The Transcription Factor E2F1 Modulates Apoptosis of Neurons

Hou, Sheng T.; Callaghan, Debbie; Fournier, Marie-Christine; Hill, Irene E.; Kang, Liping; Massie, Bernard; Morley, Paul; Murray, Christine; Rasquinha, Ingrid; Slack, Ruth S.; MacManus, J. P.

doi:10.1046/j.1471-4159.2000.0750091.x

Cited by 106 publications

(92 citation statements)

References 62 publications

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“…E2F1 is thought to promote the exit from G 0 phase (34), and its overexpression induces apoptosis in quiescent cells (35) and postmitotic neurons (26,36). We found that E2F1 abrogated necdin-induced growth arrest and morphological differentiation of N1E-115 cells (Figs.…”

Section: E2f1 Abrogates Necdin-induced Growth Arrest Of N1e-115 Cellsmentioning

confidence: 67%

Ectopic Expression of Necdin Induces Differentiation of Mouse Neuroblastoma Cells

Kobayashi

Taniura

Yoshikawa

2002

Journal of Biological Chemistry

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Necdin is expressed predominantly in postmitotic neurons, and ectopic expression of this protein strongly suppresses cell growth. Necdin has been implicated in the pathogenesis of Prader-Willi syndrome, a human neurodevelopmental disorder associated with genomic imprinting. Here we demonstrate that ectopic expression of necdin induces a neuronal phenotype in neuroblastoma cells. Necdin was undetectable in mouse neuroblastoma N1E-115 cells under undifferentiated and differentiated conditions. N1E-115 cells transfected with necdin cDNA showed morphological differentiation such as neurite outgrowth and expression of the synaptic marker proteins synaptotagmin and synaptophysin. In addition, Western blot analysis of the retinoblastoma protein (Rb) family members Rb, p130, and p107 revealed that necdin cDNA transfectants contained an increased level of p130 and a reduced level of p107, a pattern seen in differentiated G 0 cells. The transcription factors E2F1 and E2F4 physically interacted with necdin via their carboxyl-terminal transactivation domains, but only E2F1 abrogated necdin-induced growth arrest and neurite outgrowth of neuroblastoma cells. Overexpression of E2F1 in differentiated N1E-115 cells induced apoptosis, which was antagonized by co-expression of necdin. These results suggest that necdin promotes the differentiation and survival of neurons through its antagonistic interactions with E2F1.Necdin is a 325-amino acid protein encoded in a cDNA sequence that has been isolated from a subtraction library of neurally differentiated mouse embryonal carcinoma P19 cells (1). The necdin gene is expressed in most of the terminally differentiated neurons, although its expression levels vary among neuronal cell types, being the highest in the hypothalamus and brain stem (2, 3). The human necdin gene is mapped to chromosome 15q11.2-q12, a region deleted in Prader-Willi syndrome (PWS) 1 (4 -6). PWS is a neurodevelopmental disorder associated with genomic imprinting, and its major symptoms such as feeding problems, gross obesity, and hypogonadism are consistent with a hypothalamic defect. Human and mouse necdin genes are maternally imprinted and transcribed only from the paternal allele (4, 5, 7). Necdin is not expressed in the cells prepared from PWS patients whose chromosome 15q11.2-q13 region in the paternal allele is deleted. Disruption of the paternal allele of mouse necdin gene results in early postnatal lethality (8), reduction in specific hypothalamic neurons such as luteinizing hormone-releasing hormone-and oxytocin-containing neurons, and behavioral alternations, which are reminiscent of human PWS (9). Therefore, it is likely that a defect in necdin expression is responsible, at least in part, for various clinical symptoms of PWS. However, little is known about the functional roles of necdin in neuronal differentiation and development.Accumulating evidence has suggested that necdin is a growth suppressor expressed in terminally differentiated cells. Ectopic expression of necdin suppresses the proliferation of...

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Section: E2f1 Abrogates Necdin-induced Growth Arrest Of N1e-115 Cellsmentioning

confidence: 67%

Ectopic Expression of Necdin Induces Differentiation of Mouse Neuroblastoma Cells

Kobayashi

Taniura

Yoshikawa

2002

Journal of Biological Chemistry

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“…E2F1 is upregulated in neurons subjected to apoptotic stimuli in vitro 46,68,104,105,107,109 and in vivo 37 and is elevated in degenerating neurons of patients with Alzheimer disease and with Down's syndrome. 93,110 In addition, neurons treated with an E2F1 antisense 68,104 as well as neurons cultured from mice null for E2F1 107,109,[111][112][113] are at least partially protected from diverse apoptotic stimuli. Although such data can be taken to support a mechanism of E2F1-dependent gene activation, here again an alternative interpretation is possible.…”

Section: Does E2f-dependent Gene Activation Have a Role In Neuron Death?mentioning

confidence: 99%

Cell cycle molecules and vertebrate neuron death: E2F at the hub

2003

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Vertebrate neuron cell death is both a normal developmental process and the catastrophic outcome of nervous system trauma or degenerative disorders. Although the mechanisms of such death include an evolutionarily conserved core apoptotic pathway that is highly homologous to that first described by Horvitz and co-workers in Caenorhabditis elegans, it appears that many instances of neuron death additionally require the transcription-dependent induction of proapoptotic molecules. One such proapoptotic transcriptional pathway revealed by studies over the past decade revolves about the transcription factor E2F and those molecules that either regulate E2F activity or that are direct or indirect transcriptional targets of E2F. Many of the molecules associated with the E2F apoptotic pathway in postmitotic neurons also participate in the cell cycle in proliferating cells. Observations in human material and in animal and cell culture models show widespread correlation between changes in expression, activity and subcellular localization of E2F-related cell cycle molecules and developmental and catastrophic neuron death. A variety of experimental approaches support a causal role for such changes in the death process and are beginning to indicate how the neuronal E2F pathway activates the core apoptotic machinery. The discovery and elaboration of the neuronal apoptotic E2F pathway provides abundant targets as well as small molecule candidates for potential therapeutic intervention in nervous system trauma and degenerative disease.

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“…Apoptotic stimuli induce Rb phosphorylation through activation of cyclin-dependent kinases to activate E2F1 in neurons Hou et al, 2002). In addition, forced expression of E2F1 in postmitotic neurons using viral vectors induces apoptosis (Azuma-Hara et al, 1999;Hou et al, 2000;O'Hare et al, 2000). These findings suggest that the regulation of E2F1 activity is crucial for the control of neuronal apoptosis.…”

Section: Introductionmentioning

confidence: 96%

Necdin Downregulates Cdc2 Expression to Attenuate Neuronal Apoptosis

Kurita

Kuwajima²,

Nishimura³

et al. 2006

J. Neurosci.

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The cell cycle-regulatory transcription factor E2F1 induces apoptosis of postmitotic neurons in developmental and pathological situations. E2F1 transcriptionally activates many proapoptotic genes including the cyclin-dependent protein kinase cell division cycle 2 (Cdc2). Necdin is a potent mitotic suppressor expressed predominantly in postmitotic neurons and interacts with E2F1 to suppress E2F1-mediated gene transcription. The necdin gene NDN is maternally imprinted and expressed only from the paternal allele. Deletion of the paternal NDN is implicated in the pathogenesis of Prader-Willi syndrome, a genomic imprinting-associated neurodevelopmental disorder. Here, we show that paternally expressed necdin represses E2F1-dependent cdc2 gene transcription and attenuates apoptosis of postmitotic neurons. Necdin was abundantly expressed in differentiated cerebellar granule neurons (CGNs). Neuronal activity deprivation elevated the expression of both E2F1 and Cdc2 in primary CGNs prepared from mice at postnatal day 6, whereas the necdin levels remained unchanged. In chromatin immunoprecipitation analysis, endogenous necdin was associated with the cdc2 promoter containing an E2F-binding site in activity-deprived CGNs. After activity deprivation, CGNs underwent apoptosis, which was augmented in those prepared from mice defective in the paternal Ndn allele (Ndn ϩm/Ϫp ). The levels of cdc2 mRNA, protein, and kinase activity were significantly higher in Ndn ϩm/Ϫp CGNs than in wild-type CGNs under activity-deprived conditions. Furthermore, the populations of Cdc2-immunoreactive and apoptotic cells were increased in the cerebellum in vivo of Ndn ϩm/Ϫp mice. These results suggest that endogenous necdin attenuates neuronal apoptosis by suppressing the E2F1-Cdc2 system.

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The Transcription Factor E2F1 Modulates Apoptosis of Neurons

Cited by 106 publications

References 62 publications

Ectopic Expression of Necdin Induces Differentiation of Mouse Neuroblastoma Cells

Ectopic Expression of Necdin Induces Differentiation of Mouse Neuroblastoma Cells

Cell cycle molecules and vertebrate neuron death: E2F at the hub

Necdin Downregulates Cdc2 Expression to Attenuate Neuronal Apoptosis

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