13 research outputs found
Cardiacâspecific ablation of glutaredoxin 3 leads to cardiac hypertrophy and heart failure
Abstract Growing evidence suggests that redoxâsensitive proteins including glutaredoxins (Grxs) can protect cardiac muscle cells from oxidative stressâinduced damage. Mammalian Grx3 has been shown to be critical in regulating cellular redox states. However, how Grx3 affects cardiac function by modulating reactive oxygen species (ROS) signaling remains unknown. In this study, we found that the expression of Grx3 in the heart is decreased during aging. To assess the physiological role of Grx3 in the heart, we generated mice in which Grx3 was conditionally deleted in cardiomyocytes (Grx3 conditional knockout (CKO) mice). Grx3 CKO mice were viable and grew indistinguishably from their littermates at young age. No difference in cardiac function was found comparing Grx3 CKO mice and littermate controls at this age. However, by the age of 12Â months, Grx3 CKO mice exhibited left ventricular hypertrophy with a significant decrease in ejection fraction and fractional shortening along with a significant increase of ROS production in cardiomyocytes compared to controls. Deletion of Grx3 also impaired Ca2+ handling, caused enhanced sarcoplasmic reticulum (SR) calcium (Ca2+) leak, and decreased SR Ca2+ uptake. Furthermore, enhanced ROS production and alteration of Ca2+ handling in cardiomyocytes occurred, prior to cardiac dysfunction in young mice. Therefore, our findings demonstrate that Grx3 is an important factor in regulating cardiac hypertrophy and heart failure by modulating both cellular redox homeostasis and Ca2+ handling in the heart
Lysosomeâdependent FOXA1 ubiquitination contributes to luminal lineage of advanced prostate cancer
Changes in FOXA1 (forkhead box protein A1) protein levels are well associated with prostate cancer (PCa) progression. Unfortunately, direct targeting of FOXA1 in progressive PCa remains challenging due to variations in FOXA1 protein levels, increased FOXA1 mutations at different stages of PCa, and elusive postâtranslational FOXA1 regulating mechanisms. Here, we show that SKP2 (Sâphase kinaseâassociated protein 2) catalyzes K6â and K29âlinked polyubiquitination of FOXA1 for lysosomalâdependent degradation. Our data indicate increased SKP2:FOXA1 protein ratios in stage IV human PCa compared to stages IâIII, together with a strong inverse correlation (râ=ââ0.9659) between SKP2 and FOXA1 levels, suggesting that SKP2âFOXA1 protein interactions play a significant role in PCa progression. Prostate tumors of Pten/Trp53 mice displayed increased Skp2âFoxa1âPcna signaling and colocalization, whereas disruption of the Skp2âFoxa1 interplay in Pten/Trp53/Skp2 tripleânull mice demonstrated decreased Pcna levels and increased expression of Foxa1 and luminal positive cells. Treatment of xenograft mice with the SKP2 inhibitor SZL P1â41 decreased tumor proliferation, SKP2:FOXA1 ratios, and colocalization. Thus, our results highlight the significance of the SKP2âFOXA1 interplay on the luminal lineage in PCa and the potential of therapeutically targeting FOXA1 through SKP2 to improve PCa control