Overexpression of HMGA2-LPP fusion transcripts promotes expression of the α 2 type XI collagen gene

doi:10.1016/j.bbrc.2005.12.042

Biochemical and Biophysical Research Communications

Volume 340, Issue 2, 10 February 2006, Pages 476-481

https://doi.org/10.1016/j.bbrc.2005.12.042 Get rights and content

Abstract

In a subset of human lipomas, a specific t (3; 12) chromosome translocation gives rise to HMGA2-LPP fusion protein, containing the amino (N)-terminal DNA binding domains of HMGA2 fused to the carboxyl (C)-terminal LIM domains of LPP. In addition to its role in adipogenesis, several observations suggest that HMGA2-LPP is linked to chondrogenesis. Here, we analyzed whether HMGA2-LPP promotes chondrogenic differentiation, a marker of which is transactivation of the α 2 type XI collagen gene (Col11a2). Real-time PCR analysis showed that HMGA2-LPP and COL11A2 were co-expressed. Luciferase assay demonstrated that either of HMGA2-LPP, wild-type HMGA2 or the N-terminal HMGA2 transactivated the Col11a2 promoter in HeLa cells, while the C-terminal LPP did not. RT-PCR analysis revealed that HMGA2-LPP transcripts in lipomas with the fusion were 591-fold of full-length HMGA2 transcripts in lipomas without the fusion. These results indicate that in vivo overexpression of HMGA2-LPP promotes chondrogenesis by upregulating cartilage-specific collagen gene expression through the N-terminal DNA binding domains.

Section snippets

Materials and methods

Reverse transcription-polymerase chain reaction. A total of twenty samples of lipomas was obtained at biopsy or at surgery under informed consent and was rapidly frozen at −80 °C. The diagnosis was made based on the histological analysis. Total RNA was extracted using RNeasy Lipid Tissue Mini Kit (QIAGEN, Hilden, Germany). After DNase (Invitrogen, Carlsbad, CA, USA) treatment, cDNA was synthesized using 1 μg of each RNA sample, 50 ng of random hexamers, and 50 units of SuperScript II Reverse

A subset of lipomas expresses both HMGA2-LPP and COL11A2

RT-PCR analysis showed that three lipomas had HMGA2-LPP fusion transcripts (Fig. 1). These lipomas also contained COL11A2 transcripts, which are closely linked to chondrogenesis [10], [11]. On the other hand, 17 lipomas without HMGA2-LPP fusion transcripts did not have COL11A2 transcripts. Although there are no reported effects of HMGA2-LPP fusion protein on collagen gene expression, the specific co-expression of HMGA2-LPP and COL11A2 made us hypothesize that HMGA2-LPP is involved in the COL11A2

Discussion

We have recently reported that a case of intra-patellar tendon lipoma with chondrogenic differentiation contained HMGA2-LPP transcripts [7]. The present study indicates that in vivo overexpression of HMGA2-LPP fusion gene promotes chondrogenesis by upregulating cartilage-specific collagen gene expression through the N-terminal DNA binding domains of HMGA2. To the best of our knowledge, this is the first report showing the experimental evidence of the possible involvement of HMGA2-LPP in

Acknowledgments

This work was supported, in part, by grants from the Japan Society for the Promotion of Science (Grant No. 16591496), the Japan Orthopaedics and Traumatology Foundation (Grant No. 0142), and the Nakatomi Foundation.

References (26)

M.M. Petit et al.
Expression of reciprocal fusion transcripts of the HMGIC and LPP genes in parosteal lipoma
Cancer Genet. Cytogenet.
(1998)
M.M. Petit et al.
LPP, the preferred fusion partner gene of HMGIC in lipomas, is a novel member of the LIM protein gene family
Genomics
(1996)
A. Dahlen et al.
Fusion, disruption, and expression of HMGA2 in bone and soft tissue chondromas
Mod. Pathol.
(2003)
B. de Crombrugghe et al.
Transcriptional mechanisms of chondrocyte differentiation
Matrix Biol.
(2000)
Y. Matsui et al.
COL11A2 collagen gene transcription is differentially regulated by EWS/ERG sarcoma fusion protein and wild-type ERG
J. Biol. Chem.
(2003)
N. Tsumaki et al.
Modular arrangement of cartilage- and neural tissue-specific cis-elements in the mouse alpha 2(XI) collagen promoter
J. Biol. Chem.
(1998)
P. Arlotta et al.
Transgenic mice expressing a truncated form of the high mobility group I-C protein develop adiposity and an abnormally high prevalence of lipomas
J. Biol. Chem.
(2000)
A.H. Ligon et al.
Constitutional rearrangement of the architectural factor HMGA2: a novel human phenotype including overgrowth and lipomas
Am. J. Hum. Genet.
(2005)
V.C. Lui et al.
The human alpha 2(XI) collagen gene (COL11A2): completion of coding information, identification of the promoter sequence, and precise localization within the major histocompatibility complex reveal overlap with the KE5 gene
Genomics
(1996)
H.R. Ashar et al.
Disruption of the architectural factor HMGI-C: DNA-binding AT hook motifs fused in lipomas to distinct transcriptional regulatory domains
Cell
(1995)

P. Rogalla et al.

An identical HMGIC-LPP fusion transcript is consistently expressed in pulmonary chondroid hamartomas with t(3;12)(q27-28;q14-15)

Genes Chromosomes Cancer

(2000)

E.F. Schoenmakers et al.

Recurrent rearrangements in the high mobility group protein gene, HMGI-C, in benign mesenchymal tumours

Nat. Genet.

(1995)

Y. Matsui, T. Hasegawa, T. Kubo, T. Goto, K. Yukata, K. Endo, Y. Bando, N. Yasui, Intra-patellar tendon lipoma with...

Cited by (17)

Cell adhesion and transcriptional activity - Defining the role of the novel protooncogene LPP
2009, Translational Oncology
Integrating signals from the extracellular matrix through the cell surface into the nucleus is an essential feature of metazoan life. To date, many signal transducers known as shuttle proteins have been identified to act as both a cytoskeletal and a signaling protein. Among them, the most prominent representatives are zyxin and lipoma preferred (translocation) partner (LPP). These proteins belong to the LIM domain protein family and are associated with cell migration, proliferation, and transcription. LPP was first identified in benign human lipomas and was subsequently found to be overexpressed in human malignancies such as lung carcinoma, soft tissue sarcoma, and leukemia. This review portrays LPP in the context of human neoplasia based on a study of the literature to define its important role as a novel protooncogene in carcinogenesis.
Association of a high mobility group gene (HMGA2) variant with bone mineral density
2009, Bone
Citation Excerpt :
Consistent with previous reports, we detected HMGA2 mRNA and protein levels only in the fetal osteoblast hFOB cells. HMGA proteins influence the expression of genes involved in chondrogenesis such as COL11A2[20] and recombinant HMGA2 was recently shown to increase proliferation and growth of chondrocytes in vitro[21]. Thus, it is possible that HMGA2 might play a role in cartilage and bone formation early in life perhaps in an allele specific manner.
High mobility group (HMG) proteins regulate chromatin architecture and gene expression. Constitutional rearrangement of an HMG family member, HMGA2, in an 8-year old boy resulted in extreme overgrowth and advanced bone development. Moreover, a recent genome-wide association study documented an association between a variant in the 3′ untranslated region of HMGA2 (rs1042725) and height in otherwise healthy individuals. We attempted to extend these findings by testing if this HMGA2 polymorphism is associated with other skeletal measures in two large population cohorts of diverse race/ethnicity. Genotyping was completed in 1680 Afro-Caribbean men aged ≥ 40 years and 1548 Caucasian American men aged ≥ 69 years. Bone mineral density (BMD) was assessed with peripheral quantitative computed tomography. The minor allele frequency of rs1042725 was 32% among Afro-Caribbeans and 48% among Caucasians (p < 0.0001). No association was observed with height in either study cohort. However, presence of the minor allele of this SNP was associated with decreased tibia trabecular volumetric BMD in both populations (p = 0.007 Afro-Caribbean; p = 0.0007 Caucasian). Real-time quantitative RT-PCR and Western blot analysis demonstrated HMGA2 mRNA and protein expression in the human fetal osteoblast cell line, hFOB. Our analyses suggest a novel association between a common genetic variant in HMGA2 and trabecular BMD in ethnically diverse older men. Additional research is needed to better understand the role of HMGA2 in the regulation of bone metabolism.
A novel HMGA2::KITLG fusion in a dedifferentiated liposarcoma with amplification of MDM2 and HMGA2
2024, Genes Chromosomes and Cancer
Fusion of the High-mobility Group AT-Hook 2 (HMGA2) and the Gelsolin (GSN) Genes in Lipomas with t(9;12)(q33;q14) Chromosomal Translocation
2023, In Vivo
Recurrent Fusion of the Genes for High-mobility Group AT-hook 2 (HMGA2) and Nuclear Receptor Co-repressor 2 (NCOR2) in Osteoclastic Giant Cell-rich Tumors of Bone
2022, Cancer Genomics and Proteomics
Molecular cloning of WIF1 and HMGA2 reveals ear-preferential expression while uncovering a missense mutation associated with porcine ear size in WIF1
2019, Animal Genetics

View all citing articles on Scopus

View full text

Overexpression of HMGA2-LPP fusion transcripts promotes expression of the α 2 type XI collagen gene

Abstract

Section snippets

Materials and methods

A subset of lipomas expresses both HMGA2-LPP and COL11A2

Discussion

Acknowledgments

Cancer Genet. Cytogenet.

Genomics

Mod. Pathol.

Matrix Biol.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Am. J. Hum. Genet.

Genomics

Disruption of the architectural factor HMGI-C: DNA-binding AT hook motifs fused in lipomas to distinct transcriptional regulatory domains

Cell

An identical HMGIC-LPP fusion transcript is consistently expressed in pulmonary chondroid hamartomas with t(3;12)(q27-28;q14-15)

Genes Chromosomes Cancer

Recurrent rearrangements in the high mobility group protein gene, HMGI-C, in benign mesenchymal tumours

Nat. Genet.