DNA binding by c-Ets-1, but not v-Ets, is repressed by an intramolecular mechanism.

Lim, Francis; Kraut, Norbert; Framptom, J; Graf, Thomas

doi:10.1002/j.1460-2075.1992.tb05096.x

Cited by 140 publications

(120 citation statements)

References 39 publications

(37 reference statements)

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“…Human ETS-1, p54 (ETS-1, hereafter) binds DNA through domain E, the highly conserved ETS domain. The neighboring domains D and F a ect the a nity and selectivity of DNA binding by forming a`closed' structure (Hagman and Grosschedl, 1992;Lim et al, 1992;Hahn and Wasylyk, 1994;Fisher et al, 1994;Peterson et al, 1995). Domain B, also called the`Pointed' domain, is conserved among several Ets members.…”

Section: Isolation Of Huubc9 With a Yeast Two-hybrid Systemmentioning

confidence: 99%

“…This might re¯ect the importance of intra-molecular regulation of ETS-1 activity. The DNA binding activity of the ETS domain is inhibited by the surrounding domains D and F, which form a`compact',`closed' structure (Hagman and Grosschedl, 1992;Lim et al, 1992;Hahn and Wasylyk, 1994;Fisher et al, 1994;Peterson et al, 1995). Similarly, there are functional interactions between the B and C domains, that are consistent with intra-molecular regulation (Schneikert et al, 1992).…”

Section: The Transcriptional Activity Of Ets-1 Is Increased In the Prmentioning

confidence: 99%

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Modulation of ETS-1 transcriptional activity by huUBC9, a ubiquitin-conjugating enzyme

1997

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Ets transcription factors have Ets DNA binding domains, that have a winged helix ± turn ± helix structure. ETS-1, the founding member of the family, is regulated by the Ras and Ca 2+ signaling pathways and is implicated in various physiological processes leading to cell growth, di erentiation and apoptosis. We have identi®ed ETS-1 interacting factors with a yeast two-hybrid screen. The majority of the positive clones turned out to encode the human homologue of the yeast ubiquitin-conjugating enzymes UBC9 and Hus5. In two di erent yeast assays, ETS-1 interacted with huUBC9. In an in vitro GST pull-down' assay, ETS-1 and several other Ets family members complexed with huUBC9. Interestingly, in mammalian cells, coexpression of huUBC9 resulted in a substantial increase in the transcriptional activity of ETS-1. Coexpressed huUBC9 did not a ect the ETS-1 protein level, and moreover, a point mutation at Cys93, an amino acid known to be essential for ubiquitination, did not abolish the stimulation of the ETS-1 transcriptional activity. Our results indicate that the modulation of ETS-1 activity by huUBC9 results from processes other than ubiquitination and ETS-1 stabilization.

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Section: Isolation Of Huubc9 With a Yeast Two-hybrid Systemmentioning

confidence: 99%

Section: The Transcriptional Activity Of Ets-1 Is Increased In the Prmentioning

confidence: 99%

Modulation of ETS-1 transcriptional activity by huUBC9, a ubiquitin-conjugating enzyme

1997

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“…This suggested that autoinhibition was an independent phenomenon from the selection of specific DNA sequences. We therefore tested a variant in which the C-terminal fragment of the protein had been removed while keeping the exon VII-coded region intact (DC415 in Figure 7), thus creating a mutation known to release the autoinhibition state of Ets-1 (Lim et al, 1992;Jonsen et al, 1996). This DC415 variant displays similar differences than p51Ets-1 in binding to the Opt and Opt[C À1 G] DNA probes, confirming that autoinhibition and specific DNA sequence recognition are separate properties of Ets-1.…”

Section: Quantification Of P51ets-1 and P42ets-1 Binding To Dnamentioning

confidence: 99%

Characterization and functional analysis of the p42Ets-1 variant of the mouse Ets-1 transcription factor

et al. 2003

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We have identified the mouse exon VII splice variant of the Ets-1 transcription factor. The variant is expressed in all cell lines which express ets-1, at lower levels, it is also expressed in the mouse embryo in vivo. The corresponding protein, p42Ets-1, is a transcription factor as it is able to bind to specific DNA sequences and to transactivate a bona fide ETS reporter vector. A comparison of optimal DNA-binding sites shows that p42Ets-1 binds to more various DNA sequences than p51Ets-1; p42Ets-1 recognizes the same optimal consensus sequence as p51Ets-1, but also many variations of it, mainly at base À1, which is located just prior to the GGAA/T core sequence. The binding differences were quantified by surface plasmon resonance analyses and the protein region responsible for the differences in DNA sequence recognition located in the Val 280 -Glu 302 fragment, which is encoded by exon VII. The specific DNA-binding properties of each isoform translates into clear differences in activity, p42Ets-1 transactivates the natural VE-cadherin gene promoter through both ETS-binding site (EBS)2 and EBS4 whereas p51Ets-1 is mainly active on EBS4. Altogether, our data suggest that p42Ets-1 acts as a distinct transcription factor from p51Ets-1. Oncogene (2003) 22, 9156-9164.

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“…EWS/FLI-1 differs from FLI-1 at its amino-terminal domain. The amino-terminal sequences of some Ets proteins can modulate the avidity of DNA binding (12,28). Alternatively, EWS/FLI-1 and FLI-1 may bind target sites with similar affinities, but EWS/FLI-1 may be a more potent transcriptional activator.…”

Section: Ews/fli-1 Transforms Nih 3t3 Cells But Fli-1 Does Notmentioning

confidence: 99%

The Ewing's sarcoma EWS/FLI-1 fusion gene encodes a more potent transcriptional activator and is a more powerful transforming gene than FLI-1.

May¹,

Lessnick²,

Braun³

et al. 1993

Mol. Cell. Biol.

442

346

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EWS/FLI-1 is a chimeric protein formed by a tumor-specific 11;22 translocation found in both Ewing's sarcoma and primitive neuroectodermal tumor of childhood. EWS/FLI-I has been shown to be a potent transforming gene Aberrant expression and structural alteration of transcription factors are frequent, primary molecular mechanisms in oncogenesis (11). In lower mammals and avian species, these alterations are often mediated by retroviral insertion. In humans, deregulation or structural alteration of transcription factors is frequently the result of somatic genomic rearrangement.The 11;22 chromosomal translocation found in Ewing's sarcoma and primitive neuroectodermal tumor of childhood (PNET) juxtaposes the 5' sequences from a newly described gene, termed EWS, with the 3' sequences from FLI-1, which encodes a member of the Ets transcription factor family (6). Like most Ets family members (for a review, see reference 27), the carboxyl domain of FLI-1 mediates sequencespecific DNA binding. The FLI-1 amino terminus contains a putative transcription activation domain that may interact on a protein-protein level with other transcription factors. As with other Ets proteins, it is probably the combination of protein-DNA and protein-protein binding specificities that determines which genes are transcriptionally modulated by FLI-1. As a result of the 11;22 rearrangement, the aminoterminal domain of FLI-1 is replaced by a portion of EWS containing a series of degenerate, glutamine-rich repeats. The carboxyl terminus of EWS has amino acid similarity to proteins involved in RNA synthesis and processing (6). However, the function in tumor cells of the EWS aminoterminal domain that is fused to FLI-1 is unknown.We have recently demonstrated that the EWS/FLI-1 chi-

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DNA binding by c-Ets-1, but not v-Ets, is repressed by an intramolecular mechanism.

Cited by 140 publications

References 39 publications

Modulation of ETS-1 transcriptional activity by huUBC9, a ubiquitin-conjugating enzyme

Modulation of ETS-1 transcriptional activity by huUBC9, a ubiquitin-conjugating enzyme

Characterization and functional analysis of the p42Ets-1 variant of the mouse Ets-1 transcription factor

The Ewing's sarcoma EWS/FLI-1 fusion gene encodes a more potent transcriptional activator and is a more powerful transforming gene than FLI-1.

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