Recent Trends in Development of Novel Therapeutics for Modulation of 14-3-3 Protein-Protein Interactions in Diseases.

Abstract

14-3-3s constitute a group of proteins belonging to the phosphoserine/phosphothreonine family that are involved in the regulation of several physiological pathways by interacting with several client proteins. All the eukaryotic cells are known to possess 14-3-3 isoforms. In addition, 14-3-3s isolated from different eukaryotic cells share high sequence homology with each other. Seven isoforms (β, γ, ε, η, ζ, σ, and τ/θ) have been yet identified in mammals. These proteins participate in several physiological processes by either stimulating or interfering with the enzymatic activities of binding partners. These proteins take part in several human diseases upon dysregulation which include cancer and neurodegenerative disorders. Recently, a number of evidences suggest that the interaction of 14-3-3s with either oncogenic or pro-apoptotic proteins can lead to cancer development in animals. In the case of neurodegenerative disorders, 14-3-3s interact with Lewy bodies and neurofibrillary tangles in Parkinson's and Alzheimer's diseases, respectively. The current review focuses on strategies to regulate 14-3-3s' proteins in diseases. Potential strategies to regulate 14-3-3 interactions in disease conditions include the use of small interfering RNAs (siRNA), microRNA (miRNA), and modifications of 14-3-3s or their client proteins. In addition, some peptides or chemicals can also serve as potential inhibitors of 14-3-3. However, optimization of these therapeutic strategies is required for their practical implementations.