Identification of four alternatively spliced transcripts of the Ucma/GRP gene, encoding a new Gla-containing protein

Jeune, Marion Le; Tomavo, Nathalie; Tian, Tian V.; Flourens, Anne; Marchand, Nathalie; Camuzeaux, Barbara; Malléin-Gerin, Frédéric; Duterque-Coquillaud, Martine

doi:10.1016/j.yexcr.2009.10.002

Cited by 25 publications

(33 citation statements)

References 33 publications

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“…In addition, variants lacking either exon 2 or 4 or exon 4 alone were also described. The significance of the intracellular UCMA remains unclear, however it was described that it forms microtubule-dependent aggregates when overexpressed (LeJeune et al, 2010). Interestingly, we could show that not only the exon/intron organization of both genes in zebrafish (Viegas et al, 2008), but also the alternative splicing leading to the uncommon Ucma variants is mostly conserved.…”

Section: Discussionmentioning

confidence: 60%

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Ucmaa (Grp-2) is required for zebrafish skeletal development. Evidence for a functional role of its glutamate γ-carboxylation

et al. 2011

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Section: Discussionmentioning

confidence: 60%

“…Moreover, also the proposed coiled-coil oligomerization domain is conserved. In mouse splice variants lacking exon 2 exist, causing expression of Ucma variants that are targeted to the intracellular space (LeJeune et al, 2010). In addition, variants lacking either exon 2 or 4 or exon 4 alone were also described.…”

Section: Discussionmentioning

confidence: 99%

Ucmaa (Grp-2) is required for zebrafish skeletal development. Evidence for a functional role of its glutamate γ-carboxylation

et al. 2011

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“…Cellular extract preparation and Western blot analysis were carried out as previously described (35,36). Immunodetections were carried out using a polyclonal anti-ERG antibody (sc-353, Santa Cruz Biotechnology), a monoclonal anti-OPN antibody (sc-21742, Santa Cruz Biotechnology) and an anti-actin monoclonal antibody (Sigma).…”

Section: Cellular Extract Preparation and Western Blot Analysismentioning

confidence: 99%

Abnormal Expression of the ERG Transcription Factor in Prostate Cancer Cells Activates Osteopontin

Flajollet

Tian

Flourens

et al. 2011

Molecular Cancer Research

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Osteopontin (OPN) is an extracellular matrix glycophosphoprotein that plays a key role in the metastasis of a wide variety of cancers. The high level of OPN expression in prostate cells is associated with malignancy and reduced survival of the patient. Recent studies on prostate cancer (PCa) tissue have revealed recurrent genomic rearrangements involving the fusion of the 5 0 untranslated region of a prostate-specific androgen-responsive gene with a gene coding for transcription factors from the ETS family. The most frequently identified fusion gene is TMPRSS2:ERG, which causes ERG protein overexpression in PCa cells. ERG is a transcription factor linked to skeletogenesis. This study was designed to test whether ERG and the product of the TMPRSS2:ERG fusion gene modulate OPN gene expression in PCa cells. To characterize ERG and TMPRSS2:ERG transcriptional activity of OPN, we focused on ETS binding sites (EBS) localized in conserved regions of the promoter. Using in vitro and in vivo molecular assays, we showed that ERG increases OPN expression and binds to an EBS (nt À115 to À118) in the OPN promoter. Moreover, stable transfection of prostate tumor cell lines by TMPRSS2:ERG upregulates endogenous OPN expression. Finally, in human prostate tumor samples, detection of the TMPRSS2:ERG fusion gene was significantly associated with OPN overexpression. Taken together, these data suggest that OPN is an ERG-target gene in PCa where the abnormal expression of the transcription factor ERG, due to the TMPRSS2: ERG fusion, disturbs the expression of genes that play an important role in PCa cells and associated metastases. Mol Cancer Res; 9(7); 914-24. Ó2011 AACR.

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“…More recently, the UCMA/GRP protein was suggested to directly influence mineral formation and to play a role in processes involving soft tissue mineralization and abnormal calcification in the vascular system [16]. Investigation for alternatively spliced transcripts of UCMA/GRP in mice led to the identification of 4 isoforms, two of them probably secreted and two others reported to form aggregates in a structure similar to aggresome, an organelle where aggregated proteins are stored or degraded by autophagy [17]. Interestingly, the catabolic process of macroautophagy may be involved in PDB pathophysiology since SQSTM1/p62 protein plays a central role in autophagy, acting as an adaptor allowing specific molecules to undergo selective degradation by autophagy [18,19].…”

Section: Introductionmentioning

confidence: 99%

Genetic association study of UCMA/GRP and OPTN genes (PDB6 locus) with Paget's disease of bone

Michou

Conceição

Morissette

et al. 2012

Bone

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We performed a genetic association study of rare variants and single nucleotide polymorphisms (SNPs) of UCMA/GRP and OPTN genes, in French-Canadian patients with Paget's disease of bone (PDB) and in healthy controls from the same population. We reproduced the variant found in the UCMA/GRP basal promoter and tested its functionality using in vitro transient transfection assays. Interestingly, this SNP rs17152980 appears to affect the transcription level of UCMA/ GRP. In addition, we have identified five rare genetic variants in UCMA/GRP gene, four of them being population-specific, although none were found to be associated with PDB. Six Tag SNPs of UCMA/GRP gene were associated with PDB, particularly the SNP rs17152980 (uncorrected P=3.8 × 10 −3 ), although not significant after Bonferroni's correction. More importantly, we replicated the strong and statistically significant genetic association of two SNPs of the OPTN gene, the rs1561570 (uncorrected P=5.7 × 10 −7 ) and the rs2095388 (uncorrected P=4.9 × 10 −3 ), with PDB. In addition, we identified a very rare variant found to be located close to the basal promoter of the OPTN gene, at −232 bp from its distal transcription start site. Furthermore, depending on the type of allele present (G or A), the binding of several important nuclear factors such as the vitamin D or the retinoic acid receptors is predicted to be altered at this position, suggesting a significant effect in the regulation of transcription of the OPTN gene. In conclusion, we identified a functional SNP located in the basal promoter of the UCMA/GRP gene which provided a weak genetic association with PDB. In addition, we replicated the strong genetic association of two already known SNPs of the OPTN gene, with PDB in a founder effect population. We also identified a very rare variant in the promoter of OPTN, and through Joint corresponding authors: Laëtitia Michou, Rhumatologie-S763, CHUQ-CHUL, 2705 boulevard Laurier,

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Identification of four alternatively spliced transcripts of the Ucma/GRP gene, encoding a new Gla-containing protein

Cited by 25 publications

References 33 publications

Ucmaa (Grp-2) is required for zebrafish skeletal development. Evidence for a functional role of its glutamate γ-carboxylation

Ucmaa (Grp-2) is required for zebrafish skeletal development. Evidence for a functional role of its glutamate γ-carboxylation

Abnormal Expression of the ERG Transcription Factor in Prostate Cancer Cells Activates Osteopontin

Genetic association study of UCMA/GRP and OPTN genes (PDB6 locus) with Paget's disease of bone

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