Expression of mRNA for Akt, serine-threonine protein kinase, in the brain during development and its transient enhancement following axotomy of hypoglossal nerve

Owada, Yuji; Utsunomiya, Akihiro; Yoshimoto, Takashi; Kondo, Hisatake

doi:10.1007/bf02789392

Cited by 49 publications

(31 citation statements)

References 20 publications

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“…9A). Total Akt levels were reduced but not absent because of the presence of other Akt isoforms (14). Levels of phospho-GSK3␤ S9, a known consensus substrate of Akt, were also significantly reduced.…”

Section: Resultsmentioning

confidence: 95%

Akt and CHIP coregulate tau degradation through coordinated interactions

Dickey¹,

Koren²,

Zhang

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

200

174

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A hallmark of the pathology of Alzheimer's disease is the accumulation of the microtubule-associated protein tau into fibrillar aggregates. Recent studies suggest that they accumulate because cytosolic chaperones fail to clear abnormally phosphorylated tau, preserving a pool of toxic tau intermediates within the neuron. We describe a mechanism for tau clearance involving a major cellular kinase, Akt. During stress, Akt is ubiquitinated and degraded by the tau ubiquitin ligase CHIP, and this largely depends on the Hsp90 complex. Akt also prevents CHIP-induced tau ubiquitination and its subsequent degradation, either by regulating the Hsp90/CHIP complex directly or by competing as a client protein with tau for binding. Akt levels tightly regulate the expression of CHIP, such that, as Akt levels are suppressed, CHIP levels also decrease, suggesting a potential stress response feedback mechanism between ligase and kinase activity. We also show that Akt and the microtubule affinity-regulating kinase 2 (PAR1/MARK2), a known tau kinase, interact directly. Akt enhances the activity of PAR1 to promote tau hyperphosphorylation at S262/S356, a tau species that is not recognized by the CHIP/Hsp90 complex. Moreover, Akt1 knockout mice have reduced levels of tau phosphorylated at PAR1/MARK2 consensus sites. Hence, Akt serves as a major regulator of tau biology by manipulating both tau kinases and protein quality control, providing a link to several common pathways that have demonstrated dysfunction in Alzheimer's disease.Alzheimer's disease ͉ cell signaling ͉ chaperone ͉ MARK2/PAR1

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Section: Resultsmentioning

confidence: 95%

Akt and CHIP coregulate tau degradation through coordinated interactions

Dickey¹,

Koren²,

Zhang

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

200

174

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“…One of the central components in signaling pathways promoting neuronal survival is the serine/threonine kinase Akt, also known as protein kinase B. 6 This kinase is present at low levels in the adult brain, 7 but its expression and activation increase dramatically in neurons during cellular stress or injury. 8 For instance, activated Akt has been proposed as an important neuroprotective pathway in distinct acute 7,9,10,11 and chronic 12,13 models of neurodegeneration.…”

mentioning

confidence: 99%

“…6 This kinase is present at low levels in the adult brain, 7 but its expression and activation increase dramatically in neurons during cellular stress or injury. 8 For instance, activated Akt has been proposed as an important neuroprotective pathway in distinct acute 7,9,10,11 and chronic 12,13 models of neurodegeneration. In HD, Akt has been proposed as a crucial neuroprotective pathway because it is one of the serine/threonine kinases that phosphorylate the Ser421 of mutant htt (mhtt) attenuating its toxicity.…”

mentioning

confidence: 99%

PH domain leucine-rich repeat protein phosphatase 1 contributes to maintain the activation of the PI3K/Akt pro-survival pathway in Huntington's disease striatum

et al. 2009

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Dysregulation of gene expression is one of the mechanisms involved in the pathophysiology of Huntington's disease (HD). Here, we examined whether mutant huntingtin regulates the levels of PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1), a phosphatase that specifically dephosphorylates Akt at Ser473. Our results show decreased PHLPP1 protein levels in knock-in models (Hdh Q111/Q111 mouse striatum and STHdh Q111/Q111 cells), in the striatum of N-terminal exon-1 mutant huntingtin transgenic mouse models (R6/1; R6/1 : BDNF þ /À, R6/2 and Tet/HD94) and in the putamen of HD patients. Quantitative PCR analysis revealed a reduction in PHLPP1 mRNA levels in the striatum of R6/1 compared with wild-type mice. Coincident with reduced PHLPP1 protein levels, we observed increased phosphorylated Akt (Ser473) levels specifically in the striatum. The analysis of the conditional mouse model Tet/HD94 disclosed that after mutant huntingtin shutdown PHLPP1 levels returned to wild-type levels whereas phospho-Akt levels were partially reduced. In conclusion, our results show that mutant huntingtin downregulates PHLPP1 expression. In the striatum, these reduced levels of PHLPP1 can contribute to maintain high levels of activated Akt that may delay cell death and allow the recovery of neuronal viability after mutant huntingtin silencing.

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“…In the central nervous system, the gene expression for Akt1 and Akt2 is present at high levels in the brain during development, but is gradually decreased during postnatal periods [167]. In the adult, gene expression for Akt1 and Akt2 is normally subdued, but quickly increased in response to a variety of environmental factors.…”

Section: Expression Of Akt Occurs Throughout Mammalian Tissues But Imentioning

confidence: 99%

Stress in the brain: novel cellular mechanisms of injury linked to Alzheimer's disease

Chong

Maiese

2005

Brain Research Reviews

135

121

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More than a century has elapsed since the description of Alois Alzheimer's patient Auguste D. Yet, the well-documented generation of β-amyloid aggregates and neurofibrillary tangles that define Alzheimer's disease is believed to represent only a portion of the cellular processes that can determine the course of Alzheimer's disease. Understanding of the complex nature of this disorder has evolved with an increased appreciation for pathways that involve the generation of reactive oxygen species and oxidative stress, apoptotic injury that leads to nuclear degradation in both neuronal and vascular populations, and the early loss of cellular membrane asymmetry that mitigates inflammation and vascular occlusion. Recent work has identified novel pathways, such as the Wnt pathway and the serine-threonine kinase Akt, as central modulators that oversee cellular apoptosis and the formation of neurofibrillary tangles through their downstream substrates that include glycogen synthase kinase-3β, Bad, and Bcl-x L . Other closely integrated pathways control microglial activation, release of inflammatory cytokines, and caspase and calpain activation for the processing of amyloid precursor protein, tau protein cleavage, and presenilin disposal. New therapeutic avenues that are just open to exploration, such as with nicotinamide adenine dinucleotide modulation, cell cycle modulation, metabotropic glutamate system modulation, and erythropoietin targeted expression, may provide both attractive and viable alternatives to treat Alzheimer's disease.

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Expression of mRNA for Akt, serine-threonine protein kinase, in the brain during development and its transient enhancement following axotomy of hypoglossal nerve

Cited by 49 publications

References 20 publications

Akt and CHIP coregulate tau degradation through coordinated interactions

Akt and CHIP coregulate tau degradation through coordinated interactions

PH domain leucine-rich repeat protein phosphatase 1 contributes to maintain the activation of the PI3K/Akt pro-survival pathway in Huntington's disease striatum

Stress in the brain: novel cellular mechanisms of injury linked to Alzheimer's disease

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