期刊
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
卷 294, 期 5, 页码 C1277-C1287出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.90635.2007
关键词
store-operated Ca2+ channels; capacitative Ca2+ entry mechanism; programmed cell death; I kappa B; small interfering ribonucleic acid; intestinal epithelium; mucosal homeostasis; transient receptor potential canonical-1
资金
- NIDDK NIH HHS [T32 DK067872, DK-68491, DK-61972, DK-57819] Funding Source: Medline
Transient receptor potential canonical-1 (TRPC1) functions as a store-operated Ca2+ channel in intestinal epithelial cells (IECs), and induced TRPC1 expression sensitizes IECs to apoptosis by inhibiting NF-kappa B activation. However, the exact mechanism by which increased TRPC1 results in NF-kappa B inactivation remains elusive. Protein phosphatase 2A (PP2A) is a widely conserved protein serine/threonine phosphatase that is implicated in the regulation of a wide array of cellular functions including apoptosis. The present study tests the hypothesis that induced TRPC1 expression inhibits NF-kappa B activation by increasing PP2A activity through Ca2+ influx in IECs. The expression of TRPC1 induced by stable transfection with the wild-type TRPC1 gene increased PP2A activity as indicated by increases in levels of PP2A proteins and their phosphatase activity. Increased levels of PP2A activity in stable TRPC1-transfected IEC-6 cells (IEC-TRPC1) were associated with decreased nuclear levels of NF-kappa B proteins and a reduction in NF-kappa B-dependent transcriptional activity, although there were no changes in total NF-kappa B protein levels. Inhibition of PP2A activity by treatment with okadaic acid or PP2A silencing with small interfering RNA not only enhanced NF-kappa B transactivation but also prevented the increased susceptibility of IEC-TRPC1 cells to apoptosis induced by treatment with tumor necrosis factor-alpha (TNF-alpha)/cycloheximide (CHX). Decreasing Ca2+ influx by exposure to the Ca2+-free medium reduced PP2A mRNA levels, destabilized PP2A proteins, and induced NF-kappa B activation, thus blocking the increased sensitivity of IEC-TRPC1 cells to TNF-alpha/CHX-induced apoptosis. These results indicate that induced TRPC1 expression increases PP2A activity through Ca2+ influx and that increased PP2A sensitizes IECs to apoptosis as a result of NF-kappa B inactivation.
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