Abstract 747: p53 activation through stress induction mediates differential regulation of target genes.

Abstract

Abstract p53 is a sequence specific transcription factor that gets up regulated in response to stress such as DNA damage, microtubule disruption or oxidative stress. p53 protein gets stabilized upon stress induction and functions by activating and repressing large number of downstream genes involved in varying functions like cell cycle, DNA repair, apoptosis or senescence depending upon type of stress. Gene activation and repression is crucial for p53 to perform its functions in the cell. p53 mediates its activation functions through its ability to bind to cis-acting DNA elements within regulatory regions. However, p53 regulates negative expression of genes either through direct recruitment on the promoter or through indirect mechanisms. Studies show that genotoxic as well as nongenotoxic stress leads to accumulation of p53 protein in cell, though the downstream effects vary under both conditions. The various cellular mechanisms that take place in the cell following DNA damage are well studied; however less is characterized about agents that disrupt microtubule assembly. To put an insight into such differential regulation mechanism, we focused to study the difference in cellular fate upon genotoxic and non genotoxic stress. In the present study, we observed that two varying stresses that include DNA damage caused by bleomycin and microtubule disruption by colchicine mediate cell cycle arrest and increased levels of p53. At the gene level, it was observed that upon bleomycin treatment, Sin3/HDAC corepressor complex is docked onto the promoters of p53 target genes whereas colchicine treatment results in dissociation of Sin3/HDAC complex from the same promoters. Moreover, recruitment of Sin3/HDAC complex is reflective of downregulation of p53 target genes and dissociation of this complex from the promoter brings about transactivation of the same genes. Therefore, our studies highlight that mere activation of p53 in varying kind of stress is not a decisive factor in gene regulation, rather interaction of p53 with corepressor or coactivator directs succeeding processes depending upon the type of stress. Citation Format: Shilpi Mittal, Rama Kadamb, Nidhi Bansal, Daman Saluja. p53 activation through stress induction mediates differential regulation of target genes. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 747. doi:10.1158/1538-7445.AM2013-747