Three aberrant splicing variants of the HMGIC gene transcribed in uterine leiomyomas

Kurose, Kouichi; Mine, Nobuya; Iida, Aritoshi; Nagai, Hisaki; Harada, Haruhito; Araki, Tsutomu; Emi, Mitsuru

doi:10.1002/1098-2264(2000)9999:9999<::aid-gcc1081>3.3.co;2-j

Cited by 2 publications

(3 citation statements)

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“…Provided that the presence of Let-7 LCS at the 3 ¶-UTR of HMGA2 is required for Let-7 activity, several potential mechanisms can explain the overexpression of HMGA2 in uterine leiomyomas: (a) loss or reduction of Let-7 expression; (b) the truncated transcripts of HMGA2 with a partial or complete loss of Let-7 LCS, secondary to chromosomal 12q13-15 changes (7,31); and (c) expression of cryptic HMGA2 isoforms (HMGA2b-HMGA2g; refs. 17,32) that may lack Let-7 LCS.…”

Section: Let-7 Micrornas Regulate the Dominant Transcript Hmga2a And mentioning

confidence: 99%

Antiproliferative Effects by Let-7 Repression of High-Mobility Group A2 in Uterine Leiomyoma

Peng

Laser

Shi

et al. 2008

Molecular Cancer Research

125

111

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High-mobility group A2 (HMGA2) is commonly overexpressed in large leiomyomas. HMGA2 is an important regulator of cell growth, differentiation, apoptosis, and transformation. As a predicted target of Let-7 microRNAs (Let-7s), HMGA2 can be repressed by Let-7s in vitro. MicroRNA profiling analysis revealed that Let-7s were significantly dysregulated in uterine leiomyomas: high in small leiomyomas and lower in large leiomyomas. To evaluate whether Let-7 repression of HMGA2 plays a major role in leiomyomas, we analyzed the molecular relationship of HMGA2 and Let-7s, both in vitro and in vivo. We first characterized that exogenous Let-7 microRNAs could directly repress the dominant transcript of HMGA2, HMGA2a. This repression was also identified for two cryptic HMGA2 transcripts in primary leiomyoma cultures. Second, we found that the endogenous Let-7s were biologically active and played a major role in the regulation of HMGA2. Then, we illustrated that Let-7 repression of HMGA2 inhibited cellular proliferation. Finally, we examined the expression levels of Let-7c and HMGA2 in a large cohort of leiomyomas (n = 120), and we found high levels of Let-7 and low levels of HMGA2 in small leiomyomas, and low levels of Let-7 and high levels of HMGA2 in large leiomyomas. Our findings suggest that the Let-7 -mediated repression of HMGA2 mechanism can be an important molecular event in

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Section: Let-7 Micrornas Regulate the Dominant Transcript Hmga2a And mentioning

confidence: 99%

Antiproliferative Effects by Let-7 Repression of High-Mobility Group A2 in Uterine Leiomyoma

Peng

Laser

Shi

et al. 2008

Molecular Cancer Research

125

111

View full text Add to dashboard Cite

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“…Of the four novel aberrant splices, two were the same. Because the HMGIC aberrations found in several independent cases have been the same (Schoenmakers et al 1999;Kurose et al 2001), we suggest that specific sites or patterns of aberrant splicing are common features of HMGIC rearrangements.…”

Section: Discussionmentioning

confidence: 55%

“…(Schoenmakers et al 1995). HLES-1, U29117 from human lipoma cell line Li-538/SV40 ectopic sequence from HMGIC fusion mRNA, 3Ј sequence; HLES-2, U29112 from human lipoma cell line LM-30.1/SV40 ectopic sequence from HMGIC fusion mRNA, 3Ј sequence clone pCH109; HLES-3, U29115 from human lipoma cell line Li-192 ectopic sequence from HMGI-C fusion mRNA, 3Ј sequence, clone pCH148 b Exons a, b, and c (see Kurose et al 2001) …”

Section: Discussionmentioning

confidence: 99%

Gene fusion involving HMGIC is a frequent aberration in uterine leiomyomas

et al. 2001

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HMGIC, a high-mobility-group protein gene encoding an architectural transcription factor, was recently identified as the target of gene fusion in a variety of human benign mesenchymal tumors; some of these events were chromosomal translocations involving 12q13-15. HMGIC consists of three DNA-binding domains (encoded by exons 1-3), a spacer, and an acidic carboxyl-terminal regulatory domain (exons 4-5). To determine the spectrum and nature of the aberrations in uterine myomas in Japanese patients, we systematically examined the tumors of 45 patients for all possible types of gene fusions involving HMGIC, by means of 3Ј-rapid amplification of cDNA ends (RACE) and reverse transcriptase-polymerase chain reaction (RT-PCR) experiments. HMGIC gene fusions were found in 16 (36%) of the tumors; aberrant splicings to five cryptic sequences located in introns of the HMGIC gene were found in 11 of these cases, and translocations causing juxtaposition to other genes, such as COX6C and RAD51B, were found in 5. In all fusion transcripts, the first two or three exons of HMGIC were fused to ectopic sequences. Our results suggest that a fusion event, resulting in the separation of the DNA-binding domains of HMGIC from the spacer and the acidic carboxyl-terminal regulatory domain, is a common tumorigenic mechanism in the development of uterine myomas.

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Three aberrant splicing variants of the HMGIC gene transcribed in uterine leiomyomas

Cited by 2 publications

References 0 publications

Antiproliferative Effects by Let-7 Repression of High-Mobility Group A2 in Uterine Leiomyoma

Antiproliferative Effects by Let-7 Repression of High-Mobility Group A2 in Uterine Leiomyoma

Gene fusion involving HMGIC is a frequent aberration in uterine leiomyomas

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