Important roles of Akt/PKB signaling in the aging process
The increased costs associated with an ever-growing aged population are expected to pose a significant burden on health care resources. From a biological standpoint, aging is an accelerated deteriorative process in tissue structure and function that is associated with higher morbidity and mortality. The Akt / protein kinase B (PKB) is a family of serine / threonine protein kinases, which play prominent roles in a diverse number of processes including cell survival, cell growth, gene expression, apoptosis, protein synthesis, energy metabolism and oncogenesis. It is likely that age-related changes in tissue structure and function are related to alterations in Akt expression and Akt-dependent signaling. Here we review the role that Akt may play in the aging process and attempt, where possible, to highlight how these data may lead to new directions of inquiry and clinical relevance to the aged.
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- "ibits GSK - 3b , demonstrated by an increased phosphorylation at Ser9 . It is well known that Akt , a member of serine / threonine protein kinases , is an important upstream regulator for the inhibitory phosphorylation of GSK - 3b at Ser9 . Moreover , Akt - dependent signaling is linked to age - related structural and functional changes in human ( Wu et al . 2010 ) . Akt also plays crucial roles in cell survival , cell growth , gene expression , apoptosis , protein synthesis , energy metabolism and oncogenesis ( Scheid and Woodgett 2001 ; Vivanco and Sawyers 2002 ) . Therefore , we studied the involvement of Akt in Ngb - mediated GSK - 3b inhibition and attenuation of tau phosphorylation . We fo"
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ABSTRACT: J. Neurochem. (2012) 120, 157–164.
Neuroglobin (Ngb) is a recently identified member of hemoglobin family, distributed mainly in central and peripheral nervous systems. Recent studies suggest that Ngb can protect neural cells from β-amyloid-induced toxicity in Alzheimer disease (AD). Hyperphosphorylation of tau is another characterized pathological hallmark in the AD brains; however, it is not reported whether Ngb also affects tau phosphorylation. In this study, we found that the level of Ngb was significantly reduced in Tg2576 mice (a recognized mouse model of AD) and TgMAPt mice, and the level of Ngb was negatively correlated with tau phosphorylation. Over-expression of Ngb attenuates tau hyperphosphorylation at multiple AD-related sites induced by up-regulation of glycogen synthase kinase-3β (GSK-3β), a crucial tau kinase. While Ngb activates Akt and thus inhibits GSK-3β, simultaneously inhibition of Akt abolishes the effects of Ngb on GSK-3β inhibition and tau hyperphosphorylation. Our data indicate that Ngb may attenuate tau hyperphosphorylation through activating Akt signaling pathway, implying a therapeutic target for AD.
Available from: Kevin Daniel Kelley
- "The serine/threonine protein kinase, AKT is activated downstream of PI3 kinase in response to cellular quiescence mediated by mitogen depletion . Also known as protein kinase B, AKT functions as a critical mediator of growth factor signal transduction by phosphorylating target proteins involved in perpetuation or inhibition of cell growth and division . To explore whether FHIT gene expression was regulated through AKT signaling, transient transfections were performed where constitutively active AKT (AKT) or kinase-dead AKT (kd-AKT) were transfected into MCF7 cells that were the subsequently serum starved for 72 hours and treated with Wortmannin. "
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ABSTRACT: The Fragile Histidine Triad gene or FHIT functions as tumor suppressor in many epithelial cell types. Although its tumor suppressive mechanism is the subject of intense study, less is known about how FHIT gene expression itself is regulated. Here we show that PI3 kinase and its downstream target AKT suppress FHIT gene expression in response to growth factor stimulation in actively cycling cells. Upon removal of mitogens from the culture environment, FHIT mRNA and protein levels are observed to increase as a result of derepression from these protooncogenic kinases. AKT signaling through the FOXO transcription factors appears to be the basis for FHIT gene regulation. Increases in FHIT gene expression are directly dependent on endogenous FOXO3a in MCF7 breast carcinoma cells as evidenced by experiments with RNAi targeting FOXO transcription factor family members. Thus, this is the first report demonstrating that FHIT gene expression is normally repressed in actively cycling cells through the PI3K/AKT/FOXO3a axis.
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ABSTRACT: Excess cardiac iron levels are associated with cardiac damage and can result in increased morbidity and mortality. Here, we hypothesize that elevations in tissue iron can activate caspase-dependent signaling, which leads to increased cardiac apoptosis and fibrosis, and that these alterations can be attenuated by iron chelation. Using an iron-overloaded gerbil model, we show that increased cardiac iron is associated with reduced activation of Akt (Ser473 and Thr308), diminished phosphorylation of the proapoptotic regulator Bad (Ser136), and an increased Bax/Bcl-2 ratio. These iron-overload-induced alterations in Akt/Bad phosphorylation and Bax/Bcl-2 ratio were coupled with increased activation of the downstream caspase-9 (40/38- and 17-kDa fragments) and apoptosis executioner caspase-3 (19- and 17-kDa fragments), which were accompanied by evidence of elevated cytoskeletal α-fodrin cleavage (150- and 120-kDa fragments), discontinuity of myocardial membrane dystrophin immunoreactivity, increases in the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells (nucleic DNA fragmentation), and cardiac fibrosis. We demonstrate that the administration of deferasirox, a tridentate iron chelator, is associated with diminished tissue iron deposition, attenuated activation of caspases, reduced α-fodrin cleavage, improved membrane integrity, decreased TUNEL reactivity, and attenuated cardiac fibrosis. These results suggest that the activation of caspase-dependent signaling may play a role in the development of iron-induced cardiac apoptosis and fibrosis, and deferasirox, via a reduction in cardiac tissue iron levels, may be useful for decreasing the extent of iron-induced cardiac damage.
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