Abstract LB-51: p53 transcriptionally represses the SALL2 transcription factor under genotoxic stress.

Abstract

Abstract SALL2- a member of the Spalt gene family- is a poorly characterized transcription factor found deregulated in various cancers, which suggest it plays a role in the disease. We previously identified SALL2 as a novel interacting protein of neurotrophin receptors and showed that it plays a role in neuronal function, which does not necessarily explain why or how SALL2 is deregulated in cancer. Previous evidences indicate that SALL2 gene is regulated by the WT1 and AP4 transcription factors. Here, we identified SALL2 as a novel downstream target of the P53 tumor suppressor protein. Bioinformatic analysis of the SALL2 gene revealed several putative P53 half sites along the promoter region. Either overexpression of wild-type P53 or induction of the endogenous P53 by the genotoxic agent doxorubicin repressed SALL2 promoter activity in various cell lines. However, Q143A, R175H and R248W P53 mutants, which are frequently found in the tumors of cancer patients, were unable to repress SALL2 promoter activity. Chromatin immunoprecipitation analysis using a specific P53 antibody further supported the binding to, and regulation of the SALL2 promoter by P53. Importantly, by using a p53ERTAM knockin model expressing a variant of P53 that is completely dependent on 4-hydroxy-tamoxifen for its activity, we show that P53 activation diminished SALL2 RNA and protein levels during genotoxic cellular stress in primary mouse embryo fibroblasts (MEFs) and radiosentive tissues in vivo. Thus, our finding indicates that P53 represses SALL2 expression in a context-specific manner, adding knowledge to understanding SALL2 gene regulation, and a potential mechanism for its deregulation in cancer Citation Format: Carlos Farkas, Carla Martins, David Escobar, Ariel Castro, David Donner, Roxana Pincheira. p53 transcriptionally represses the SALL2 transcription factor under genotoxic stress. [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 LB-51. doi:10.1158/1538-7445.AM2013-LB-51