by
Ravi Chakra Turaga;
Lu Yin;
Jenny J Yang;
Hsiauwei Lee;
Ivaylo Ivanov;
Chunli Yan;
Hua Yang;
Hans Grossniklaus;
Siming Wang;
Cheng Ma;
Li Sun;
Zhi-Ren Liu
Integrin αν β3 expression is altered in various diseases and has been proposed as a drug target. Here we use a rational design approach to develop a therapeutic protein, which we call ProAgio, that binds to integrin αν β3 outside the classical ligand-binding site. We show ProAgio induces apoptosis of integrin αν β3 -expressing cells by recruiting and activating caspase 8 to the cytoplasmic domain of integrin αν β3. ProAgio also has anti-angiogenic activity and strongly inhibits growth of tumour xenografts, but does not affect the established vasculature. Toxicity analyses demonstrate that ProAgio is not toxic to mice. Our study reports a new integrin-targeting agent with a unique mechanism of action, and provides a template for the development of integrin-targeting therapeutics.
by
Lotte C. Houtepen;
Christiaan H. Vinkers;
Tania Carrillo-Roa;
Marieke Hiemstra;
Pol A. van Lier;
Wim Meeus;
Susan Branje;
Christine M. Heim;
Charles B. Nemeroff;
Jonathan Mill;
Leonard C Schalkwyk;
Menno P. Creyghton;
René S. Kahn;
Marian Joëls;
Elisabeth Binder;
Marco P.M. Boks
DNA methylation likely plays a role in the regulation of human stress reactivity. Here we show that in a genome-wide analysis of blood DNA methylation in 85 healthy individuals, a locus in the Kit ligand gene (KITLG; cg27512205) showed the strongest association with cortisol stress reactivity (P=5.8 × 10-6). Replication was obtained in two independent samples using either blood (N=45, P=0.001) or buccal cells (N=255, P=0.004). KITLG methylation strongly mediates the relationship between childhood trauma and cortisol stress reactivity in the discovery sample (32% mediation). Its genomic location, a CpG island shore within an H3K27ac enhancer mark, and the correlation between methylation in the blood and prefrontal cortex provide further evidence that KITLG methylation is functionally relevant for the programming of stress reactivity in the human brain. Our results extend preclinical evidence for epigenetic regulation of stress reactivity to humans and provide leads to enhance our understanding of the neurobiological pathways underlying stress vulnerability.