Restoration of CREB function ameliorates cisplatin cytotoxicity in renal tubular cells

摘要

the camp-responsive element binding protein (CREB) is important in the survival of a variety of cell types under different stress conditions (5, 8, 13, 15). Earlier, we found that during oxidant injury activation of the extracellular signal-regulated kinase (ERK) and consequent induction of CREB-mediated transcription is essential for survival of mouse proximal tubule cells (3,4). CREB activation is mediated, at least in part, by the activated ERK (5, 20). By contrast, ERK contributes to the death of proximal tubule cells in cisplatin-induced nephrotox-icity (2). We interrogated possible sites of divergence between cisplatin- and oxidant-induced ERK activation and found that unlike oxidant stress, cisplatin-induced ERK-dependent phos-phorylation of CREB was not followed by its transcriptional activation. Our studies now show that histone deacetylase (HDAC) inhibitors, which are known to reverse transcriptional repression and gene silencing induced by HDACs (18), is capable of restoring CREB transcriptional activation (6, 16). Importantly this report further establishes the role of CREB transcription in the survival of renal cells under stress