Expression of Transcription Factor E2F1 and Telomerase in Glioblastomas: Mechanistic Linkage and Prognostic Significance

Alonso, Marta M.; Fueyo, Juan; Shay, Jerry W.; Aldape, Kenneth; Jiang, Hong; Lee, Ok Hee; Johnson, D. Gale; Xu, Jing; Kondo, Yasuko; Kanzawa, Takao; Kyo, Satoru; Bekele, B. Nebiyou; Zhou, Xian; Nigro, Janice; McDonald, J. Matthew; Yung, W. K. Alfred; Gomez-Manzano, Candelaria

doi:10.1093/jnci/dji340

Cited by 55 publications

(56 citation statements)

References 51 publications

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“…In gliomas, for instance, it has been reported an almost universal dysfunction of the Rb pathway (3), with the ultimate increase in E2F1 transcriptional function (12). Our group has recently reported the presence of E2F1 overexpression in malignant gliomas and its value as a prognostic of survival (13). In this study presented here, we investigated the role of E2F1 in the development and maintenance of brain cancer using a transgenic mouse model engineered to express E2F1 within glial cells and/or neural precursor cells (GFAP-tgE2F1).…”

Section: Introductionmentioning

confidence: 84%

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

Olson¹,

Johnson

Jiang³

et al. 2007

Cancer Research

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The Rb/E2F pathway is deregulated in most human brain tumors, and the finding that loss of E2F1 reduced pituitary tumorigenesis in Rb +/À mice suggests that loss of pRb induces brain tumors by activating E2F1. We therefore investigated the role of E2F1 in the development and maintenance of brain cancer using a transgenic mouse model engineered to express E2F1 specifically within glial cells (GFAP-tgE2F1). GFAP-tgE2F1 mice developed a highly penetrant phenotype characterized by neurologic defects, and examination of the brains revealed the presence of brain tumors in 20% of these animals. Importantly, the distribution of tumors according to mouse age suggests the existence of a bimodal pattern of tumor development, forcing a comparison with the human disease. Mice, at an early age, with deregulated E2F1 show the formation of embryonal brain tumors such as medulloblastoma, choroid plexus carcinoma, and primary neuroectodermal tumor. Conversely, at an older age, mice escaping embryonal tumor formation present with malignant gliomas, which are typically identified in the human adult population. Thus, this study offers the first evidence for a global role of E2F1 in the formation and maintenance of multilineage brain tumors, irrefutably establishing E2F1 as an oncogene in the brain.

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Section: Introductionmentioning

confidence: 84%

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

Olson¹,

Johnson

Jiang³

et al. 2007

Cancer Research

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“…Indeed, increased expression of cyclins and downregulation of CDKIs, including p27Kip1 and p16Ink4a/p19Arf, have been described in gliomas (Tamiya et al, 2001;Alonso et al, 2005;Arifin et al, 2006), but altered expression of Rb (which is likely associated with increased bioavailability of nuclear E2F1) has been associated with worse prognosis (Hilton et al, 2004). Our data suggest an important role of E2F1 in the transition between proliferation and differentiation of OPC and reveal the existence of an HDAC1-dependent switch during the downregulation of critical E2F1 targets, such as Uhrf1.…”

Section: Discussionmentioning

confidence: 99%

E2F1 Coregulates Cell Cycle Genes and Chromatin Components during the Transition of Oligodendrocyte Progenitors from Proliferation to Differentiation

Magri

Swiss²,

Jabłońska

et al. 2014

J. Neurosci.

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Cell cycle exit is an obligatory step for the differentiation of oligodendrocyte progenitor cells (OPCs) into myelinating cells. A key regulator of the transition from proliferation to quiescence is the E2F/Rb pathway, whose activity is highly regulated in physiological conditions and deregulated in tumors. In this paper we report a lineage-specific decline of nuclear E2F1 during differentiation of rodent OPC into oligodendrocytes (OLs) in developing white matter tracts and in cultured cells. Using chromatin immunoprecipitation (ChIP) and deep-sequencing in mouse and rat OPCs, we identified cell cycle genes (i.e., Cdc2) and chromatin components (i.e., Hmgn1, Hmgn2), including those modulating DNA methylation (i.e., Uhrf1), as E2F1 targets. Binding of E2F1 to chromatin on the gene targets was validated and their expression assessed in developing white matter tracts and cultured OPCs. Increased expression of E2F1 gene targets was also detected in mouse gliomas (that were induced by retroviral transformation of OPCs) compared with normal brain. Together, these data identify E2F1 as a key transcription factor modulating the expression of chromatin components in OPC during the transition from proliferation to differentiation.

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“…The ICOVIR model is based on the potential of E2F1 promoter for autoregulation by E2F1 protein. Importantly, our group has previously shown that E2F1 is overexpressed in malignant gliomas and that E2F overexpression is strongly associated with a poor prognosis in patients with high-grade gliomas (33). In light of these results, the correlation between E2F1 free activity and ICOVIR-5-mediated oncolytic effect is significant.…”

Section: Discussionmentioning

confidence: 80%

ICOVIR-5 Shows E2F1 Addiction and Potent Antiglioma Effect In vivo

Alonso¹,

Cascalló

Gomez-Manzano³

et al. 2007

Cancer Research

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During 2007, f200,000 people in the United States will be diagnosed with brain tumors. Gliomas account for 77% of primary malignant brain tumors, and the prognosis has hardly changed in the past 20 years, with only 30% of patients with malignant glioma surviving 5 years after diagnosis. Oncolytic adenoviruses are promising therapies for the treatment of gliomas. Here, report the antiglioma activity of the tumor-selective ICOVIR-5 adenovirus, which encompasses an early 1A adenoviral (E1A) deletion in the retinoblastoma (Rb) protein-binding region, substitution of the E1A promoter for E2F-responsive elements, and an RGD-4C peptide motif inserted into the adenoviral fiber to enhance adenoviral tropism. Mechanistic studies showed a dramatic addiction of ICOVIR-5 to the E2F1 oncogene in vitro and in vivo. This addiction was mediated by the occupancy of the ectopic adenoviral E2F1-responsive elements by the endogenous E2F1 protein resulting in high level of E1A expression in cancer cells and potent antiglioma effect. Importantly, we showed for the first time the ability of oncolytic adenoviruses to enhance E2F transcriptional activity in vivo, and we provided direct evidence of the interaction of the E2F1 protein with native and ectopic adenovirus promoters. Restoration of Rb function led to the association of Rb/E2F1 repressor complexes with ICOVIR-5 ectopic E2F1 promoter and subsequent downmodulation of E1A, dramatically impairing adenoviral replication. In xenografted mice, intratumoral injection of ICOVIR-5 resulted in a significant improvement of the median survival (P < 0.0001), and furthermore, led to 37% of long-term survivors free of disease. The antitumor activity of ICOVIR-5 suggests that it has the potential to be an effective agent in the treatment of gliomas.

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Expression of Transcription Factor E2F1 and Telomerase in Glioblastomas: Mechanistic Linkage and Prognostic Significance

Abstract: E2F1 may participate in telomerase activity regulation in malignant glioma cells. Its expression appears to be strongly associated with the survival of patients with malignant brain tumors.

Cited by 55 publications

References 51 publications

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

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

E2F1 Coregulates Cell Cycle Genes and Chromatin Components during the Transition of Oligodendrocyte Progenitors from Proliferation to Differentiation

ICOVIR-5 Shows E2F1 Addiction and Potent Antiglioma Effect In vivo

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