The Intracellular Localization of APE1/Ref-1: More than a Passive Phenomenon?

Abstract

Human apul'inic/apyrimidinic endonuclease l/redox effector factor-1 (APEl/Ref·l) is a perfect paradigm of the functional complexity of a biological macromolecule. First, it plays a crucial role, by both redox-dependent and -independent mechanisms, as a transcriptional coactivator for different trnnscription factors, either ubiquitous (i.e., AP-1, Egr-1, NF-KB, p53, HIF) or tissue-specific (i.e., PEBP-2, Pax-Sand -8, TTF-1), in controlling different cellular processes such as apoptosis, proliferation, and differentiation. Second, it acts, as an apurinidapyrimidinic endonuclease, during the second step of the DNA base excision repair pathway, which is responsible for the repair of cellular alkylation and oxidative DNA damages. Thil'd, it controls the intracellular reactive oxygen species production by negatively regulating the activity of the Ras-related GTPase Rael. Despite these known functions of APEl/Ref-1, information is still scanty about the molecular mechanisms responsible for the coordinated control of its several activities. Some evidence suggests that the expression and subcellular localization of APEl/Ref-1 are finely tuned. APEl/Ref-1 is a ubiquitous protein, but its expression pattern differs according to the different cell types. APEl/Ref-1 subcellular localization is mainly nuclear, but cytop1asmic staining has also been reported, the latter being associated with mitochondria and/or presence within the endoplasmic reticulum. It is not by chance that both expression and sub cellular localization a1·e altered in several metabolic and proliferative disorde1·s, such as in tumors and aging. Moreover, a fundamental role played by different posttranslational modifications in modulating APEl/Ref·l functional activity is becoming eYident. In the present review, we tded to put togethe1· a growing body of information concerning APEl/Ref-l's different functions, shedding new light on present and future directions to understand fully this unique molecule. Antioxid. Redox Signal. 7,[367][368][369][370][371][372][373][374][375][376][377][378][379][380][381][382][383][384]

E2F1 and E2F2 prevent replicative stress and subsequent p53-dependent organ involution

“…23 However, ROS or Apex1 protein accumulation was not detected in young DKO mice (Figures 1f and g), and only older diabetic DKO mice showed elevated ROS accumulation (Figure 1g), indicating that activation of p53 pathway in DKO pancreas is not ROS dependent.…”

Chimeric adenoviral vector Ad5/F35-mediated APE1 siRNA enhances sensitivity of human colorectal cancer cells to radiotherapy in vitro and in vivo

“…36 NF-kB activity was found to be a redox regulated by and dependent on APE1. 13 Our data showed irradiation-induced activation of NF-kB.…”

Cytoplasmic Localization and Redox Cysteine Residue of APE1/Ref-1 Are Associated with Its Anti-Inflammatory Activity in Cultured Endothelial Cells

“…The APE1/Ref-1 subcellular localization is mainly nuclear, but cytoplasmic identification has also been reported, especially during high metabolic or proliferative states (Duguid et al, 1995;Kakolyris et al, 1998;Tell et al, 2005). Some evidence suggests that APE1/Ref-1 expression and subcellular localization are finely tuned.…”

“…Although APE1/Ref-1 is mainly observed in the nucleus, cytoplasmic APE1/Ref-1 has been reported in response to various stimuli Lee et al, 2011;Tell et al, 2005). However, the functional role of cytoplasmic APE1/Ref-1 has not been experimentally defined.…”