Important roles of Akt/PKB signaling in the aging process.
ABSTRACT 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.
SourceAvailable from: Iakov N Rudenko[Show abstract] [Hide abstract]
ABSTRACT: Autosomal recessive parkinsonism genes contribute to maintenance of mitochondrial function. Two of these, PINK1 and parkin, act in a pathway promoting autophagic removal of depolarized mitochondria. Although recruitment of parkin to mitochondria is PINK1-dependent, additional components necessary for signaling are unclear. We performed a screen for endogenous modifiers of parkin recruitment to depolarized mitochondria and identified hexokinase 2 (HK2) as a novel modifier of depolarization-induced parkin recruitment. Hexose kinase activity was required for parkin relocalization, suggesting the effects are shared among hexokinases including the brain-expressed HK1. Knockdown of both HK1 and HK2 led to a stronger block in parkin relocalization than either isoform alone and expression of HK2 in primary neurons promoted YFP-parkin recruitment to depolarized mitochondria. Mitochondrial parkin recruitment was attenuated with AKT inhibition, which is known to modulate HK2 activity and mitochondrial localization. We therefore propose that Akt-dependent recruitment of hexokinases is a required step in the recruitment of parkin prior to mitophagy.Human Molecular Genetics 08/2013; DOI:10.1093/hmg/ddt407 · 6.68 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: 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.Journal of Neurochemistry 04/2011; 120(1):157-64. DOI:10.1111/j.1471-4159.2011.07275.x · 4.24 Impact Factor
[Show abstract] [Hide abstract]
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.American Journal of Cancer Research 01/2011; 1(1):62-70. · 3.97 Impact Factor