Apurinic/apyrimidinic endonuclease 1 (APE1) is a multifunctional enzyme involved in the base excision repair (BER) pathway, which repairs oxidative base damage caused by endogenous and exogenous agents. APE1 acts as a reductive activator of many transcription factors (TFs) and has also been named redox effector factor 1, Ref-1. For example, APE1 activates activator protein-1, nuclear factor kappa B, hypoxia-inducible factor 1alpha, paired box gene 8, signal transducer activator of transcription 3 and p53, which are involved in apoptosis, inflammation, angiogenesis and survival pathways. APE1/Ref-1 maintains cellular homeostasis (redox) via the activation of TFs that regulate various physiological processes and that crosstalk with redox balancing agents (for example, thioredoxin, catalase and superoxide dismutase) by controlling levels of reactive oxygen and nitrogen species. The efficiency of APE1/Ref-1's function(s) depends on pairwise interaction with participant protein(s), the functions regulated by APE1/Ref-1 include the BER pathway, TFs, energy metabolism, cytoskeletal elements and stress-dependent responses. Thus, APE1/Ref-1 acts as a 'hub-protein' that controls pathways that are important for cell survival. In this review, we will discuss APE1/Ref-1's versatile nature in various human etiologies, including neurodegeneration, cancer, cardiovascular and other diseases that have been linked with alterations in the expression, subcellular localization and activities of APE/Ref-1. APE1/Ref-1 can be targeted for therapeutic intervention using natural plant products that modulate the expression and functions of APE1/Ref-1. In addition, studies focusing on translational applications based on APE1/Ref-1-mediated therapeutic interventions are discussed.
Animals ; DNA Damage ; DNA Repair ; DNA-(Apurinic or Apyrimidinic Site) Lyase/analysis/genetics/*metabolism ; Humans ; *Molecular Targeted Therapy/methods ; Neoplasms/*drug therapy/genetics/*metabolism ; Neurodegenerative Diseases/*drug therapy/genetics/*metabolism ; Oxidative Stress ; Phytochemicals/pharmacology/*therapeutic use ; Polymorphism, Genetic ; Protein Interaction Maps

OBJECTIVETo investigate the relationship between the single nucleotide polymorphisms(SNPs) in the redox domain of aprimidinic/apurinic endonuclease/redox factor-1(APEX) gene and the development of sporadic colorectal cancer.

METHODSOne hundred and fifty cases of sporadic colorectal cancers and 143 peripheral blood samples from healthy population were screened for genetic polymorphisms or mutations in the redox domain by denaturing gradient gel electrophoresis followed by DNA sequencing.

RESULTSThere were two SNPs identified in the redox domain of APEX gene, namely, 453G to T and 1247A to G. The gene frequencies of 453T and 1247G were 1.3% and 5.7%, respectively, in patient group, while 1.05% and 4.55%, respectively, in healthy population. The genotype distribution at the two sites in healthy population was consistent with Hardy-Weinberg equilibrium. There was no difference in gene frequencies at the two sites between cancer patients and healthy population.

CONCLUSIONThe polymorphisms in the redox domain of APEX gene are irrelevant to the development of sporadic colorectal cancer, but their distribution may vary greatly among tribes.

Aged ; Alleles ; Base Sequence ; Binding Sites ; genetics ; China ; Colorectal Neoplasms ; enzymology ; genetics ; pathology ; DNA Mutational Analysis ; DNA, Neoplasm ; chemistry ; genetics ; DNA-(Apurinic or Apyrimidinic Site) Lyase ; genetics ; metabolism ; Female ; Gene Frequency ; Genotype ; Humans ; Male ; Middle Aged ; Molecular Sequence Data ; Oxidation-Reduction ; Point Mutation ; Polymorphism, Single Nucleotide