Genomic structure of the human KDR/flk-1 gene

Li, Yin; Wu, Yaxu; Ballinger, Carol A.; Patterson, Cam

doi:10.1007/s003359900783

Cited by 14 publications

(11 citation statements)

References 14 publications

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“…The overall genomic organization of the VEGFR3 gene is highly similar to the previously published organization of the Vegfr1 and VEGFR2 genes (44,45). The coding capacity of the different exons is indicated in Fig.…”

Section: Organization and Sequence Variation Of The Human Vegfr3 Genementioning

confidence: 71%

VEGFR3gene structure, regulatory region, and sequence polymorphisms

Iljin

Karkkainen

Lawrence³

et al. 2001

The FASEB Journal

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Vascular endothelial growth factor receptor 3 (VEGFR-3) is required for cardiovascular development during embryogenesis. In adults, this receptor is expressed in lymphatic endothelial cells, and mutant VEGFR3 alleles have been implicated in human hereditary lymphedema. To better understand the basis of its specific endothelial lineage-restricted expression, we have characterized the VEGFR3 gene and its regulatory 5' flanking region. The human gene contains 31 exons, of which exons 30a and 30b are alternatively spliced. The VEGFR3 proximal promoter is TATA-less and contains stretches of sequences homologous with the mouse Vegfr3 promoter region. In transfection experiments of cultured cells, the Vegfr3 promoter was shown to control endothelial cell-specific transcription of downstream reporter genes. This result was further confirmed in vivo; in a subset of transgenic mouse embryos, a 1.6 kb Vegfr3 promoter fragment directed weak lymphatic endothelial expression of the LacZ marker gene. This suggests that endothelial cell-specific elements occur in the proximal promoter, although further enhancer elements are probably located elsewhere. The sequence, organization, and variation in the VEGFR3 gene and its regulatory region provide important tools for the molecular genetic analysis of the lymphatic system and its disorders.

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Section: Organization and Sequence Variation Of The Human Vegfr3 Genementioning

confidence: 71%

VEGFR3gene structure, regulatory region, and sequence polymorphisms

Iljin

Karkkainen

Lawrence³

et al. 2001

The FASEB Journal

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“…However, it should be noted that these results were obtained in transient transfection experiments with KDR/flk-1 cDNA. The KDR/flk-1 gene is multiply spliced, and its expression is highly restricted to cells of endothelial lineage (36,58). Therefore, the effect of KS-SM on KDR expression in endothelial cells and its physiological role in endothelial cell growth and VEGF responsiveness remain to be directly determined.…”

Section: Fig 4 Ks-sm-mediated Activation Is Gene Dependent (A) Bjamentioning

confidence: 99%

The Human Herpesvirus 8 Homolog of Epstein-Barr Virus SM Protein (KS-SM) Is a Posttranscriptional Activator of Gene Expression

Gupta

Ruvolo

Patterson

et al. 2000

J Virol

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Homologs of the Epstein-Barr virus (EBV) SM protein exist in several human and nonhuman herpesviruses.Structure and function differ significantly among these proteins. We have cloned and characterized the human herpesvirus 8 (HHV8) gene, KS-SM, which is homologous to the EBV SM and herpes simplex virus ICP27 genes, from an HHV8-infected primary effusion lymphoma. KS-SM is shown to be a posttranscriptional activator of gene expression in cotransfection studies. KS-SM activated gene expression in a gene-specific, promoter-independent manner. In particular, KS-SM enhanced the expression of KDR/flk-1, a receptor for vascular endothelial growth factor (VEGF), in cotransfection studies. Since expression of KDR/flk-1 is increased in Kaposi's sarcoma and HHV8-infected cell cultures and VEGF enhances the proliferation of HHV8-infected cells, KS-SM may play a pathogenic role in Kaposi's sarcoma.

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“…Given the importance of KDR/flk-1 in endothelial cell biology, we have cloned the entire human KDR/flk-1 gene (11) and have sought to define the mechanisms governing its transcriptional regulation. The human KDR/flk-1 gene is TATA-less and has a core promoter containing tandemly repeated GC boxes (12).…”

mentioning

confidence: 99%

The Human KDR/flk-1 Gene Contains a Functional Initiator Element That Is Bound and Transactivated by TFII-I

Patterson

1999

Journal of Biological Chemistry

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KDR/flk-1, the receptor for vascular endothelial growth factor, is required for normal vascular development. KDR/flk-1 is a TATA-less gene, containing four upstream Sp1 sites and a single transcription start site, although analysis of the start site sequence discloses only weak similarities with the consensus initiator element (Inr) sequence. In vitro transcription assays, however, demonstrate that the region from ؊10 to ؉10 relative to the start site contains Inr activity that is orientation-and position-dependent, and mutagenesis of the KDR/flk-1 Inr reduces promoter activity to 28% of the wild-type promoter in transient transfection assays. Gel shift assays confirm that nuclear proteins specifically bind the Inr, and competition experiments demonstrate that TFII-I, a multifunctional Inr-binding nuclear protein, is a component of these DNA-protein complexes. TFII-I transactivates the wild-type KDR/flk-1 promoter, but not a promoter containing a mutated Inr, in transient transfection assays. Immunodepletion of TFII-I from nuclear extracts prior to in vitro transcription assays abolishes transcription from the KDR/flk-1 Inr, an effect that can be rescued by adding back purified TFII-I, reflecting the importance of TFII-I in KDR/ flk-1 Inr activity. These experiments demonstrate that the KDR/flk-1 gene contains a functional Inr that is bound by TFII-I and that both the functional Inr and TFII-I activity are essential for transcription.

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Genomic structure of the human KDR/flk-1 gene

Cited by 14 publications

References 14 publications

VEGFR3gene structure, regulatory region, and sequence polymorphisms

VEGFR3gene structure, regulatory region, and sequence polymorphisms

The Human Herpesvirus 8 Homolog of Epstein-Barr Virus SM Protein (KS-SM) Is a Posttranscriptional Activator of Gene Expression

The Human KDR/flk-1 Gene Contains a Functional Initiator Element That Is Bound and Transactivated by TFII-I

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