL-1) to induce inhibitor (IkappaB) degradation or nuclear translocation of NFkappaB was, however, unaffected by MMAC/PTEN expression, suggesting that PI 3-kinase utilizes another equally important mechanism to control NFkappaB activation. It is conceivable that NFkappaB is directly phosphorylated through such a mechanism because treatment with protein phosphatase 2A significantly reduced its DNA binding activity. Moreover, IL-1-induced phosphorylation of p50 NFkappaB was potently inhibited in MMAC/PTEN-expressing cells. Whereas the mediators of NFkappaB phosphorylation remain to be identified, IL-1 was found to induce physical interactions between the PI 3-kinase target Akt kinase and the IkappaB.IkappaB kinase complex. Physical interactions between these proteins were antagonized by MMAC/PTEN consistent with their potential involvement in NFkappaB activation. Taken together, our observations suggest that PI 3-kinase regulates NFkappaB activation through a novel phosphorylation-dependent mechanism.
Department of Neuro-Oncology and the Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
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D
Koul
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Yao
J L
JL
Abbruzzese
W K
WK
Yung
S A
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Reddy
D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D016207:Cytokines; D016328:NF-kappa B; D025521:Tumor Suppressor Proteins; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human