Down's syndrome-like skeletal abnormalities in Ets2 transgenic mice

Sumarsono, Sony Heru; Wilson, Trevor; Tymms, Martin J.; Venter, Deon J.; Corrick, C M; Kola, Rihanna; Lahoud, Mireille H.; Papas, Takis S.; Seth, Arun; Kola, Ismail

doi:10.1038/379534a0

Cited by 182 publications

(97 citation statements)

References 11 publications

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“…The PMT/EF plasmid was obtained by cloning the EWS-FLI-1 type 1 open reading frame into the HindIII restriction site of pMT-CB6+ vector which contains the sheep metallothionein promoter and a Neo resistance gene (Sumarsono et al, 1996). This plasmid was used to stably transfect Hela cells in the presence of 2 mg/ml of G418.…”

Section: Cell Linesmentioning

confidence: 99%

Analysis of the expression of cell cycle regulators in Ewing cell lines: EWS-FLI-1 modulates p57KIP2 and c-Myc expression

et al. 2001

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Ewing tumour is characterized by speci®c chromosome translocations which fuse EWS to a subset of genes encoding ETS transcription factors, most frequently FLI-1. We report the analysis of the expression of various cell cycle regulators both in Ewing tumour derived cell lines and in di erent cellular models with either inducible or constitutive EWS-FLI-1 cDNA expression. In Ewing cell lines, cyclin D1, CDK4, Rb, p27 KIP1 and c-Myc were consistently highly expressed whereas p57 KIP2 , p15 INK4B and p14 ARF demonstrated undetectable or low expression levels. The amount of p16 INK4A , p21 CIP1 , p18 INKAC and CDK6 was variable from one cell line to the other. The inducible expression of EWS-FLI-1 led to a strong upregulation of c-Myc and a considerable downregulation of p57 KIP2 . Other proteins did not show evident modi®cation. High c-Myc and very low p57 KIP2 expression levels were also observed in neuroblastoma NGP cells constitutively expressing EWS-FLI-1 as compared to parental cells. Analysis of the p57 KIP2 promoter indicated that EWS-FLI-1 downregulates, possibly through an indirect mechanism, the transcription of this gene. Finally, we show that ectopic expression of p57 KIP2 in Ewing cells blocks proliferation through a complete G1 arrest. These results suggest that the modulation of p57 KIP2 expression by EWS-FLI-1 is a fundamental step in Ewing tumorigenesis. Oncogene (2001) 20, 3258 ± 3265.

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Section: Cell Linesmentioning

confidence: 99%

Analysis of the expression of cell cycle regulators in Ewing cell lines: EWS-FLI-1 modulates p57KIP2 and c-Myc expression

et al. 2001

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“…In Drosophila, ETS family members play important developmental roles: E74 plays a role in early gene regulation following ecdysone triggering (Burtis et al, 1990;Fletcher et al, 1995); pointed P2 and yan play critical roles in eye development (O'Neill et al, 1994); and D-elg plays a role in developmental programming (Schulz et al, 1993). In humans and mice ETS proteins may function in a wide range of biological processes such as hematopoiesis (Scott et al, 1994a;Muthusamy et al, 1995), organogenesis and branching morphogenesis (Kola et al, 1993), and skeletal/cartilage development (Sumarsono et al, 1996). These proteins have also been implicated in regulation of gene expression appropriate for lymphoid-function (Bhat et al, 1989, Ho et al, 1990Bhat and Thompson, 1990;Thomas et al, 1995) and invasive processes such as tumor metastasis and extracellular matrix degradation (Wernert et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

A novel epithelial-expressed ETS gene, ELF3: human and murine cDNA sequences, murine genomic organization, human mapping to 1q32.2 and expression in tissues and cancer

et al. 1997

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The ETS family of genes are implicated in cancers such as Ewings sarcoma, acute myeloid leukemia and chronic myelomoncytic leukemia. Further, they have important functions in embryonic development. Hence, identi®ca-tion and characterization of members of this family are important. We identify a novel ETS family member, ELF3, and report its human and murine cDNA sequences. The mouse cDNA has an alternatively spliced transcript with an extra 60 bp inserted. Hence we present the organization of the murine Elf3 gene together with its exon/intron structure. This gene consists of 9 exons and 8 introns spanning 4.8 kb. ELF3 binds and transactivates ETS sequences and interestingly also shows the ability to bind a GGAT-like purine core, a preferential ETS1/ETS2 type binding site. The expression of ELF3, unlike most other ETS family members, is absent in hematopoietic cells and hematopoietic organs in humans and mice. Intriguingly, the gene is speci®cally expressed in cell lines of epithelial origin and in organs such as lung, stomach, intestine, kidney that have specialized epithelial cells. We localize the human gene to 1q32.2, a region that is ampli®ed in epithelial tumors of the breast, lung and prostate. Finally, we show that ELF3 expression is increased in a lung carcinoma and adenocarcinoma, as compared to normal tissue. ELF3 is also expressed in cell lines derived from lung cancers. These results suggest that this novel ETS gene may be involved in lung tumorigenesis.

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“…Pointed P2 and yan play critical roles in Drosophila eye development (O'Neill et al, 1994). ETS2 is involved in skeletal/cartilage development (Sumarsono et al, 1996). PU.1 null mutation results in hematopoietic abnormalities , and ETS1 is involved in transactivation of genes required for T cell function (Muthusamy et al, 1995;Sun et al, 1995;Thomas et al, 1995Thomas et al, , 1997 and angiogenesis Vandenbunder et al, 1994;Wernert et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

A novel transcription factor, ELF5, belongs to the ELF subfamily of ETS genes and maps to human chromosome 11p13–15, a region subject to LOH and rearrangement in human carcinoma cell lines

Zhou

Tymms

et al. 1998

Oncogene

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The ETS transcription factors are a large family implicated in the control of cellular proliferation and tumorigenesis. In addition, chromosomal translocations involving ETS family members are associated with a range of di erent human cancers. Given the extensive involvement of ETS factors in tumorigenesis, it becomes important to identify any additional ETS genes that may also play oncogenic roles. We identify a novel gene, ELF5, that appears to belong to the ELF (E74-likefactor) subfamily of the ETS transcription factor family, based upon similarity within the`ETS domain'. ELF5 displays a similar, but more restricted, expression pattern to that of the newly isolated epithelium-speci®c ETS gene, ELF3. Unlike most other ETS family members, ELF5 is not expressed in hematopoietic compartments, but is restricted to organs such as lung, stomach, kidney, prostate, bladder and mammary gland. ELF5 is localized to human chromosome 11p13 ± 15, a region that frequently undergoes loss of heterozygosity (LOH) in several types of carcinoma, including those of breast, kidney and prostate. We ®nd that ELF5 expression is not detectable in a number of carcinoma cell lines, some of which display loss or rearrangement of an ELF5 allele. Similar to other ETS family members, ELF5 displays speci®c binding to DNA sequences containing a GGAA-core. In addition, ELF5 is able to transactivate through these ETS sequences, present upstream from a minimal promoter. Our data suggest that ELF5 may play roles in mammary, lung, prostate and/or kidney function, and possibly also in tumorigenesis.

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Down's syndrome-like skeletal abnormalities in Ets2 transgenic mice

Cited by 182 publications

References 11 publications

Analysis of the expression of cell cycle regulators in Ewing cell lines: EWS-FLI-1 modulates p57KIP2 and c-Myc expression

Analysis of the expression of cell cycle regulators in Ewing cell lines: EWS-FLI-1 modulates p57KIP2 and c-Myc expression

A novel epithelial-expressed ETS gene, ELF3: human and murine cDNA sequences, murine genomic organization, human mapping to 1q32.2 and expression in tissues and cancer

A novel transcription factor, ELF5, belongs to the ELF subfamily of ETS genes and maps to human chromosome 11p13–15, a region subject to LOH and rearrangement in human carcinoma cell lines

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