Testosterone for the Treatment of Mammary and Prostate Cancers: Historical Perspectives and New Directions

Rogosnitzky, Moshe; Danks, Rachel

doi:10.5772/24866

Cited by 2 publications

(1 citation statement)

References 79 publications

(82 reference statements)

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“…We found that LSS‐stressed HUVECs expressing either sh WWP2 or the RAP1‐K31R mutant showed higher levels of ROS, peroxidized lipids, and oxidative DNA damage ( Figure 4 a,b,c ), indicating that the dysregulation of RAP1 ubiquitination results in increased ROS production. Given that a previous study demonstrated that treatment with Tranilast, an antioxidant and immunosuppressive drug, [ 47 ] rescued barrier function in KRIT1 ‐deficient cells dysregulated by high ROS production, [ 48 ] we examined the effect of Tranilast in our system. Similar to the effect observed in KRIT1 ‐deficient cells, Tranilast treatment normalized ROS levels and reduced permeability in HUVECs with WWP2 knockdown or expression of the RAP1‐K31R mutant (Figure 4c,d ).…”

Section: Resultsmentioning

confidence: 99%

Spatial Mechano‐Signaling Regulation of GTPases through Non‐Degradative Ubiquitination

Sewduth,

Carai,

Ivanisevic

et al. 2023

Advanced Science

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Blood flow produces shear stress exerted on the endothelial layer of the vessels. Spatial characterization of the endothelial proteome is required to uncover the mechanisms of endothelial activation by shear stress, as blood flow varies in the vasculature. An integrative ubiquitinome and proteome analysis of shear‐stressed endothelial cells demonstrated that the non‐degradative ubiquitination of several GTPases is regulated by mechano‐signaling. Spatial analysis reveals increased ubiquitination of the small GTPase RAP1 in the descending aorta, a region exposed to laminar shear stress. The ubiquitin ligase WWP2 is identified as a novel regulator of RAP1 ubiquitination during shear stress response. Non‐degradative ubiquitination fine‐tunes the function of GTPases by modifying their interacting network. Specifically, WWP2‐mediated RAP1 ubiquitination at lysine 31 switches the balance from the RAP1/ Talin 1 (TLN1) toward RAP1/ Afadin (AFDN) or RAP1/ RAS Interacting Protein 1 (RASIP1) complex formation, which is essential to suppress shear stress‐induced reactive oxygen species (ROS) production and maintain endothelial barrier integrity. Increased ROS production in endothelial cells in the descending aorta of endothelial‐specific Wwp2‐knockout mice leads to increased levels of oxidized lipids and inflammation. These results highlight the importance of the spatially regulated non‐degradative ubiquitination of GTPases in endothelial mechano‐activation.

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Section: Resultsmentioning

confidence: 99%