Inhibition of NF-kappa B stabilizes gadd45 alpha mRNA.
Zheng-X; Zhang-YD; Chen-YQ; Castranova-V; Shi-XL; Chen-F
Biochem Biophys Res Commun 2005 Apr; 329(1):95-99
Growth arrest- and DNA damage-inducible protein a (gadd45alpha) is an important regulator for cell cycle, genomic stability, and cell apoptosis. In the present report, we demonstrated that NF-kappaB inhibition due to Ikkbeta deficiency enhanced the stability of gadd45alpha mNRA. Using embryo fibroblast cells derived from wild type (wt) or Ikkbeta gene knockout (Ikkbeta-/-) mice, reverse transcription-polymerase chain reaction revealed a three- to fourfold increase of gadd45alpha mRNA in Ikkbeta-/- cells compared with wt cells. The deficiency in Ikkbeta substantially decreased basal NF-kappaB activity and increased accumulation of reactive oxygen species (ROS). However, such deficiency had no effect on the basal expression or activity of Akt, FoxO3a, p53, and c-myc that regulate the transcription of gadd45alpha gene positively or negatively. Analysis of gadd45alpha mRNA stability showed a ROS-dependent increase in the half-life of gadd45alpha mRNA in Ikkbeta-/- cells. Immunoprecipitation experiments indicated an increased binding of a RNA stabilizing protein, nucleolin, to gadd45alpha mRNA in Ikkbeta-/- cells. The binding of nucleolin to gadd45alpha mRNA could be prevented by the antioxidant, N-acetyl-cysteine. Thus, these data are the first to suggest that inhibition of Ikkbeta-NF-kappaB signaling up-regulates the expression of gadd45alpha mNRA through a post-transcriptional, rather than a transcriptional, mechanism.
Antioxidants; Antioxidation; Genetics; Genes; Gene-mutation; DNA-damage; Cell-function; Cellular-function; Cell-biology
The Health Effects Laboratory Division, Pathology and Physiology Research Branch, National Institute for Occupational Safety and Health, 1095 Willowdale Road, Morgantown, WV 26505, USA
Biochemical and Biophysical Research Communications