Down-regulation of the tumor suppressor PTEN by the tumor necrosis factor-alpha/nuclear factor-kappaB (NF-kappaB)-inducing kinase/NF-kappaB pathway is linked to a default IkappaB-alpha autoregulatory loop.
The PTEN (phosphatase and tensin homolog deleted on chromosome ten) tumor suppressor gene affects multiple cellular processes including cell growth, proliferation, and cell migration by antagonizing phosphatidylinositol 3-kinase (PI3K). However, mechanisms by which PTEN expression is regulated have not been studied extensively. Similar to PTEN, tumor necrosis factor-alpha (TNF-alpha) affects a wide spectrum of diseases including inflammatory processes and cancer by acting as a mediator of apoptosis, inflammation, and immunity. In this study, we show that treatment of cancer cell lines with TNF-alpha decreases PTEN expression. In addition, overexpression of TNF-alpha downstream signaling targets, nuclear factor-kappaB (NF-kappaB)-inducing kinase (NIK) and p65 nuclear factor NF-kappaB, lowers PTEN expression, suggesting that TNF-alpha-induced down-regulation of PTEN is mediated through a TNF-alpha/NIK/NF-kappaB pathway. Down-regulation of PTEN by NIK/NF-kappaB results in activation of the PI3K/Akt pathway and augmentation of TNF-alpha-induced PI3K/Akt stimulation. Importantly, we demonstrate that this effect is associated with a lack of an inhibitor of kappaB (IkappaB)-alpha autoregulatory loop. Moreover, these findings suggest the interaction between PI3K/Akt and NF-kappaB via transcriptional regulation of PTEN and offer one possible explanation for increased tumorigenesis in systems in which NF-kappaB is chronically activated. In such a tumor system, these findings suggest a positive feedback loop whereby Akt activation of NF-kappaB further stimulates Akt via down-regulation of the PI3K inhibitor PTEN.
Kim
Sunghoon
S
Department of Surgery, The University of Texas Medical Branch, Galveston, Texas 77555-0536, USA.
Domon-Dell
Claire
C
Kang
Junghee
J
Chung
Dai H
DH
Freund
Jean-Noel
JN
Evers
B Mark
BM
D001483:Base Sequence; D002460:Cell Line; D018076:DNA, Complementary / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D005246:Feedback; D006706:Homeostasis; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D000097782:NF-kappaB-Inducing Kinase
D018076:DNA, Complementary; D020672:I-kappa B Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D000097782:NF-kappaB-Inducing Kinase; C000606204:NFKBIA protein, human; C494918:AKT1 protein, human; C494929:PTEN protein, human