Cell cycle regulators in neuronal death evoked by excitotoxic stress: implications for neurodegeneration and its treatment

Park, David; Obeidat, Akef; Giovanni, Andrew; Greene, Lloyd A.

doi:10.1016/s0197-4580(00)00220-7

Cited by 142 publications

(116 citation statements)

References 75 publications

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“…29 Activation of E2F1-mediated transcription in neurons upon injury, AD and PD has been reported before and has been associated to neuronal damage. 9,45,46 In our study, we observe that upon KA, the Ccnd1/Rb/E2F1 axis is positively regulated leading to an increase in transcription of PCNA and Cyclin E1 in neurons. Such regulation was absent in the RBPJKcKOs.…”

Section: Discussionsupporting

confidence: 50%

Notch signaling in response to excitotoxicity induces neurodegeneration via erroneous cell cycle reentry

et al. 2015

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Neurological disorders such as Alzheimer's disease, stroke and epilepsy are currently marred by the lack of effective treatments to prevent neuronal death. Erroneous cell cycle reentry (CCR) is hypothesized to have a causative role in neurodegeneration. We show that forcing S-phase reentry in cultured hippocampal neurons is sufficient to induce neurodegeneration. We found that kainic-acid treatment in vivo induces erroneous CCR and neuronal death through a Notch-dependent mechanism. Ablating Notch signaling in neurons provides neuroprotection against kainic acid-induced neuronal death. We further show that kainic-acid treatment activates Notch signaling, which increases the bioavailability of CyclinD1 through Akt/GSK3β pathway, leading to aberrant CCR via activation of CyclinD1-Rb-E2F1 axis. In addition, pharmacological blockade of this pathway at critical steps is sufficient to confer resistance to kainic acid-induced neurotoxicity in mice. Taken together, our results demonstrate that excitotoxicity leads to neuronal death in a Notch-dependent manner through erroneous CCR.

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Section: Discussionsupporting

confidence: 50%

Notch signaling in response to excitotoxicity induces neurodegeneration via erroneous cell cycle reentry

et al. 2015

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“…Importantly, mutated Mfn2 that is not targeted to mitochondria does not impede the cell cycle control function, suggesting that Mfn2 control of cell cycle is fusion independent and Mfn2 function as a signaling GTPase [106]. There is compelling evidence that after induction of cell death, postmitotic neurons re-enter the cell cycle at G1-S and the deregulation of cell cycle proteins participate in cell death (for a detailed review see [109][110][111][112]). For example, DNA damage induced cell death triggers post-mitotic neurons to undergo S phase reentry, and inhibition of the cell cycle machinery can protect neurons against DNA damage [113][114][115][116].…”

Section: The Role Of Mitochondrial Fusion In Cell Death: Mfn1 and Mfnmentioning

confidence: 99%

Mitochondrial dynamics in the regulation of neuronal cell death

2007

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Mitochondria undergo continuous fission and fusion events in physiological situations. Fragmentation of mitochondria during cell death has been shown to play a key role in cell death progression, including release of the mitochondrial apoptotic proteins. Ultrastructural changes in mitochondria, such as cristae remodeling, is also involved in cell death initiation. Here, we emphasize the important role of mitochondrial fission/fusion machinery in neuronal cell death. Unlike many other cell types such as immortalized cell lines, neurons are distinct morphologically and functionally. We will discuss how this uniqueness presents special challenges in the cellular response to neurotoxic stresses, and how this affects the mitochondrial dynamics in the regulation of cell death in neurons.

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“…6 Third, Rb phosphorylation is rarely observed in vivo, 4 although cyclin D1/CDK4 complex phosphorylates Rb protein in apoptotic cultured neurons. 6 Fourth, cyclin D1 induction following ischemia is associated with regeneration and resistance to apoptosis rather than a mediator of apoptosis. 5,7,8 Fifth, effectors or mediators of cyclin D1/CDK4-mediated death signal are still unknown.…”

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confidence: 99%

“…4,5 Second, cyclin D1 level is unaltered in cultured embryonic neurons following apoptosis induction. 6 Third, Rb phosphorylation is rarely observed in vivo, 4 although cyclin D1/CDK4 complex phosphorylates Rb protein in apoptotic cultured neurons. 6 Fourth, cyclin D1 induction following ischemia is associated with regeneration and resistance to apoptosis rather than a mediator of apoptosis.…”

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confidence: 99%

LIM kinase-2 induces programmed necrotic neuronal death via dysfunction of DRP1-mediated mitochondrial fission

et al. 2014

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Although the aberrant activation of cell cycle proteins has a critical role in neuronal death, effectors or mediators of cyclin D1/ cyclin-dependent kinase 4 (CDK4)-mediated death signal are still unknown. Here, we describe a previously unsuspected role of LIM kinase 2 (LIMK2) in programmed necrotic neuronal death. Downregulation of p27 Kip1 expression by Rho kinase (ROCK) activation induced cyclin D1/CDK4 expression levels in neurons vulnerable to status epilepticus (SE). Cyclin D1/CDK4 complex subsequently increased LIMK2 expression independent of caspase-3 and receptor interacting protein kinase 1 activity. In turn, upregulated LIMK2 impaired dynamic-related protein-1 (DRP1)-mediated mitochondrial fission without alterations in cofilin phosphorylation/expression and finally resulted in necrotic neuronal death. Inhibition of LIMK2 expression and rescue of DRP1 function attenuated this programmed necrotic neuronal death induced by SE. Therefore, we suggest that the ROCK-p27 Kip1 -cyclin D1/CDK4-LIMK2-DRP1-mediated programmed necrosis may be new therapeutic targets for neuronal death. The cell cycle is essential for a vital process, including proliferation, differentiation and survival of various cells. Cell cycle progression is regulated by two classes of proteins, the cyclins and the cyclin-dependent kinases (CDKs). Among them, cyclin D1 forms a complex with CDK4 and inactivates retinoblastoma protein (Rb) through phosphorylation resulting in activating E2 promoter-binding factor (E2F) family of transcription factors. Active E2F induces various gene transcriptions involving the cell cycle. 1 In post-mitotic neurons, some pathological conditions upregulate cyclin D1/CDK4 complex expression to induce activation of E2F members that contributes to increased transcription of proapoptotic molecules. 2,3 However, it is unclear whether cyclin D1 expression directly induces neuronal death for a number of following reasons. First, due to a time lag between cyclin D1/CDK4 expression and the onset of DNA fragmentation, most cyclin D1-positive neurons show TUNEL negativity. 4,5 Second, cyclin D1 level is unaltered in cultured embryonic neurons following apoptosis induction. 6 Third, Rb phosphorylation is rarely observed in vivo, 4 although cyclin D1/CDK4 complex phosphorylates Rb protein in apoptotic cultured neurons. 6 Fourth, cyclin D1 induction following ischemia is associated with regeneration and resistance to apoptosis rather than a mediator of apoptosis. 5,7,8 Fifth, effectors or mediators of cyclin D1/CDK4-mediated death signal are still unknown. Finally, neuronal death induced by various insults is morphologically necrotic rather than apoptotic. 9-12 Therefore, it is likely that some essential factors are missing in the cyclin D/CDK4-mediated neuronal death pathway.LIM kinases (LIMK1 and LIMK2) phosphorylate cofilin that is a stimulus-responsive mediator of actin dynamics. [13][14][15] Interestingly, non-phosphorylated cofilin targets mitochondrial membranes in response to apoptotic stimuli for cytochrome c releas...

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Cell cycle regulators in neuronal death evoked by excitotoxic stress: implications for neurodegeneration and its treatment

Cited by 142 publications

References 75 publications

Notch signaling in response to excitotoxicity induces neurodegeneration via erroneous cell cycle reentry

Notch signaling in response to excitotoxicity induces neurodegeneration via erroneous cell cycle reentry

Mitochondrial dynamics in the regulation of neuronal cell death

LIM kinase-2 induces programmed necrotic neuronal death via dysfunction of DRP1-mediated mitochondrial fission

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