Regulation of PTEN expression in intestinal epithelial cells by c-Jun NH2-terminal kinase activation and nuclear factor-kappaB inhibition.
The tumor suppressor protein phosphatase and tensin homologue deleted on chromosome ten (PTEN) plays an important role in intestinal cell proliferation and differentiation and tumor suppression by antagonizing phosphatidylinositol 3-kinase. Despite its importance, the molecular mechanisms regulating PTEN expression are largely undefined. Here, we show that treatment of the colon cancer cell line HT29 with the differentiating agent sodium butyrate (NaBT) increased PTEN protein and mRNA expression and induced c-Jun NH2-terminal kinase (JNK) activation. Inhibition of JNK by chemical or genetic methods attenuated NaBT-induced PTEN expression. In addition, our findings showed a cross-talk between nuclear factor kappaB (NF-kappaB) and JNK with respect to PTEN regulation. Overexpression of the NF-kappaB superrepressor increased PTEN expression and JNK activity, whereas overexpression of the p65 NF-kappaB subunit reduced both basal and NaBT-mediated JNK activation and PTEN expression. Moreover, we showed that overexpression of PTEN or treatment with NaBT increased expression of the cyclin-dependent kinase inhibitor p27(kip1) in HT29 cells; this induction was attenuated by inhibition of PTEN or JNK expression or overexpression of p65. Finally, we show a role for PTEN in NaBT-mediated cell death and differentiation. Our findings suggest that the JNK/PTEN and NF-kappaB/PTEN pathways play a critical role in normal intestinal homeostasis and colon carcinogenesis.
Wang
Qingding
Q
Department of Surgery, The University of Texas Medical Branch, Galveston, Texas 77555-0536, USA.
Zhou
Yuning
Y
Wang
Xiaofu
X
Chung
Dai H
DH
Evers
B Mark
BM
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002087:Butyrates / Q000494:pharmacology; D018938:Caco-2 Cells; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis*; D015398:Signal Transduction
D002087:Butyrates; C436291:CDKN1B protein, human; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D050760:Cyclin-Dependent Kinase Inhibitor p27; D048031:JNK Mitogen-Activated Protein Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
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