Editors' ChoiceReactive Oxygen Species

A Radical Approach to Gene Transcription

Science's STKE  25 Mar 2003:
Vol. 2003, Issue 175, pp. tw115-TW115
DOI: 10.1126/stke.2003.175.tw115

Shibanuma et al. demonstrated that Hic-5 (hydrogen peroxide-inducible clone-5) shuttles to the nucleus in response to H2O2 and other oxidants, thereby translating changes in redox state into changes in gene expression. Hic-5, a LIM- and LD- domain-containing focal adhesion protein isolated on the basis of an increase in mRNA expression in response to H2O2 and transforming growth factor-β1 (TGF-β1), has been implicated in cell growth and differentiation and has been postulated to function as an adaptor. However, recent research localizing a portion of cellular Hic-5 to the nucleus, together with identification of Hic-5 as a steroid receptor coactivator, is inconsistent with such a restricted role. The authors used immunofluorescence analysis in mammalian cell lines to demonstrate that Hic-5 accumulated in the nucleus after treatment of cells with H2O2, N-ethylmaleimide, and diethyl maleate, whereas other proteins associated with focal adhesions, including the highly homologous paxillin, did not. Mutational analysis indicated that the COOH-terminal LIM domains functioned together as an unconventional nuclear localization signal, whereas NH2-terminal amino acids associated with two LD motifs were involved in oxidant-sensitive nuclear export. Hic-5 mutants that localized to the nucleus activated a reporter for c-fos, which is transcriptionally activated by H2O2. Moreover, a Hic-2 mutant unable to bind to and activate the c-fos reporter inhibited H2O2-sensitive c-fos induction. One of the LD motifs involved in nuclear export has been implicated in interactions with focal adhesion kinase and cell spreading, leading the authors to suggest that this region integrates adhesion and oxidative signals and couples them to changes in gene expression.

M. Shibanuma, J.-R. Kim-Kaneyama, K. Ishino, N. Sakamoto, T. Hishiki, K. Yamaguchi, K. Mori, J.-I. Mashimo, K. Nose, Hic-5 communicates between focal adhesions and the nucleus through oxidant-sensitive nuclear export signal. Mol. Biol. Cell 14, 1158-1171 (2003). [Abstract] [Full Text]