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Am J Physiol Renal Physiol. 2008 Mar;294(3):F577-81. Epub 2007 Dec 19.

Restoration of CREB function ameliorates cisplatin cytotoxicity in renal tubular cells.

Author information

1
Department of Internal Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA. iarany@ped.umsmed.edu

Abstract

We have shown that mouse proximal tubule cells (TKPTS) survive H(2)O(2) stress by activating the cAMP-responsive element binding protein (CREB)-mediated transcription via the canonical EGFR-Ras/ERK pathway. By contrast, cisplatin activates EGFR/Ras/ERK signaling in TKPTS cells yet promotes cell death rather than survival. We now demonstrate that the cisplatin-induced activated EGFR/Ras/ERK signaling cascade fails to activate CREB-mediated transcription even in the presence of phosphorylated CREB. CREB-mediated transcription as well as survival was restored by the histone deacetylase (HDAC) inhibitor trichostatine A (TSA), an effective chemotherapeutic agent. Similar to severe oxidant stress, TSA-mediated survival could be abrogated by inhibition of CREB-mediated transcription. These studies confirm the importance of CREB-mediated transcription in the survival of renal cells subjected to either oxidant- or cisplatin-induced stress. The use of cisplatin and TSA in combined chemotherapy protocols may be an effective strategy to enhance cancer cell death and limit nephrotoxicity.

PMID:
18094030
DOI:
10.1152/ajprenal.00487.2007
[Indexed for MEDLINE]
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