Transcription factors

S-nitrosation of critical cysteines essential for DNA binding, transformation, and transcrip-tional transactivation usually inhibit functions of transcription factors, e.g., c-Myb [146], AP-1 [147], and heterogeneous nuclear ribonucleoprotein [148]. Many transcription factors contain cysteine-coordinated zinc-finger domains, which are prone to S-nitrosation. The zinc-finger domain of yeast transcription activator LAC9 [149] and the estrogen receptor [150] are disrupted by nitric oxide. When S-nitrosated, zinc release and DNA binding ability of the transcription factors are inhibited. Other zinc-finger type transcription factors, glucocorticoid receptor [151], and Yin Yang 1 [152] are also inhibited by S-nitrosation. The zinc-sulfur moieties of many other proteins, including NOS, alcohol dehydrogenase, and metallothionein, can also be S-nitrosated and bound zinc released [84,85,153-156]. SoxR has iron-sulfur centers, which are also disrupted by nitric oxide; however, protein-bound dinitrosyl-iron-dithiol adducts form instead of S-nitrosothiols [157] as a result.

The effect of S-nitrosation on NF-kP activation is more complicated. NF-kP complexes with I-kP protein and remains in an inactive state until I-kP is phosphorylated by I-kP kinase, ubiquitinated, and degraded by the 26S proteasome. Many studies show that S-nitrosation of NF-kP with endogenous NO inhibits DNA binding, promoter activity, and gene transcription [158-163]. By contrast, S-nitrosation of IKKP [164] leads to phosphorylation of I-kP, stabilizes the complex, and inhibits NF-kP [165,166]. Additionally, S-nitrosation and consequent activation of p21ras has been shown to be involved in NF-kP activation [167].

HIF1a function is controlled by O2-regulated hydroxylation, rapid ubiquitination, and proteolysis by the proteasome. The HIF1a protein accumulates under normoxic conditions upon NOS induction or treatment with NO donors [135,136], which could be explained by the fact that the activity of prolyl hydroxylase activity is inhibited by GSNO [168]. Additionally, exposure to GSNO or induction of iNOS results in the S-nitrosation of Cys800 of HIF1a, enhancing its binding to its transcriptional coactivator CREB and increasing its transcriptional activity [31,169].

Importantly, S-nitrosation of transcription factors also control the expression of different forms of NOS [159,170-174] and other proteins involved in S-nitrosothiol metabolism. In E. coli, OxyR is S-nitrosated and activated when cells are exposed to S-nitrosothiols [108,175], leading to nitrosative stress adaptation. Deletion of OxyR renders cells hypersensitive to S-nitrosothiols.

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