Transgenic E2F1 Expression in the Mouse Brain Induces a Human-Like Bimodal Pattern of Tumors

Olson, Melissa V.; Johnson, D. Gale; Jiang, Hong; Xu, Jing; Alonso, Marta M.; Aldape, Kenneth; Fuller, Gregory N.; Bekele, B. Nebiyou; Yung, W. K. Alfred; Gomez-Manzano, Candelaria; Fueyo, Juan

doi:10.1158/0008-5472.can-06-2973

Cited by 28 publications

(17 citation statements)

References 23 publications

(20 reference statements)

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“…5C). Furthermore, expression of E2F1 has recently been shown to be sufficient to cause brain tumors in mice (27). Here, we show that brain tumors harbor high levels of E2F1, whereas levels in normal brain are quite low (Fig.…”

Section: Discussionsupporting

confidence: 60%

Differential Apaf-1 levels allow cytochrome c to induce apoptosis in brain tumors but not in normal neural tissues

Johnson

Huang²,

Parrish

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Brain tumors are typically resistant to conventional chemotherapeutics, most of which initiate apoptosis upstream of mitochondrial cytochrome c release. In this study, we demonstrate that directly activating apoptosis downstream of the mitochondria, with cytosolic cytochrome c, kills brain tumor cells but not normal brain tissue. Specifically, cytosolic cytochrome c is sufficient to induce apoptosis in glioblastoma and medulloblastoma cell lines. In contrast, primary neurons from the cerebellum and cortex are remarkably resistant to cytosolic cytochrome c. Importantly, tumor tissue from mouse models of both high-grade astrocytoma and medulloblastoma display hypersensitivity to cytochrome c when compared with surrounding brain tissue. This differential sensitivity to cytochrome c is attributed to high Apaf-1 levels in the tumor tissue compared with low Apaf-1 levels in the adjacent brain tissue. These differences in Apaf-1 abundance correlate with differences in the levels of E2F1, a previously identified activator of Apaf-1 transcription. ChIP assays reveal that E2F1 binds the Apaf-1 promoter specifically in tumor tissue, suggesting that E2F1 contributes to the expression of Apaf-1 in brain tumors. Together, these results demonstrate an unexpected sensitivity of brain tumors to postmitochondrial induction of apoptosis. Moreover, they raise the possibility that this phenomenon could be exploited therapeutically to selectively kill brain cancer cells while sparing the surrounding brain parenchyma.astrocytoma ͉ caspase ͉ cell death ͉ medulloblastoma ͉ neurons

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Section: Discussionsupporting

confidence: 60%

Differential Apaf-1 levels allow cytochrome c to induce apoptosis in brain tumors but not in normal neural tissues

Johnson

Huang²,

Parrish

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…Such regulation mediated by E2F1 should be important for appropriate neurogenesis to occur, given that abnormalities in this process are related to the formation of different tumors (Johnson and DeGregori 2006). In the CNS, there are experimental evidences supporting the involvement of E2F genes in the development of medulloblastoma (Olson et al 2007), most of them focusing on a pro-oncogenic activity. Considering an additional potential tumor suppressor role of E2F1, our results suggest that an aberrant expression of E2F1 leading to a loss of function could also affect the proliferation of GNPs and contribute to pathological cerebellar development.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of E2F1 in cerebellar neuroprogenitor cells and cell cycle arrest during postnatal brain development

Suzuki

Ariza

Porcionatto

et al. 2011

In Vitro Cell.Dev.Biol.-Animal

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In the developing cerebellum, proliferation of granular neuroprogenitor (GNP) cells lasts until the early postnatal stages when terminal maturation of the cerebellar cortex occurs. GNPs are considered cell targets for neoplastic transformation, and disturbances in cerebellar GNP cell proliferation may contribute to the development of pediatric medulloblastoma. At the molecular level, proliferation of GNPs is regulated through an orchestrated action of the SHH, NOTCH, and WNT pathways, but the underlying mechanisms still need to be dissected. Here, we report that expression of the E2F1 transcription factor in rat GNPs is inversely correlated with cell proliferation rate during postnatal development, as opposed to its traditional SHH-dependent induction of cell cycle. Proliferation of GNPs peaked at postnatal day 3 (P3), with a subsequent continuing decrease in proliferation rates occurring until P12. Such gradual decline in proliferating neuroprogenitors paralleled the extent of cerebellum maturation confirmed by histological analysis with cresyl violet staining and temporal expression profiling of SHH, NOTCH2, and WNT4 genes. A time course analysis of E2F1 expression in GNPs revealed significantly increased levels at P12, correlating with decreased cell proliferation. Expression of the cell cycle inhibitor p18 ( Ink4c ), a target of E2F1, was also significantly higher at P12. Conversely, increased E2F1 expression did not correlate with either SMAC/DIABLO and BCL2 expression profiles or apoptosis of cerebellar cells. Altogether, these results suggest that E2F1 may also be involved in the inhibition of GNP proliferation during rat postnatal development despite its conventional mitogenic effects.

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“…There is strong causative evidence for E2F- and MYC-dependent transcription in the pathogenesis of human and murine medulloblastoma (Fig. 1e) 15,16 , and in the proliferation and differentiation of neuronal progenitors in the external germinal layer (EGL) of the cerebellum, a putative cell of origin for a large percentage of medulloblastomas 17–19 . Other members of the E2F6 complex include HP1, and MBT domain–containing Polycomb proteins (L3MBTL) 5 .…”

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confidence: 99%

Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma

Northcott¹,

et al. 2009

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We used high-resolution SNP genotyping to identify regions of genomic gain and loss in the genomes of 212 medulloblastomas, malignant pediatric brain tumors. We found focal amplifications of 15 known oncogenes and focal deletions of 20 known tumor suppressor genes (TSG), most not previously implicated in medulloblastoma. Notably, we identified previously unknown amplifications and homozygous deletions, including recurrent, mutually exclusive, highly focal genetic events in genes targeting histone lysine methylation, particularly that of histone 3, lysine 9 (H3K9). Post-translational modification of histone proteins is critical for regulation of gene expression, can participate in determination of stem cell fates and has been implicated in carcinogenesis. Consistent with our genetic data, restoration of expression of genes controlling H3K9 methylation greatly diminishes proliferation of medulloblastoma in vitro. Copy number aberrations of genes with critical roles in writing, reading, removing and blocking the state of histone lysine methylation, particularly at H3K9, suggest that defective control of the histone code contributes to the pathogenesis of medulloblastoma.

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Transgenic E2F1 Expression in the Mouse Brain Induces a Human-Like Bimodal Pattern of Tumors

Cited by 28 publications

References 23 publications

Differential Apaf-1 levels allow cytochrome c to induce apoptosis in brain tumors but not in normal neural tissues

Differential Apaf-1 levels allow cytochrome c to induce apoptosis in brain tumors but not in normal neural tissues

Upregulation of E2F1 in cerebellar neuroprogenitor cells and cell cycle arrest during postnatal brain development

Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma

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