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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.

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Department of Internal Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA.


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.

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