p27 small interfering RNA induces cell death through elevating cell cycle activity in cultured cortical neurons: a proof-of-concept study

Akashiba, Hiroki; Matsuki, Naoaki; Nishiyama, N.

doi:10.1007/s00018-006-6002-1

Cited by 7 publications

(13 citation statements)

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“…44,65 In this context, interfering RNA against p27 Kip1 has been shown to induce cell death in cultured cortical neurons. 70 In contrast, no signs of apoptosis were evident in RGCs incorporating BrdU in our experiments, thus indicating that the mechanisms regulating endoreplication in the chick retina may differ from those in the mouse. This differential apoptotic response that allows the survival of avian RGCs with a DNA content above 4C may explain the presence of hyperploid RGCs in the chick but not in the mouse retina.…”

Section: Discussioncontrasting

confidence: 53%

p27^Kip1participates in the regulation of endoreplication in differentiating chick retinal ganglion cells

Ovejero‐Benito

Frade

2015

Cell Cycle

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Nuclear DNA duplication in the absence of cell division (i.e. endoreplication) leads to somatic polyploidy in eukaryotic cells. In contrast to some invertebrate neurons, whose nuclei may contain up to 200,000-fold the normal haploid DNA amount (C), polyploid neurons in higher vertebrates show only 4C DNA content. To explore the mechanism that prevents extra rounds of DNA synthesis in these latter cells we focused on the chick retina, where a population of tetraploid retinal ganglion cells (RGCs) has been described. We show that differentiating chick RGCs that express the neurotrophic receptors p75 and TrkB while lacking retinoblastoma protein, a feature of tetraploid RGCs, also express p27 Kip1 . Two different short hairpin RNAs (shRNA) that significantly downregulate p27 Kip1 expression facilitated DNA synthesis and increased ploidy in isolated chick RGCs. Moreover, this forced DNA synthesis could not be prevented by Cdk4/6 inhibition, thus suggesting that it is triggered by a mechanism similar to endoreplication. In contrast, p27 Kip1 deficiency in mouse RGCs does not lead to increased ploidy despite previous observations have shown ectopic DNA synthesis in RGCs from p27 Kip1¡/¡ mice. This suggests that a differential mechanism is used for the regulation of neuronal endoreplication in mammalian versus avian RGCs.

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Section: Discussioncontrasting

confidence: 53%

p27^Kip1participates in the regulation of endoreplication in differentiating chick retinal ganglion cells

Ovejero‐Benito

Frade

2015

Cell Cycle

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“…Nevertheless, we argue that miR-26b-induced CCE is unlikely to be merely a coincident event for the following reasons: (1) it is established by numerous publications that induction of CCE in postmitotic neurons is tightly linked and can lead to cell death in various systems, even in the absence of transcriptional induction of apoptotic genes Andrusiak et al, 2012); (2) in our system, induction of proliferative markers Ki67 and PCNA was an early event observed 3 d post miR-26b transfection; and (3) one of the most pronounced effects of miR-26b OE was strong downregulation of the cell cycle inhibitor p27 kip1 , the event sufficient to induce death of cortical neurons in vitro and in vivo (Akashiba et al, 2006;Ye and Blain, 2010).…”

Section: Mir-26b Directly Regulates Expression Of Rb Protein In Neuromentioning

confidence: 59%

MiR-26b, Upregulated in Alzheimer's Disease, Activates Cell Cycle Entry, Tau-Phosphorylation, and Apoptosis in Postmitotic Neurons

et al. 2013

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MicroRNA (miRNA) functions in the pathogenesis of major neurodegenerative diseases such as Alzheimer's disease (AD) are only beginning to emerge. We have observed significantly elevated levels of a specific miRNA, miR-26b, in the defined pathological areas of human postmortem brains, starting from early stages of AD (Braak III). Ectopic overexpression of miR-26b in rat primary postmitotic neurons led to the DNA replication and aberrant cell cycle entry (CCE) and, in parallel, increased tau-phosphorylation, which culminated in the apoptotic cell death of neurons. Similar tau hyperphosphorylation and CCE are typical features of neurons in pre-AD brains. Sequence-specific inhibition of miR-26b in culture is neuroprotective against oxidative stress. Retinoblastoma protein (Rb1), a major tumor suppressor, appears as the key direct miR-26b target, which mediates the observed neuronal phenotypes. The downstream signaling involves upregulation of Rb1/E2F cell cycle and pro-apoptotic transcriptional targets, including cyclin E1, and corresponding downregulation of cell cycle inhibitor p27/Kip1. It further leads to nuclear export and activation of Cdk5, a major kinase implicated in tau phosphorylation, regulation of cell cycle, and death in postmitotic neurons. Therefore, upregulation of miR-26b in neurons causes pleiotropic phenotypes that are also observed in AD. Elevated levels of miR-26b may thus contribute to the AD neuronal pathology.

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“…Glutamate excitotoxicity activates calpain protease that downregulates the expression of the cyclin-dependent kinase inhibitor p27 [34]. Elevated expression of p27 promotes survival of sympathetic neurons from DNAdamage-induced injury [36], whereas ablation of p27 induces cell death of cultured cortical neurons [33] and enhances kainate-induced seizures and hippocampal degeneration [37]. One of the possible mechanisms attributed to a anti-apoptotic role of p27 may be to prevent inappropriate cell cycle reentry (see review in [38]).…”

Section: Discussionmentioning

confidence: 99%

“…Ischemic injury reduces p27 expression and activates inappropriate cell cycle reentry as an early sign of neuronal cell death [33]. GCSF and TSA maintained p27 expression in wildtype but not in LMO4 null cortical neurons in the face of ischemia-like insult caused by KCN exposure (Fig.…”

Section: Effect Of Gcsf On the Expression Of The Cell Cycle Regulatormentioning

confidence: 93%

“…The cyclin-dependent kinase inhibitor p27 is a known target of Stat3 signaling [32] and is important to prevent inappropriate cell cycle entry and cell death in differentiated cortical neurons [33,34]. GCSF upregulated the expression of p27 in wild-type but not in LMO4 null cortical neurons (Fig.…”

Section: Effect Of Gcsf On the Expression Of The Cell Cycle Regulatormentioning

confidence: 97%

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LIM domain only 4 protein promotes granulocyte colony-stimulating factor-induced signaling in neurons

Gomez-Smith

Qin

Zhou

et al. 2009

Cell. Mol. Life Sci.

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Granulocyte colony-stimulating factor (GCSF) is currently in clinical trials to treat neurodegenerative diseases and stroke. Here, we tested whether LIM domain only 4 protein (LMO4), a hypoxia-inducible gene that protects neurons from ischemic injury, could modulate the neuroprotective effect of GCSF. We showed that GCSF treatment acetylates and phosphorylates Stat3, activates expression of a Stat3-dependent anti-apoptotic gene, p27, and increases neuron survival from ischemic injury. LMO4 participates in Stat3 signaling in hepatocytes and associates with histone deacetylase 2 (HDAC2) in cancer cells. In the absence of LMO4, GCSF fails to rescue neurons from ischemic insults. In wild-type neurons, inhibition of HDAC promoted Stat3 acetylation and the antiapoptotic effect of GCSF. In LMO4 null cortical neurons, expression of wild-type but not HDAC-interaction-deficient LMO4 restored GCSF-induced Stat3 acetylation and p27 expression. Thus, our results indicate that LMO4 enhances GCSF-induced Stat3 signaling in neurons, in part by sequestering HDAC.

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p27 small interfering RNA induces cell death through elevating cell cycle activity in cultured cortical neurons: a proof-of-concept study

Cited by 7 publications

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p27^Kip1participates in the regulation of endoreplication in differentiating chick retinal ganglion cells

p27^Kip1participates in the regulation of endoreplication in differentiating chick retinal ganglion cells

MiR-26b, Upregulated in Alzheimer's Disease, Activates Cell Cycle Entry, Tau-Phosphorylation, and Apoptosis in Postmitotic Neurons

LIM domain only 4 protein promotes granulocyte colony-stimulating factor-induced signaling in neurons

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p27 small interfering RNA induces cell death through elevating cell cycle activity in cultured cortical neurons: a proof-of-concept study

Cited by 7 publications

References 0 publications

p27Kip1participates in the regulation of endoreplication in differentiating chick retinal ganglion cells

p27Kip1participates in the regulation of endoreplication in differentiating chick retinal ganglion cells

MiR-26b, Upregulated in Alzheimer's Disease, Activates Cell Cycle Entry, Tau-Phosphorylation, and Apoptosis in Postmitotic Neurons

LIM domain only 4 protein promotes granulocyte colony-stimulating factor-induced signaling in neurons

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p27^Kip1participates in the regulation of endoreplication in differentiating chick retinal ganglion cells

p27^Kip1participates in the regulation of endoreplication in differentiating chick retinal ganglion cells