Dataset Information

14-3-3? turns TGF-?'s function from tumor suppressor to metastasis promoter in breast cancer by contextual changes of Smad partners from p53 to Gli2.

ABSTRACT: Transforming growth factor ? (TGF-?) functions as a tumor suppressor in premalignant cells but as a metastasis promoter in cancer cells. The dichotomous functions of TGF-? are proposed to be dictated by different partners of its downstream effector Smads. However, the mechanism for the contextual changes of Smad partners remained undefined. Here, we demonstrate that 14-3-3? destabilizes p53, a Smad partner in premalignant mammary epithelial cells, by downregulating 14-3-3?, thus turning off TGF-?'s tumor suppression function. Conversely, 14-3-3? stabilizes Gli2 in breast cancer cells, and Gli2 partners with Smads to activate PTHrP and promote TGF-?-induced bone metastasis. The 14-3-3?-driven contextual changes of Smad partners from p53 to Gli2 may serve as biomarkers and therapeutic targets of TGF-?-mediated cancer progression.

SUBMITTER: Xu J

PROVIDER: S-EPMC4325275 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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14-3-3ζ turns TGF-β's function from tumor suppressor to metastasis promoter in breast cancer by contextual changes of Smad partners from p53 to Gli2.

Xu Jia J Acharya Sunil S Sahin Ozgur O Zhang Qingling Q Saito Yohei Y Yao Jun J Wang Hai H Li Ping P Zhang Lin L Lowery Frank J FJ Kuo Wen-Ling WL Xiao Yi Y Ensor Joe J Sahin Aysegul A AA Zhang Xiang H-F XH Hung Mien-Chie MC Zhang Jitao David JD Yu Dihua D

Cancer cell 20150201 2

Transforming growth factor β (TGF-β) functions as a tumor suppressor in premalignant cells but as a metastasis promoter in cancer cells. The dichotomous functions of TGF-β are proposed to be dictated by different partners of its downstream effector Smads. However, the mechanism for the contextual changes of Smad partners remained undefined. Here, we demonstrate that 14-3-3ζ destabilizes p53, a Smad partner in premalignant mammary epithelial cells, by downregulating 14-3-3σ, thus turning off TGF- ...[more]

PMID: 25670079

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Project description:ObjectiveMetabolic stress primes monocytes for accelerated chemokine-mediated adhesion, migration, and recruitment into vascular lesions by increasing actin remodeling. The mechanism linking metabolic stress to accelerated actin turnover and enhanced monocyte migration was not known. We tested the hypothesis that in metabolically primed monocytes, the acceleration of monocyte chemoattractant protein-1-induced chemotaxis is mediated by the hyperactivation of cofilin.Approach and resultsMetabolic priming was induced by exposing human THP-1 monocytes to diabetic conditions, that is, human native low-density lipoprotein plus high glucose concentrations. In healthy monocytes, monocyte chemoattractant protein-1 induced the phosphorylation and inactivation of cofilin. This response was completely blocked in metabolically primed monocytes but restored by overexpression of the thiol transferase, glutaredoxin 1. Cofilin kinase, LIM kinase 1, and cofilin phosphatase, Slingshot-1L, were not affected by metabolic stress. However, metabolic priming increased 3.8-fold the S-glutathionylation of the Slingshot-1L-binding protein 14-3-3ζ (zeta), resulting in its caspase-dependent degradation. Glutaredoxin 1 overexpression inhibited low-density lipoprotein plus high glucose-induced S-glutathionylation and degradation of 14-3-3ζ. The C25S mutant of 14-3-3ζ was resistant to both S-glutathionylation and degradation induced by low-density lipoprotein plus high glucose. Overexpression of the C25S mutant restored monocyte chemoattractant protein-1-induced cofilin phosphorylation and prevented accelerated migration of metabolically stressed monocytes, suggesting that loss of 14-3-3ζ increases the pool of free Slingshot-1L phosphatase, thereby preventing the phosphorylation and deactivation of cofilin in response to chemokine activation.ConclusionsBy preventing the inactivation of cofilin, metabolic stress-induced degradation of 14-3-3ζ promotes the conversion of blood monocytes into a hypermigratory, proatherogenic phenotype.

Project description:Sepsis is a potential fetal organ destruction brought on through an overzealous immunologic reaction to infection, causing severe inflammation, septic shock, and damage to different organs. Although there has been progress in the identification and controlling of clinical sepsis, the fatality rates are still significant. This study, for the first time, intended to examine the possible ameliorative impact of Nebivolol, a β1-adrenergic antagonist antihypertensive drug, against nephrotoxicity resulted from cecal ligation and puncture (CLP)-induced sepsis in rats, on molecular basis. Sixty male Wistar albino rats were chosen. Oxidative stress indicators and biochemical markers of kidney activity were evaluated. Inflammatory mediators, fibrosis- and apoptosis-related proteins and gene expressions were investigated. Moreover, renal histopathological investigation was performed. CLP-induced nephrotoxicity characterized by markedly elevated serum levels of creatinine, blood urea nitrogen, uric acid, and renal malondialdhyde. On the other hand, it decreased serum total protein level, renal superoxide dismutase activity and reduced glutathione level. Additionally, it significantly elevated the renal inflammatory mediators (tumor necrosis factor-alpha, ilnerlukin (IL)-6, and IL-1β) and Caspase-3 protein, reduced IL-10 level, amplified the expression of transforming growth factor-beta 1 (TGF-β1), p-Smad2/3 and alpha-smooth-muscle actin proteins, downregulated the B cell lymphoma-2 (Bcl-2) gene and elevated the transcription of Bcl-2-associated X-protein (Bax), p53 and Nuclear factor-kappa B (NF-κB) genes. Furtheremor, kidney tissues exhibited significant histopathological changes with CLP. On the contrary, Nebivolol significantly improved all these biochemical changes and enhanced the histopathological alterations obtained by CLP. This research showed, for the first time, that Nebivolol effectively mitigated the CLP-induced kidney dysfunction via its antioxidant, antifibrotic and anti-apoptotic activity through modulation of oxidative stress, TGF-β/NF-κB and TGF-β/Smad/p53 signaling pathways.

Dataset Information

14-3-3? turns TGF-?'s function from tumor suppressor to metastasis promoter in breast cancer by contextual changes of Smad partners from p53 to Gli2.

Publications

14-3-3ζ turns TGF-β's function from tumor suppressor to metastasis promoter in breast cancer by contextual changes of Smad partners from p53 to Gli2.

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