Splicing Variants, Protein-Protein Interactions, and Drug Targeting in Hutchinson-Gilford Progeria Syndrome and Small Cell Lung Cancer

Abstract

Alternative splicing (AS) is a biological operation that enables a messenger RNA to encode protein variants (isoforms) that give one gene several functions or properties. This process provides one of the major sources of use for understanding the proteomic diversity of multicellular organisms. In combination with post-translational modifications, it contributes to generating a variety of protein–protein interactions (PPIs) that are essential to cellular homeostasis or proteostasis. However, cells exposed to many kinds of stresses (aging, genetic changes, carcinogens, etc.) sometimes derive cancer or disease onset from aberrant PPIs caused by DNA mutations. In this review, we summarize how splicing variants may form a neomorphic protein complex and cause diseases such as Hutchinson-Gilford progeria syndrome (HGPS) and small cell lung cancer (SCLC), and we discuss how protein–protein interfaces obtained from the variants may represent efficient therapeutic target sites to treat HGPS and SCLC.

TXNL4B regulates radioresistance by controlling the PRP3‐mediated alternative splicing of FANCI

“… 12 In fact, in lung cancer, the deregulation of isoforms of splicing regulators exists in common. 13 Some of the alternative splicing factors have been reported in the regulation of lung cancer. Min Chen et al.…”

“…12 In fact, in lung cancer, the deregulation of isoforms of splicing regulators exists in common. 13 Some of the alternative splicing factors have been reported in the regulation of lung cancer. Min Chen et al found 10 key alternative splicing factors in lung squamous cell carcinoma (LUSC) through bivariate cox regression analysis.…”

“…Possible mechanisms of alternative splicing are related to alter protein domains, induce nonsense‐mediated decay, or cause protein truncation 12 . In fact, in lung cancer, the deregulation of isoforms of splicing regulators exists in common 13 . Some of the alternative splicing factors have been reported in the regulation of lung cancer.…”

Alternative Splicing in Human Physiology and Disease

“…Another interesting review analyzing the implication of alternative splicing in cancer is the one by Kim et al However, this review focuses on Hutchinson–Gilford progeria syndrome and small-cell lung cancer. The authors summarize how the formation of a neomorphic protein complex by protein isoforms encoded by distinct splice variants contribute to the pathogenesis of these diseases and suggest therapeutic strategies directed against these protein isoforms [ 13 ]. In malignant states, several cellular processes and mechanisms are deregulated, including autophagy.…”