Activation of cell-cycle-associated proteins in neuronal death: a mandatory or dispensable path?

Copani, Agata; Sortino, Maria Angela; Nicoletti, Ferdinando; Bruno, Valeria; Ubertia, Daniela; Memo, Maurizio

doi:10.1016/s0166-2236(00)01663-5

Cited by 218 publications

(145 citation statements)

References 59 publications

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“…Although it appears that they face continuing stress to re-enter the cell cycle, a series of anti-growth factors prevent them from normally doing so (Copani and Nicoletti, 2005). A growing number of in vivo and in vitro studies, however, show that post-mitotic neurons can re-enter the cell cycle after brain injury in rat and humans (Hayashi et al, 2000, Copani et al, 2001, Love, 2003, Becker and Bonni, 2004, Greene et al, 2004, Herrup et al, 2004, Kuan et al, 2004, Di Giovanni et al, 2005, Copani et al, 1999, Liu and Greene, 2001, Rao et al, 2007. This cell cycle re-entry is a critical element of the DNA damage response of post mitotic neurons leading to apoptosis (Kruman et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Src kinase inhibition decreases thrombin-induced injury and cell cycle re-entry in striatal neurons

Liu

Cheng

Ander

et al. 2008

Neurobiology of Disease

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Since Src kinase inhibitors decrease brain injury produced by intracerebral hemorrhage (ICH) and thrombin is activated following ICH, this study determined whether Src kinase inhibitors decrease thrombin induced brain injury. Thrombin injections into adult rat striatum produced focal infarction and motor deficits. The Src kinase inhibitor PP2 decreased thrombin-induced Src activation, infarction in striatum and motor deficits in vivo. Thrombin applied to cultured post-mitotic striatal neurons caused: injury to axons and dendrites; many TUNEL positive neuronal nuclei; and re-entry into the cell cycle as manifested by cyclin D1 expression, induction of several other cell cycle genes and cyclin-dependent kinase 4 activation. PP2 dose-dependently attenuated thrombin-induced injury to the cultured neurons; and attenuated thrombin-induced neuronal cell cycle re-entry. These results are consistent with the hypotheses that Src kinase inhibitors decrease injury produced by ICH by decreasing thrombin activation of Src kinases and, at least in part, by decreasing Src induced cell cycle re-entry.

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Section: Discussionmentioning

confidence: 99%

Src kinase inhibition decreases thrombin-induced injury and cell cycle re-entry in striatal neurons

Liu

Cheng

Ander

et al. 2008

Neurobiology of Disease

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“…Significantly, many factors and external agents that modulate the proliferation of granule cells, such as seizures, are also known to cause cell damage leading to their death (Bengzon et al, 1997). Furthermore, damaged or degenerating neurons are known to activate cell cycle-associated proteins such as cyclins and ubiquitins and initiate abortive DNA synthesis leading to polyploidy that can persist for many months before the death of a cell (Neve et al, 2000;Katchanov et al, 2001;Copani et al, 2001;Yang et al, 2001). Finally, although not demonstrated directly in neurons, unscheduled DNA synthesis is an evolutionary device to provide additional gene copies to enhance transcription in metabolically more active cells or in situations of higher demand, as shown in hepatocytes (Anatskaya et al, 1994).…”

Section: Are All Brdu-labeled Cells New?mentioning

confidence: 99%

Adult Neurogenesis in Mammals: An Identity Crisis

2002

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“…15 Another potential cell death mechanism is the inappropriate expression or activation of cell-cycle proteins. 16 The cell cycle is associated with the phasespecific expression or modification of defined sets of cell-cycle regulatory genes that regulate cellular proliferation, differentiation or entry into a quiescent state. 17 However re-entry of quiescent, terminally differentiated neurons, into the cell cycle may result in a mitotic catastrophe and cell death.…”

Section: Amyotrophic Lateral Sclerosis (Als) Is Characterizedmentioning

confidence: 99%

“…17 However re-entry of quiescent, terminally differentiated neurons, into the cell cycle may result in a mitotic catastrophe and cell death. 16,18,19 For entry into the cell cycle, quiescent neurons of the adult brain must first exit G 0 and enter the G 1 phase of the cell cycle. Multiple cell-cycle proteins regulate progression through G 1 , the most important being the products of retinoblastoma (pRb) tumor suppressor and E2F gene families.…”

mentioning

confidence: 99%

Alterations in G1 to S Phase Cell-Cycle Regulators during Amyotrophic Lateral Sclerosis

Ranganathan

Bowser

2003

The American Journal of Pathology

150

110

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Amyotrophic lateral sclerosis (ALS) is characterizedby progressive degeneration of the motor neurons in the cerebral cortex, brain stem, and spinal cord. However, the mechanisms that regulate the initiation and/or progression of motor neuron loss in this disease remain enigmatic. Cell-cycle proteins and transcriptional regulators such as cyclins, cyclin-associated kinases, the retinoblastoma gene product (pRb), and E2F-1 function during cellular proliferation, differentiation, and cell death pathways. Recent data has implicated increased expression and activation of various cell-cycle proteins in neuronal cell death. We have examined the expression and subcellular distribution of G 1 to S phase cell-cycle regulators in the spinal cord, motor cortex, and sensory cortex from clinically and neuropathologically diagnosed sporadic ALS cases and age-matched controls. Our results indicate hyperphosphorylation of the retinoblastoma protein in motor neurons during ALS, concurrent with increased levels of cyclin D, and redistribution of E2F-1 into the cytoplasm of motor neurons and glia. These data suggest that G 1 to S phase activation occurs during ALS and may participate in molecular mechanisms regulating motor neuron death. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease exemplified by neuronal loss in the motor cortex, brainstem, and spinal cord ventral horn. This progressive neurodegeneration results in muscle atrophy, paralysis, and death. Disease onset may occur at any age but is most common between 40 to 70 years of age. The average time interval from diagnosis to mortality is ϳ4 years. 1,2 Familial ALS comprises a fraction (5 to 10%) of ALS cases and is predominantly inherited in an autosomal dominant manner and includes mutations in the SOD1 and the ALS2 genes. [3][4][5][6][7] The etiology of ALS is thought to be multifactorial. Factors believed to participate in motor neuron degeneration include glutamate-mediated excitotoxicity, free radical accumulation because of oxidative stress, increased intracellular calcium, mitochondrial dysfunction, cytoskeletal abnormalities, astrogliosis, and genetic mutations. 8 -13 Neuronal dysfunction because of retrograde degeneration of the presynaptic axons may occur as the result of insufficient release of activity-dependent target-derived neurotrophic factors. 14 One important consequence of inappropriate trophic factor support is altered intracellular signaling to the nucleus. Signaling from the cell surface to the nucleus modulates chromatin structure and the activity of transcription factors, resulting in altered gene transcription. One potential mechanism leading to neuronal death in ALS includes altered expression of pro-and anti-apoptotic genes. 15 Another potential cell death mechanism is the inappropriate expression or activation of cell-cycle proteins. 16 The cell cycle is associated with the phasespecific expression or modification of defined sets of cell-cycle regulatory genes that regulate cellular proliferation, differentiation or entry into...

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Activation of cell-cycle-associated proteins in neuronal death: a mandatory or dispensable path?

Cited by 218 publications

References 59 publications

Src kinase inhibition decreases thrombin-induced injury and cell cycle re-entry in striatal neurons

Src kinase inhibition decreases thrombin-induced injury and cell cycle re-entry in striatal neurons

Adult Neurogenesis in Mammals: An Identity Crisis

Alterations in G1 to S Phase Cell-Cycle Regulators during Amyotrophic Lateral Sclerosis

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