FoxO mediates APP-induced AICD-dependent cell death

Wang, X; Wang, Z; Chen, Y; Huang, Xin; Hu, Yi; Zhang, R; Ho, Margaret S.; Xue, Lei

doi:10.1038/cddis.2014.196

Cited by 54 publications

(66 citation statements)

References 53 publications

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“…The other cleavage products created by α- and β-cleavage, CTF83 and CTF99, respectively, do not have well defined roles. However, γ-secretase cleavage of the CTFs results in the release of the APP Intracellular Domain (AICD), which binds Fe65 and TIP60 for potential transcriptional activation of downstream targets (Cao and Sudhof, 2001), ultimately promoting cell death and impairing neurogenesis (Ghosal et al, 2010; Wang et al, 2014). The final and most-studied products of APP cleavage are the Aβ species, predominantly Aβ 40 and some Aβ 42 .…”

Section: App Processing and The Endosomementioning

confidence: 99%

More than Cholesterol Transporters: Lipoprotein Receptors in CNS Function and Neurodegeneration

Lane-Donovan

Philips

Herz

2014

Neuron

128

117

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Members of the low-density lipoprotein (LDL) receptor gene family have a diverse set of biological functions that transcend lipid metabolism. Lipoprotein receptors have broad effects in both the developing and adult brain and participate in synapse development, cargo trafficking, and signal transduction. In addition, several family members play key roles in Alzheimer's disease pathogenesis and neurodegeneration. This review summarizes our current understanding of the role lipoprotein receptors play in CNS function and AD pathology, with a special emphasis on amyloid-independent roles in endocytosis and synaptic dysfunction.

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Section: App Processing and The Endosomementioning

confidence: 99%

More than Cholesterol Transporters: Lipoprotein Receptors in CNS Function and Neurodegeneration

Lane-Donovan

Philips

Herz

2014

Neuron

128

117

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“…Very recently, FOXO has also been implicated in drug-mediated cytoskeletal stress because of its effects on neuronal mt organization following pharmacological damage, which requires Akt kinase [19, 20]. Importantly, some FOXO transcription factors also influence the PTX-induced inhibition of the androgen receptor (AR), suggesting a connection between the mt-dependent trafficking of the AR and the clinical efficacy of PTX as well as that of other taxanes [21].…”

Section: Introductionmentioning

confidence: 99%

Multiplicity of acquired cross-resistance in paclitaxel-resistant cancer cells is associated with feedback control of TUBB3 via FOXO3a-mediated ABCB1 regulation

et al. 2016

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Acquired drug resistance is a primary obstacle for effective cancer therapy. The correlation of point mutations in class III β-tubulin (TUBB3) and the prominent overexpression of ATP-binding cassette P-glycoprotein (ABCB1), a multidrug resistance gene, have been protruding mechanisms of resistance to microtubule disruptors such as paclitaxel (PTX) for many cancers. However, the precise underlying mechanism of the rapid onset of cross-resistance to an array of structurally and functionally unrelated drugs in PTX-resistant cancers has been poorly understood. We determined that our established PTX-resistant cancer cells display ABCB1/ABCC1-associated cross-resistance to chemically different drugs such as 5-fluorouracil, docetaxel, and cisplatin. We found that feedback activation of TUBB3 can be triggered through the FOXO3a-dependent regulation of ABCB1, which resulted in the accentuation of induced PTX resistance and encouraged multiplicity in acquired cross-resistance. FOXO3a-directed regulation of P-glycoprotein (P-gp) function suggests that control of ABCB1 involves methylation-dependent activation. Consistently, transcriptional overexpression or downregulation of FOXO3a directs inhibitor-controlled protease-degradation of TUBB3. The functional PI3K/Akt signaling is tightly responsive to FOXO3a activation alongside doxorubicin treatment, which directs FOXO3a arginine hypermethylation. In addition, we found that secretome factors from PTX-resistant cancer cells with acquired cross-resistance support a P-gp-dependent association in multidrug resistance (MDR) development, which assisted the FOXO3a-mediated control of TUBB3 feedback. The direct silencing of TUBB3 reverses induced multiple cross-resistance, reduces drug-resistant tumor mass, and suppresses the impaired microtubule stability status of PTX-resistant cells with transient cross-resistance. These findings highlight the control of the TUBB3 response to ABCB1 genetic suppressors as a mechanism to reverse the profuse development of multidrug resistance in cancer.

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“…Although Foxo3 has not been identified as an upstream regulator of APP processing, a recent study identified Foxo3 as a downstream target of APP, which induces APP intracellular domain (AICD)-induced death in neuronal and non-neuronal tissues (Wang et al, 2014). Glutamate treatment led to an ∼2-fold increase in APP promoter activity in 12 h, which gradually increased to 2.5-fold by 24 h (Fig.…”

Section: Activation Of Foxo3 Is Neurotoxic In Glutamate-treated Cellsmentioning

confidence: 99%

Cdk5–Foxo3 axis: initially neuroprotective, eventually neurodegenerative in Alzheimer's disease models

Shi

Viccaro

Lee

et al. 2016

Journal of Cell Science

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Deregulated Cdk5 causes neurotoxic amyloid beta peptide (Aβ) processing and cell death, two hallmarks of Alzheimer's disease, through the Foxo3 transcriptional factor in hippocampal cells, primary neurons and an Alzheimer's disease mouse model. Using an innovative chemical genetic screen, we identified Foxo3 as a direct substrate of Cdk5 in brain lysates. Cdk5 directly phosphorylates Foxo3, which increased its levels and nuclear translocation. Nuclear Foxo3 initially rescued cells from ensuing oxidative stress by upregulating MnSOD (also known as SOD2). However, following prolonged exposure, Foxo3 upregulated Bim (also known as BCL2L11) and FasL (also known as FASLG) causing cell death. Active Foxo3 also increased Aβ(1-42) levels in a phosphorylationdependent manner. These events were completely inhibited either by expressing phosphorylation-resistant Foxo3 or by depleting Cdk5 or Foxo3, highlighting a key role for Cdk5 in regulating Foxo3. These results were confirmed in an Alzheimer's disease mouse model, which exhibited increased levels and nuclear localization of Foxo3 in hippocampal neurons, which preceded neurodegeneration and Aβ plaque formation, indicating this phenomenon is an early event in Alzheimer's disease pathogenesis. Collectively, these results show that Cdk5-mediated phospho-regulation of Foxo3 can activate several genes that promote neuronal death and aberrant Aβ processing, thereby contributing to the progression of neurodegenerative pathologies.

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FoxO mediates APP-induced AICD-dependent cell death

Cited by 54 publications

References 53 publications

More than Cholesterol Transporters: Lipoprotein Receptors in CNS Function and Neurodegeneration

More than Cholesterol Transporters: Lipoprotein Receptors in CNS Function and Neurodegeneration

Multiplicity of acquired cross-resistance in paclitaxel-resistant cancer cells is associated with feedback control of TUBB3 via FOXO3a-mediated ABCB1 regulation

Cdk5–Foxo3 axis: initially neuroprotective, eventually neurodegenerative in Alzheimer's disease models

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