Evidence forRAD51L1/HMGIC fusion in the pathogenesis of uterine leiomyoma

Takahashi, Tomoko; Nagai, Nobuo; Oda, Hiromune; Ohama, Koso; Kamada, Nanao; Miyagawa, Kiyoshi

doi:10.1002/1098-2264(2000)9999:9999<::aid-gcc1078>3.0.co;2-8

Cited by 40 publications

(19 citation statements)

References 24 publications

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“…HMGA2 expression in adult tissues is normally restricted to lung, kidney and synovia, [38][39][40] and reactivation of this gene has been previously associated with the development of benign tumors of mesenchymal origin as well as in sporadic cases of leukemia. Recently, quantitative real-time PCR analysis has shown that HMGA2 transcripts are overexpressed in CD34 þ cells from patients with myelofibrosis with myeloid metaplasia in comparison with normal CD34 þ cells from healthy donors.…”

Section: Discussionmentioning

confidence: 99%

Disruption and aberrant expression of HMGA2 as a consequence of diverse chromosomal translocations in myeloid malignancies

et al. 2004

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Chromosomal translocations that target HMGA2 at chromosome band 12q14 are seen in a variety of malignancies, notably lipoma, pleomorphic salivary adenoma and uterine leiomyoma. Although some HMGA2 fusion genes have been reported, several lines of evidence suggest that the critical pathogenic event is the expression of truncated HMGA2 isoforms. We report here the involvement of HMGA2 in six patients with myeloid neoplasia, dysplastic features and translocations or an inversion involving chromosome bands 12q13-15 and either 7p12, 8q22, 11q23, 12p11, 14q31 or 20q11. Breaks within or very close to HMGA2 were found in all six cases by molecular cytogenetic analysis, leading to overexpression of this gene as assessed by RT-PCR. Truncated transcripts consisting of HMGA2 exons 1-2 or exons 1-3 spliced to intron-derived sequences were identified in two patients, but were not seen in controls. These findings suggest that abnormalities of HMGA2 play an important and previously unsuspected role in myelodysplasia.

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Section: Discussionmentioning

confidence: 99%

Disruption and aberrant expression of HMGA2 as a consequence of diverse chromosomal translocations in myeloid malignancies

et al. 2004

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“…Evidence has also been presented that RAD51L1 (formerly RAD51B), a member of the RAD51 recombination repair gene family (Albala et al 1997;Shinohara et al 1992), is the chromosome 14 target gene and preferential fusion partner of HMGIC in uterine leiomyomas with t(12;14) (Amant et al 2001;Ingraham et al 1999;Schoenmakers et al 1999;Takahashi et al 2001). Although the RAD51L1 protein has not yet been shown to catalyze recombination reactions, RAD51L1 appears to be an essential gene (Shu et al 1999) expressed in almost all organs and tissues (Rice et al 1997) and probably plays a role in regulation of cell cycle progression (Havre et al 1998(Havre et al , 2000.…”

Section: The Genetic Findingsmentioning

confidence: 99%

“…Although the RAD51L1 protein has not yet been shown to catalyze recombination reactions, RAD51L1 appears to be an essential gene (Shu et al 1999) expressed in almost all organs and tissues (Rice et al 1997) and probably plays a role in regulation of cell cycle progression (Havre et al 1998(Havre et al , 2000. In view of the purported function of HMGIC in regulation of cell proliferation (Reeves 2000) and the probable role of RAD51L1 in cell cycle regulation, it is reasonable to speculate that the disruption of genomic structure associated with the RAD51L1/HMGIC fusion (Ingraham et al 1999;Schoenmakers et al 1999;Takahashi et al 2001) might result in dysregulated cell growth.…”

Section: The Genetic Findingsmentioning

confidence: 99%

Etiology and pathogenesis of uterine leiomyomas: a review.

Flake

Andersen

Dixon

2003

Environ Health Perspect

490

392

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Uterine leiomyomas, or fibroids, represent a major public health problem. It is believed that these tumors develop in the majority of American women and become symptomatic in one-third of these women. They are the most frequent indication for hysterectomy in the United States. Although the initiator or initiators of fibroids are unknown, several predisposing factors have been identified, including age (late reproductive years), African-American ethnicity, nulliparity, and obesity. Nonrandom cytogenetic abnormalities have been found in about 40% of tumors examined. Estrogen and progesterone are recognized as promoters of tumor growth, and the potential role of environmental estrogens has only recently been explored. Growth factors with mitogenic activity, such as transforming growth factor-β 3, basic fibroblast growth factor, epidermal growth factor, and insulin-like growth factor-I, are elevated in fibroids and may be the effectors of estrogen and progesterone promotion. These data offer clues to the etiology and pathogenesis of this common condition, which we have analyzed and summarized in this review.

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“…The involvement of Rad51B in benign tumors was first found in uterine leiomyomas harboring a balanced chromosome translocation between chromosomes 12 and 14 with the high mobility group protein HMGA2 (HMGIC) as the partner (25,26). Chimeric transcripts encoding either RAD51L1/HMGA2 or HMGA2/ RAD51L1 have been found in some uterine leiomyomas (25,27,28). In pseudo-Meigs' syndrome, which is characterized by uterine leiomyomas, ascites, and pleural effusion, a combination of the HMGA2/RAD51L1 fusion and a loss of the second RAD51L1 allele were observed (29).…”

Section: Introductionmentioning

confidence: 99%

Haploinsufficiency of RAD51B Causes Centrosome Fragmentation and Aneuploidy in Human Cells

Date

Katsura²,

Ishida³

et al. 2006

Cancer Research

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The Rad51-like proteins, Rad51B, Rad51C, Rad51D, XRCC2, and XRCC3, have been shown to form two distinct complexes and seem to assist Rad51 in the early stages of homologous recombination. Although these proteins share sequence similarity with Rad51, they do not show functional redundancy. Among them, Rad51B is unique in that the gene maps to the human chromosome 14q23-24, the region frequently involved in balanced chromosome translocations in benign tumors particularly in uterine leiomyomas. Despite accumulating descriptive evidence of altered Rad51B function in these tumors, the biological significance of this aberration is still unknown. To assess the significance of reduced Rad51B function, we deleted the gene in the human colon cancer cell line HCT116 by gene targeting. Here, we show that haploinsufficiency of RAD51B causes mild hypersensitivity to DNAdamaging agents, a mild reduction in sister chromatid exchange, impaired Rad51 focus formation, and an increase in chromosome aberrations. Remarkably, haploinsufficiency of RAD51B leads to centrosome fragmentation and aneuploidy. In addition, an f50% reduction in RAD51B mRNA levels by RNA interference also leads to centrosome fragmentation in the human fibrosarcoma cell line HT1080. These findings suggest that the proper biallelic expression of RAD51B is required for the maintenance of chromosome integrity in human cells. (Cancer Res 2006; 66(12): 6018-24)

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Evidence forRAD51L1/HMGIC fusion in the pathogenesis of uterine leiomyoma

Cited by 40 publications

References 24 publications

Disruption and aberrant expression of HMGA2 as a consequence of diverse chromosomal translocations in myeloid malignancies

Disruption and aberrant expression of HMGA2 as a consequence of diverse chromosomal translocations in myeloid malignancies

Etiology and pathogenesis of uterine leiomyomas: a review.

Haploinsufficiency of RAD51B Causes Centrosome Fragmentation and Aneuploidy in Human Cells

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