Gains and overexpression identify DEK and E2F3 as targets of chromosome 6p gains in retinoblastoma

Grasemann, Corinna; Gratias, Sandrine; Stephan, Harald; Schüler, Andreas; Schramm, Alexander; Klein-Hitpaß, Ludger; Rieder, Harald; Schneider, Stephanie; Kappes, Ferdinand; Eggert, Angelika; Lohmann, Dietmar

doi:10.1038/sj.onc.1208792

Cited by 104 publications

(96 citation statements)

References 33 publications

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“…[22][23][24][25][26][27][28][29] This is consistent with the findings that E2F3 overexpression can stimulate cell proliferation and contribute to oncogenic transformation in vitro. 4,11 Studies using mice lacking E2F3 also support an oncogenic role for E2F3.…”

Section: Discussionsupporting

confidence: 78%

“…[22][23][24] In addition, the E2F3 gene, located at chromosome 6p22, is amplified in a subset of retinoblastomas and transitional cell carcinomas of the urinary bladder. [25][26][27][28][29] E2F3 amplification is associated with the more malignant (high grade, advanced stage) and invasive bladder tumors. 27,28 These findings suggest that increased E2F3 activity may be involved in the development of some cancers and contribute to a more aggressive phenotype.…”

Section: Introductionmentioning

confidence: 99%

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E2F3a Stimulates Proliferation, p53-Independent Apoptosis and Carcinogenesis in a Transgenic Mouse Model

2005

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Previously published online as a Cell Cycle E-publication: http://www.landesbioscience.com/journals/cc/abstract.php?id=2307 KEY WORDSE2F3, cell cycle, transgenic mouse, apoptosis, skin carcinogenesis ABBREVIATIONS RbRetinoblastoma ABSTRACTMutation or inactivation of the retinoblastoma (Rb) tumor suppressor occurs in most human tumors and results in the deregulation of several members of the E2F family of transcription factors. Among the E2F family, E2F3 has been implicated as a key regulator of cell proliferation and E2F3 gene amplification and overexpression is detected in some human tumors. To study the role of E2F3 in tumor development, we established a transgenic mouse model expressing E2F3a in a number of epithelial tissues via a keratin 5 (K5) promoter. Transgenic expression of E2F3a leads to hyperproliferation, hyperplasia and increased levels of p53-independent apoptosis in transgenic epidermis. Consistent with data from human cancers, the E2F3a transgene is found to have a weak oncogenic activity on its own and to significantly enhance the response to a skin carcinogenesis protocol. The phenotype of K5 E2F3a transgenic mice is distinct from similar transgenic mice expressing E2F1 or E2F4. In particular, E2F3a has a unique apoptotic activity and lacks the tumor suppressive property of E2F1 in this model system.

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Section: Discussionsupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

E2F3a Stimulates Proliferation, p53-Independent Apoptosis and Carcinogenesis in a Transgenic Mouse Model

2005

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“…Rb negatively regulates the activity of several members of the E2F family of transcription factors. E2F3a has been shown to be particularly important for promoting cell proliferation downstream of Rb (Leone et al, 1998;Humbert et al, 2000;Ziebold et al, 2001;Saavedra et al, 2002) and E2F3 gene amplification and overexpression occurs in several types of human cancers (Veltman et al, 2003;Feber et al, 2004;Oeggerli et al, 2004;Grasemann et al, 2005;Orlic et al, 2006). We recently generated transgenic mice expressing E2F3a in squamous epithelial tissues (Paulson et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Transgenic expression of E2F3a causes DNA damage leading to ATM-dependent apoptosis

et al. 2008

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Many early stage human tumors display markers of a DNA-damage response (DDR), including ataxia telangiectasia mutated (ATM) kinase activation. This suggests that DNA damage accumulates during the process of carcinogenesis and that the ATM-dependent response to this damage may function to suppress cancer progression. The E2F3a transcription factor plays an important role in regulating cell proliferation and is amplified in a subset of human cancers. Similar to human premalignant lesions, we find activated ATM and other markers of the DDR in the hyperplastic epidermis of transgenic mice expressing E2F3a through a keratin 5 (K5) promoter. Primary keratinocytes from K5 E2F3a transgenic mice contain increased levels of DNA breaks compared to wild-type cells. E2F3a overexpression also induced DNA damage in primary human fibroblasts that was inhibited by blocking DNA replication. The absence of ATM impaired apoptosis induced by E2F3a and treating K5 E2F3a transgenic mice with caffeine, an inhibitor of ATM and Rad3-related (ATR), promoted skin tumor development. These findings demonstrate that the deregulated expression of E2F3a causes DNA damage under physiological conditions and indicate that the ATM-dependent response to this damage is important for the induction of apoptosis and tumor suppression.

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“…20 DEK is over-expressed in numerous solid tumors and in some at the earliest stages of tumorigenesis. 52 It is over-expressed through various mechanisms including increased transcription via the Rb/ E2F pathway, 21 6p22.3 Alifications, [22][23][24] steroid hormone signaling, 25 and mutations in its degradation machinery. 26,27 DEK overexpression can inhibit cell death and differentiation as well as promote proliferation, and invasion in multiple types of cancer.…”

Section: Introductionmentioning

confidence: 99%

DEK over-expression promotes mitotic defects and micronucleus formation

Matrka

Hennigan

Kappes³

et al. 2015

Cell Cycle

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The DEK gene encodes a nuclear protein that binds chromatin and is involved in various fundamental nuclear processes including transcription, RNA splicing, DNA replication and DNA repair. Several cancer types characteristically over-express DEK at the earliest stages of transformation. In order to explore relevant mechanisms whereby DEK supports oncogenicity, we utilized cancer databases to identify gene transcripts whose expression patterns are tightly correlated with that of DEK. We identified an enrichment of genes involved in mitosis and thus investigated the regulation and possible function of DEK in cell division. Immunofluorescence analyses revealed that DEK dissociates from DNA in early prophase and re-associates with DNA during telophase in human keratinocytes. Mitotic cell populations displayed a sharp reduction in DEK protein levels compared to the corresponding interphase population, suggesting DEK may be degraded or otherwise removed from the cell prior to mitosis. Interestingly, DEK overexpression stimulated its own aberrant association with chromatin throughout mitosis. Furthermore, DEK colocalized with anaphase bridges, chromosome fragments, and micronuclei, suggesting a specific association with mitotically defective chromosomes. We found that DEK over-expression in both non-transformed and transformed cells is sufficient to stimulate micronucleus formation. These data support a model wherein normal chromosomal clearance of DEK is required for maintenance of high fidelity cell division and chromosomal integrity. Therefore, the overexpression of DEK and its incomplete removal from mitotic chromosomes promotes genomic instability through the generation of genetically abnormal daughter cells. Consequently, DEK over-expression may be involved in the initial steps of developing oncogenic mutations in cells leading to cancer initiation

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Gains and overexpression identify DEK and E2F3 as targets of chromosome 6p gains in retinoblastoma

Cited by 104 publications

References 33 publications

E2F3a Stimulates Proliferation, p53-Independent Apoptosis and Carcinogenesis in a Transgenic Mouse Model

E2F3a Stimulates Proliferation, p53-Independent Apoptosis and Carcinogenesis in a Transgenic Mouse Model

Transgenic expression of E2F3a causes DNA damage leading to ATM-dependent apoptosis

DEK over-expression promotes mitotic defects and micronucleus formation

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