Structure, Sequence, and Chromosome 19 Localization of HumanUSF2and Its Rearrangement in a Patient with Multicystic Renal Dysplasia

Lawrence Livermore National Laboratory, Livermore, California, United States
Genomics (Impact Factor: 2.28). 01/1997; 38(2):141-8. DOI: 10.1006/geno.1996.0609
Source: PubMed


The precise etiology of hydronephrosis caused by pelvi-ureteric junction obstruction is not yet known but there is convincing evidence for a genetic cause, with linkage analysis predicting a hereditary hydronephrosis locus on chromosome 6p. In previous studies, a patient was described with a de novo autosomal t(6;19)(p21;q13.1) translocation and suffering from bilateral multicystic renal dysplasia (MRD) caused by a bilateral complete pelvi-ureteric junction obstruction. In an effort to elucidate a possible correlation between this translocation and hereditary hydronephrosis, we have carried out an extensive molecular characterization of a chromosome 19 cosmid clone previously identified as spanning the translocation in this unique index case. DNA sequencing across a 9.2-kb BamHI fragment that straddles the translocation indicates the presence of DNA sequences with a high degree of similarity to the USF2 gene that encodes the transcription factor USF2 (upstream stimulator factor 2). The genomic structure of USF2 consists of 10 exons distributed over a DNA region of about 11 kb. The putative promoter region is GC-rich and lacks TATA and CCAAT boxes, suggesting that expression of the USF2 gene may be controlled by a typical housekeeping gene promoter. The chromosome 19 breakpoint in the MRD patient appeared to have occurred in intron 7 of the USF2 gene. Northern blot analysis of a variety of human tissues revealed that the USF2 gene is ubiquitously expressed. Furthermore, Northern blot and 3'-RACE analysis of mRNA isolated from lung fibroblasts of the MRD patient failed to detect a fusion transcript involving USF2 sequences, suggesting gene disruption rather than the generation of a fusion gene as a possible underlying mechanism.

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    • "This was first highlighted by a study investigating hormone refractory prostate cancer samples. Half of the hormone refractory prostate cancer samples displayed a loss of chromosome 19q ter-q13.1 [57] which includes the region with the usf2 gene [58]. A reintroduction of an intact human chromosome 19 into a tumorigenic prostate cell line reduced tumorigenicity in athymic nude mice [59]. "
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    ABSTRACT: The upstream stimulatory factor 2 (USF2) is a regulator of important cellular processes and is supposed to have also a role during tumor development. However, the knowledge about the mechanisms that control the function of USF2 is limited. The data of the current study show that USF2 function is regulated by phosphorylation and identified GSK3β as an USF2-phosphorylating kinase. The phosphorylation sites within USF2 could be mapped to serine 155 and threonine 230. In silico analyses of the 3-dimensional structure revealed that phosphorylation of USF2 by GSK3β converts it to a more open conformation which may influence transactivity, DNA binding and target gene expression. Indeed, experiments with GSK-3β-deficient cells revealed that USF2 transactivity, DNA binding and target gene expression were reduced upon lack of GSK3β. Further, experiments with USF2 variants mimicking GSK3β phosphorylated USF2 in GSK3β-deficient cells showed that phosphorylation of USF2 by GSK3β did not affect cell proliferation but increased cell migration. Together, this study reports a new mechanism by which USF2 may contribute to cancerogenesis.
    Full-text · Article · Sep 2014 · PLoS ONE
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    • "Urinary tract abnormalities were found in both cases. Observed multi-cystic dysplastic kidney disease could be associated with some changes of USF2 gene, located at the 19q13.1 band (Groenen et al., 1996). Disruption of the USF2 gene may cause multicystic renal dysplasia with pelviureteric obstruction, and massive hydronephrosis. "
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    Full-text · Article · Jul 2007 · Prenatal Diagnosis
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    ABSTRACT: Vesico-ureteral reflux (VUR) is a frequent condition, but in most instances, the precise cause is unknown. We here review the evidence of a genetic aetiology of VUR, inherited as an autosomal dominant trait, with variable expression. We discuss the possible pathogenetic relationship between VUR and other types of uropathies and possible strategies towards the identification of genes underlying VUR are presented. The isolation of the gene(s) responsible for uropathies will not only lead to a better insight into the embryology of the urological system, the pathogenesis of uropathies, but also to a renewed interest from clinicians in congenital uropathies.
    No preview · Article · May 1998 · European Journal of Pediatrics
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