Growth arrest and DNA-damage-inducible, alpha Adenovirus (Ad-GADD45)

Cell cycle progression is subject to arrest at G1 and G2 checkpoints in response to DNA damage, presumably to allow time for DNA repair prior to entry into the S and M phases, respectively. The p53 tumor suppressor is required for one such G1 checkpoint, where it functions to upregulate expression of GADD 45 and p21. GADD 45 stimulates DNA excision repair in vitro, inhibits entry of cells into S phase and acts in concert with GADD 153 to induce growth arrest. GADD 153 is also inducible by DNA damage, but its induction has been reported to be independent of p53. GADD 45-like proteins, GADD 45Î2 and GADD 45Î3, are induced by environmental stress. A related DNA-damage inducible gene, GADD 34, synergizes with GADD 45 or GADD 153 in suppressing cell growth. PA26, an additional GADD related gene, is a possible target of p53 and it is expressed as three distinct isoforms (PA26-T1, PA26-T2 and PA26-T3) . GADD45 responds to environmental stresses by mediating activation of the p38/JNK pathway via MTK1/MEKK4 kinase. The DNA damage-induced transcription of GADD-45 is mediated by both p53-dependent and -independent mechanisms.