The subcellular localization of E2F-4 is cell-cycle dependent

Lindeman, Geoffrey J.; Gaubatz, Stefan; Livingston, David M.; Ginsberg, Doron

doi:10.1073/pnas.94.10.5095

Cited by 179 publications

(195 citation statements)

References 42 publications

(40 reference statements)

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“…Alternatively, the strong proliferative block provided by p16 in these astrocytomas may generate a strong signal for the nuclear compartmentalization of E2F-4. The latter possibility would be consistent with the previously described, cell cycle dependent compartmentalization of this particular E2F-family member (Lindeman et al, 1997).…”

Section: Discussionsupporting

confidence: 91%

The E2F-family proteins induce distinct cell cycle regulatory factors in p16-arrested, U343 astrocytoma cells

et al. 1998

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We previously demonstrated that P16 Ink4a (p16) expression in p16-de®cient U343 astrocytoma cells causes a G 1 cell cycle arrest, profound changes in cytoskeletal proteins and alterations in expression and activity of the pRB and E2F family proteins. We examine here the e ects of expressing wild type or mutant versions of the downstream targets of p16 in U343 astrocytomas. We ®rst attempted to block proliferation of U343 cells using the dominant mutant of pRB, Dp34. Expression of this mutant in the human osteosarcoma, SAOS-2, potently blocked proliferation but did not a ect the cell cycle of U343 cells. We next showed that expression of E2F-1, E2F-2, E2F-3 and E2F-4 are each able to overcome this p16-dependent cell cycle arrest but exhibit distinct biological activities. Adenoviral-mediated expression of E2F-1, E2F-2, E2F-3, or E2F-4 overcame the p16-dependent cell cycle block and induced alterations in cell morphology. E2F-5, only in conjunction with DP1, promoted cell cycle progression. For both E2F-1 and E2F-2, but not E2F-3 or E2F-5/DP1, cell cycle re-entry was associated with almost quantitative cell death. Only small numbers of dying cells were observed in E2F-4-expressing cultures. Expression of the di erent E2F's altered the expression of distinct sets of cell cycle regulatory proteins. E2F-1 induced endogenous E2F-4 expression and also caused an increase in pRB, p107 and cyclin E levels. Expression of E2F-4 caused a weak increase in E2F-1 levels but also strongly induced pRB, p107, p130 and cyclin E. However, E2F-1 and E2F-4 clearly regulate expression of distinct genes, demonstrated when E2F-4 caused a threefold increase in the levels of cdk2 whereas E2F-1 failed to increase in this cyclin dependent kinase. Similarly, expression of E2F-1 or E2F-2 were shown to have distinct e ects on the expression of cdk2, cyclin E and pRB despite both of these closely related E2F-family members potently inducing cell death. Thus, E2F-1, E2F-2, E2F-3 and E2F-4 are able to overcome the p16-dependent proliferative block in U343 astrocytoma cells. While overcoming this cell cycle block, each of the E2F's uniquely a ect the expression of a number of cell cycle regulatory proteins and have distinct abilities to promote cell death.

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Section: Discussionsupporting

confidence: 91%

The E2F-family proteins induce distinct cell cycle regulatory factors in p16-arrested, U343 astrocytoma cells

et al. 1998

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“…This abnormal cytoplasmic localisation in the malignant cells might reflect gene mutation, posttranscriptional modification or abnormal phosphorylation of its protein in breast cancer and needs further investigation. In addition, we found that E2F-4 was expressed in both the nuclei and cytoplasm of the normal and malignant mammary epithelial cells, in agreement with Lindeman et al 66 who reported both nuclear and cytoplasmic expression of E2F-4. We also found that the nuclear overexpression of E2F-4 was associated with higher-grade tumours and positive lymph node disease, which may suggest an oncogenic rather than a tumour suppressor role in breast cancer.…”

Section: C) Telomeric Repeat Binding Factor-2supporting

confidence: 92%

High‐resolution analysis of 16q22.1 in breast carcinoma using DNA amplifiable probes (multiplex amplifiable probe hybridization technique) and immunohistochemistry

Rakha

Armour

Pinder

et al. 2005

Intl Journal of Cancer

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Loss of the chromosomal material at 16q22.1 is one of the most frequent genetic aberrations found in both lobular and low-grade nonlobular invasive carcinoma of the breast, indicating the presence of a tumour suppressor gene (TSG) at this region in these tumours. However, the TSG (s) at the 16q22.1 in the more frequent nonlobular carcinomas is still unknown. Multiplex Amplifiable Probe Hybridisation (MAPH) is a simple, accurate and a high-resolution technique that provides an alternative approach to DNA copy-number measurement. The aim of our study was to examine the most likely candidate genes at 16q22.1 using MAPH assay combined with protein expression analysis by immunohistochemistry. We identified deletion at 16q22.1 that involves some or all of these genes. We also noticed that the smallest region of deletion at 16q22.1 could be delineated to a 3 Mb region centromeric to the P-cadherin gene. Apart from the correlation between E-cadherin protein expression and its gene copy number, no correlation was detected between the expression of E2F-4, CTCF, TRF2 or P-cadherin with their gene's copy number. In the malignant tissues, no significant loss or decrease of protein expression of any gene other than E-cadherin was seen in association with any specific tumour type. No expression of VE-cadherin or Ksp-cadherin was detected in the normal and/or malignant tissues of the breast in these cases. However, there was a correlation between increased nuclear expression of E2F-4 and tumours with higher histological grade (p ‫؍‬ 0.04) and positive lymph node disease (p ‫؍‬ 0.02), suggesting that it may have an oncogenic rather than a tumour suppressor role. The malignant breast tissues also showed abnormal cytoplasmic cellular localisation of CTCF, compared to its expression in the normal parenchymal cells. In conclusion, we have demonstrated that MAPH is a potential technique for assessment of genomic imbalances in malignant tissues. Although our results support E-cadherin as the TSG in invasive lobular carcinoma, they argue against the candidacy of E2F-4, CTCF, TRF2, P-cadherin, Ksp-cadherin and VE-cadherin as TSGs in breast cancer.

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“…To test this possibility, we transfected into satellite-cell derived myotubes a plasmid encoding an E2F-4 chimeric protein carrying a nuclear localization signal (E2F-4-NLS) (Muller et al, 1997). The NLS ensures that the protein is carried into the nucleus, since wild type E2F-4 is cytoplasmic (Magae et al, 1996;de la Luna et al, 1996;Lindeman et al, 1997;Muller et al, 1997;Verona et al, 1997). Similar to the other E2Fs, E2F-4-NLS did not activate S phase in myotubes (data not shown).…”

Section: E2f Does Not Activate Dna Synthesis In Td Myotubesmentioning

confidence: 85%

E2F activates late-G1 events but cannot replace E1A in inducing S phase in terminally differentiated skeletal muscle cells

Pajalunga¹,

Tognozzi²,

Tiainen

et al. 1999

Oncogene

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We have previously shown that the adenovirus E1A oncogene can reactivate the cell cycle in terminally di erentiated cells. Current models imply that much or all of this E1A activity is mediated by the release of the E2F transcription factors from pocket-protein control. In contrast, we show here that overexpression of E2F-1, E2F-2 and E2F-4, or a chimeric E2F-4 tethered to a nuclear localization signal cannot reactivate postmitotic skeletal muscle cells (myotubes). This is not due to lack of transcriptional activity, as demonstrated on both a reporter construct and a number of endogenous target genes. Although cyclin E was strongly overexpressed in E2F-transduced myotubes, it lacked associated kinase activity, possibly explaining the inability of the myotubes to enter S phase and accumulate cyclin A. Although E2F is not su cient to trigger DNA synthesis in myotubes, its activity is necessary even in the presence of E1A, as dominant-negative DP-1 mutants inhibit E1A-mediated cell cycle reentry. Our data show that, to reactivate myotubes, E1A must exert other functions, in addition to releasing E2F. They also establish mouse myotubes as an experimental system uniquely suited to study the most direct E2F functions in the absence of downstream cell cycle e ects.

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The subcellular localization of E2F-4 is cell-cycle dependent

Cited by 179 publications

References 42 publications

The E2F-family proteins induce distinct cell cycle regulatory factors in p16-arrested, U343 astrocytoma cells

The E2F-family proteins induce distinct cell cycle regulatory factors in p16-arrested, U343 astrocytoma cells

High‐resolution analysis of 16q22.1 in breast carcinoma using DNA amplifiable probes (multiplex amplifiable probe hybridization technique) and immunohistochemistry

E2F activates late-G1 events but cannot replace E1A in inducing S phase in terminally differentiated skeletal muscle cells

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