APE1/Ref-1 regulates PTEN expression mediated by Egr-1

Abstract

APE1/Ref-1, the mammalian ortholog of E. coli Xth, and a multifunctional protein possessing both DNA repair and transcriptional regulatory activities, has dual role in controlling cellular response to oxidative stress. It is rate-limiting in repair of oxidative DNA damage including strand breaks and also has co-transcriptional activity by modulating genes expression directly regulated by Egr-1 and p53 transcription factors. PTEN, a phosphoinositide phosphatase, acts as an 'off' switch in the PI-3 kinase/Akt signalling pathway and regulates cell growth and survival. It is shown here that transient alteration in the APE1 level in HeLa cells modulates PTEN expression and that acetylatable APE1 is required for the activation of the PTEN gene. Acetylation of APE1 enhances its binding to distinct trans-acting complexes involved in activation or repression. The acetylated protein is deacetylated in vivo by histone deacetylases. It was found that exposure of HeLa cells to H(2)O(2) and to histone deacetylase inhibitors increases acetylation of APE1 and induction of PTEN. The absence of such induction in APE1-downregulated HeLa cells confirmed APE1's role in regulating inducible PTEN expression. That APE1-dependent PTEN expression is mediated by Egr-1 was supported by experiments with cells ectopically expressing Egr-1. Thus, the data open new perspectives in the comprehension of the many functions exerted by APE1 in controlling cell response to oxidative stress.

Loss of PTEN Expression by Blocking Nuclear Translocation of EGR1 in Gefitinib-Resistant Lung Cancer Cells Harboring Epidermal Growth Factor Receptor–Activating Mutations

“…expression loss in our resistant sublines. The expression of PTEN has also been reported to be regulated by the EGR1 transcription factor, and three EGR1-binding sites have been identified in the PTEN gene promoter (29,30,43). In this study, we showed a close correlation between PTEN expression and EGR1 expression in drug-resistant PC-9/GEF cells, suggesting that the nuclear translocation of EGR1 directly regulates the expression of PTEN: EGR1 activates transcription of the PTEN gene through binding to its consensus motif in the promoter (44).…”

Unveiling the non-repair face of the Base Excision Repair pathway in RNA processing: A missing link between DNA repair and gene expression?

“…Through the redoxmediated activation of NF-ĸB and Hif1α, for example, APE1 indirectly drives IL-8 and VEGF expression, respectively, thus acting as a key regulator of inflammatory and tumor-associated neo-angiogenesis processes. Moreover, APE1 has been implicated in chemoresistance, considering its ability to stimulate the expression of the multi-drug resistance gene MDR1 through the interaction with Y-box-binding protein 1 (YB-1) [53], and its regulatory abilities on the PTEN tumor suppressor [54,55]. We recently characterized a direct role of APE1 in the transcription of SIRT1 gene through the binding of nCaRE-sequences present on its promoter, demonstrating that BER-mediated DNA repair promotes the initiation of transcription of SIRT1 gene upon oxidative DNA damage [41].…”

Subcellular localization of apurinic endonuclease 1 promotes lung tumor aggressiveness via NF-κB activation

“…Ape1 was originally identified as a DNA repair enzyme with apurinic and apyrimidinic endonuclease activity in the base excision repair pathway (Bhakat et al, 2009;. The redox state of cysteine residues in the DNA-binding domain of several transcription factors, such as Erg-1 (Fantini et al, 2008), HIF-1a (Huang et al, 1996), p53 (Gaiddon et al, 1999) and nuclear factor (NF)-kB p50 subunit (Nishi et al, 2002;Ando et al, 2008), has been shown to affect DNA binding. NF-kB is a transcription factor important for the expression of numerous genes contributing to inflammation, and innate and adaptive immune responses (Aggarwal, 2004;Karin, 2006).…”