Covalent Modification of CDK2 by 4-Hydroxynonenal as a Mechanism of Inhibition of Cell Cycle Progression

Chemical Research in Toxicology
Jeannie M CamarilloLawrence J Marnett

Abstract

Oxidative stress is a contributing factor in a number of chronic diseases, including cancer, atherosclerosis, and neurodegenerative diseases. Lipid peroxidation that occurs during periods of oxidative stress results in the formation of lipid electrophiles, which can modify a multitude of proteins in the cell. 4-Hydroxy-2-nonenal (HNE) is one of the most well-studied lipid electrophiles and has previously been shown to arrest cells at the G1/S transition. Recently, proteomic data have shown that HNE is capable of covalently modifying CDK2, the kinase responsible for the G1/S transition. Here, we identify the sites adducted by HNE using recombinant CDK2 and show that HNE treatment suppresses the kinase activity of the enzyme. We further identify sites of adduction in HNE-treated intact human colorectal carcinoma cells (RKO) and show that HNE-dependent modification in cells is long-lived, disrupts CDK2 function, and correlates with a delay of progression of the cells into S-phase. We propose that adduction of CDK2 by HNE directly alters its activity, contributing to the cell cycle delay.

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Citations

Dec 17, 2016·Chemical Research in Toxicology·Jeannie M CamarilloLawrence J Marnett
Jul 8, 2016·American Journal of Physiology. Cell Physiology·Mason BreitzigNarasaiah Kolliputi
Dec 24, 2019·Essays in Biochemistry·Corinne M Spickett, Andrew R Pitt
Jun 20, 2019·Biochemistry. Biokhimii︠a︡·O V KosmachevskayaA F Topunov
Jun 1, 2021·ACS Central Science·Vincent M CrowleyBenjamin F Cravatt
Dec 14, 2018·Journal of Medicinal Chemistry·Solomon TadesseShudong Wang

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