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Induced TRPC1 expression sensitizes intestinal epithelial cells to apoptosis by inhibiting NF-kappaB activation through Ca2+ influx.


ABSTRACT: Apoptosis occurs within crypts and at the intestinal luminal surface and plays a critical role in mucosal homoeostasis. NF-kappaB (nuclear factor-kappaB) is the central regulator of the transcription of genes involved in apoptosis, and its activity is highly regulated in the intestinal mucosa. We have recently demonstrated that TRPC1 (transient receptor potential canonical-1) is expressed in IECs (intestinal epithelial cells) and functions as a Ca2+ permeable channel activated by Ca2+ store depletion. The present study tests the hypothesis that TRPC1 channels are implicated in the regulation of apoptosis by inhibiting NF-kappaB through the induction of TRPC1-mediated Ca2+ influx in the IEC-6 line. The expression of TRPC1 induced by stable transfection of IEC-6 cells with the wild-type TRPC1 gene (IEC-TRPC1 cells) increased Ca2+ influx after Ca2+ store depletion and repressed NF-kappaB transactivation, which was associated with an increase in susceptibility to apoptosis induced by exposure to TNFalpha (tumour necrosis factor-alpha) plus CHX (cycloheximide) (TNF-alpha/CHX), or STS (staurosporine). By contrast, the induction of endogenous NF-kappaB activity, by the depletion of cellular polyamines, promoted resistance to apoptosis, which was prevented by the ectopic expression of the IkappaBalpha super-repressor. Furthermore, inhibition of TRPC1 expression by transfection with siRNA (small interfering RNA) targeting TRPC1 (siTRPC1) decreased Ca2+ influx, increased NF-kappaB transactivation, and prevented the increased susceptibility of IEC-TRPC1 cells to apoptosis. Decreasing Ca2+ influx by exposure to a Ca2+-free medium also induced NF-kappaB activity and blocked the increased susceptibility to apoptosis of stable IEC-TRPC1 cells. These results indicate that induced TRPC1 expression sensitizes IECs to apoptosis by inhibiting NF-kappaB activity as a result of the stimulation of Ca2+ influx.

SUBMITTER: Marasa BS 

PROVIDER: S-EPMC1479765 | biostudies-literature | 2006 Jul

REPOSITORIES: biostudies-literature

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Induced TRPC1 expression sensitizes intestinal epithelial cells to apoptosis by inhibiting NF-kappaB activation through Ca2+ influx.

Marasa Bernard S BS   Rao Jaladanki N JN   Zou Tongtong T   Liu Lan L   Keledjian Kaspar M KM   Zhang Ai-hong AH   Xiao Lan L   Chen Jie J   Turner Douglas J DJ   Wang Jian-Ying JY  

The Biochemical journal 20060701 1


Apoptosis occurs within crypts and at the intestinal luminal surface and plays a critical role in mucosal homoeostasis. NF-kappaB (nuclear factor-kappaB) is the central regulator of the transcription of genes involved in apoptosis, and its activity is highly regulated in the intestinal mucosa. We have recently demonstrated that TRPC1 (transient receptor potential canonical-1) is expressed in IECs (intestinal epithelial cells) and functions as a Ca2+ permeable channel activated by Ca2+ store depl  ...[more]

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