|Contrasting behavior of the p18INK4c and p16INK4a tumor suppressors in both replicative and oncogene-induced senescence.|
Gagrica, S; Brookes, S; Anderton, E; Rowe, J; Peters, G
The cyclin-dependent kinase (CDK) inhibitors, p18(INK4c) and p16(INK4a), both have the credentials of tumor suppressors in human cancers and mouse models. For p16(INK4a), the underlying rationale is its role in senescence, but the selective force for inactivation of p18(INK4c) in incipient cancer cells is less clear. Here, we show that in human fibroblasts undergoing replicative or oncogene-induced senescence, there is a marked decline in the levels of p18(INK4c) protein and RNA, which mirrors the accumulation of p16(INK4a). Downregulation of INK4c is not dependent on p16(INK4a), and RAS can promote the loss of INK4c without cell-cycle arrest. Downregulation of p18(INK4c) correlates with reduced expression of menin and E2F1 but is unaffected by acute cell-cycle arrest or inactivation of the retinoblastoma protein (pRb). Collectively, our data question the idea that p18(INK4c) acts as a backup for loss of p16(INK4a) and suggest that the apparent activation of p18(INK4c) in some settings represents delayed senescence rather than increased expression. We propose that the contrasting behavior of the two very similar INK4 proteins could reflect their respective roles in senescence versus differentiation.
|Dietary sodium intake regulates angiotensin II type 1, mineralocorticoid receptor, and associated signaling proteins in heart.|
Ricchiuti, V; Lapointe, N; Pojoga, L; Yao, T; Tran, L; Williams, GH; Adler, GK
The Journal of endocrinology
Liberal or high-sodium (HS) intake, in conjunction with an activated renin-angiotensin-aldosterone system, increases cardiovascular (CV) damage. We tested the hypothesis that sodium intake regulates the type 1 angiotensin II receptor (AT(1)R), mineralocorticoid receptor (MR), and associated signaling pathways in heart tissue from healthy rodents. HS (1.6% Na(+)) and low-sodium (LS; 0.02% Na(+)) rat chow was fed to male healthy Wistar rats (n=7 animals per group). Protein levels were assessed by western blot and immunoprecipitation analysis. Fractionation studies showed that MR, AT(1)R, caveolin-3 (CAV-3), and CAV-1 were located in both cytoplasmic and membrane fractions. In healthy rats, consumption of an LS versus a HS diet led to decreased cardiac levels of AT(1)R and MR. Decreased sodium intake was also associated with decreased cardiac levels of CAV-1 and CAV-3, decreased immunoprecipitation of AT(1)R-CAV-3 and MR-CAV-3 complexes, but increased immunoprecipitation of AT(1)R/MR complexes. Furthermore, decreased sodium intake was associated with decreased cardiac extracellular signal-regulated kinase (ERK), phosphorylated ERK (pERK), and pERK/ERK ratio; increased cardiac striatin; decreased endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS (peNOS), but increased peNOS/eNOS ratio; and decreased cardiac plasminogen activator inhibitor-1. Dietary sodium restriction has beneficial effects on the cardiac expression of factors associated with CV injury. These changes may play a role in the cardioprotective effects of dietary sodium restriction.
|The pathogenic role of the canonical Wnt pathway in age-related macular degeneration.|
Zhou, T; Hu, Y; Chen, Y; Zhou, KK; Zhang, B; Gao, G; Ma, JX
Investigative ophthalmology & visual science
The authors' previous studies showed that the Wnt signaling pathway is activated in the retinas and retinal pigment epithelia of animal models of age-related macular degeneration (AMD) and diabetic retinopathy (DR). The purpose of this study was to investigate the role of the canonical Wnt pathway in pathogenesis of these diseases.The Wnt pathway was activated using the Wnt3a-conditioned medium and adenovirus expressing a constitutively active mutant of beta-catenin (Ad-S37A) in ARPE19, a cell line derived from human RPE. Ad-S37A was injected into the vitreous of normal rats to activate the Wnt pathway in the retina. Accumulation of beta-catenin was determined by Western blot analysis, and its nuclear translocation was revealed by immunocytochemistry. Inflammatory factors were quantified by Western blot analysis and ELISA. Oxidative stress was determined by measuring intracellular reactive oxygen species (ROS) generation and nitrotyrosine levels.The Wnt3a-conditioned medium and Ad-S37A both increased beta-catenin levels and its nuclear translocation in ARPE19 cells, suggesting activation of the canonical Wnt pathway. Activation of the Wnt pathway significantly upregulated the expression of VEGF, NF-kappaB, and TNF-alpha. Further, Ad-S37A induced ROS generation in a dose-dependent manner. Wnt3a also induced a twofold increase of ROS generation. Intravitreal injection of Ad-S37A upregulated the expression of VEGF, ICAM-1, NF-kappaB, and TNF-alpha and increased protein nitrotyrosine levels in the retinas of normal rats.Activation of the canonical Wnt pathway is sufficient to induce retinal inflammation and oxidative stress and plays a pathogenic role in AMD and DR.Full Text Article
|Cisd2 deficiency drives premature aging and causes mitochondria-mediated defects in mice.|
Yi-Fan Chen, Cheng-Heng Kao, Ya-Ting Chen, Chih-Hao Wang, Chia-Yu Wu, Ching-Yen Tsai, Fu-Chin Liu, Chu-Wen Yang, Yau-Huei Wei, Ming-Ta Hsu, Shih-Feng Tsai, Ting-Fen Tsai, Yi-Fan Chen, Cheng-Heng Kao, Ya-Ting Chen, Chih-Hao Wang, Chia-Yu Wu, Ching-Yen Tsai, Fu-Chin Liu, Chu-Wen Yang, Yau-Huei Wei, Ming-Ta Hsu, Shih-Feng Tsai, Ting-Fen Tsai, Yi-Fan Chen, Cheng-Heng Kao, Ya-Ting Chen, Chih-Hao Wang, Chia-Yu Wu, Ching-Yen Tsai, Fu-Chin Liu, Chu-Wen Yang, Yau-Huei Wei, Ming-Ta Hsu, Shih-Feng Tsai, Ting-Fen Tsai
CISD2, the causative gene for Wolfram syndrome 2 (WFS2), is a previously uncharacterized novel gene. Significantly, the CISD2 gene is located on human chromosome 4q, where a genetic component for longevity maps. Here we show for the first time that CISD2 is involved in mammalian life-span control. Cisd2 deficiency in mice causes mitochondrial breakdown and dysfunction accompanied by autophagic cell death, and these events precede the two earliest manifestations of nerve and muscle degeneration; together, they lead to a panel of phenotypic features suggestive of premature aging. Our study also reveals that Cisd2 is primarily localized in the mitochondria and that mitochondrial degeneration appears to have a direct phenotypic consequence that triggers the accelerated aging process in Cisd2 knockout mice; furthermore, mitochondrial degeneration exacerbates with age, and the autophagy increases in parallel to the development of the premature aging phenotype. Additionally, our Cisd2 knockout mouse work provides strong evidence supporting an earlier clinical hypothesis that WFS is in part a mitochondria-mediated disorder; specifically, we propose that mutation of CISD2 causes the mitochondria-mediated disorder WFS2 in humans. Thus, this mutant mouse provides an animal model for mechanistic investigation of Cisd2 protein function and help with a pathophysiological understanding of WFS2.Full Text Article