Association of single-nucleotide polymorphisms of the KEAP1 gene with the risk of various human diseases and its functional impact using in silico analysis. (November 2018)

• Record Type: Journal Article
• Authors: Dhamodharan, Umapathy; Ponjayanthi, Balashanmugam; Sireesh, Dornadula; Bhakkiyalakshmi, Elango; Ramkumar, Kunka Mohanram
• Is Part Of: Pharmacological research. Volume 137(2018)
• Page Start: 205
• Page End: 218
• Publication Date: 2018-11
• Subjects: Free radicals -- Keap1 -- Mutation -- Nrf2 -- Single nucleotide polymorphism; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2018.10.003
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: Keap1, Kelch-like erythroid derived Cap 'n' collar homology (ECH) associated protein 1 is a highly redox-sensitive member of the BTB-Kelch substrate adaptor protein which acts as a major upstream regulator of Nrf2 (Nuclear factor erythroid 2-related factor 2) by Cul3 ubiquitin E3 ligase complex, leading to its proteasomal degradation. Oxidative and electrophilic stresses impair the structural integrity of Keap1-Cul3 ubiquitin E3 ligase complex resulting in the dissociation of Nrf2-Keap1 binding and nuclear accumulation of Nrf2. Studies on tissue-specific Keap1 null mutation have demonstrated the important roles of Keap1 mediated Nrf2 degradation. An increasing body of evidence suggests that loss of functional mutation in Keap1 arbitrates constitutive activation and expression of Nrf2 which in turn provokes the chemotherapeutic resistance in various diseases. The current review addresses the genetic aspects of KEAP1 including somatic mutations and in silico functional profiling of human disease-associated and polymorphic amino acid substitutions.