Two novel tumor suppressor gene loci on chromosome 6q and 15q in human osteosarcoma identified through comparative study of allelic imbalances in mouse and man

Nathrath, Michaela; Kuosaite, Virginija; Rosemann, Michael; Kremer, Marcus; Poremba, Christopher; Wakana, Shigeharu; Yanagi, Masayuki; Nathrath, W; Höfler, Heinz; Imai, Kenji; Atkinson, Michael J.

doi:10.1038/sj.onc.1205764

Cited by 18 publications

(10 citation statements)

References 36 publications

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“…Deletion 6q was associated with metastasis in insulinoma (42), and deletions 6q14 and 6q16-q23 have been reported as recurrent cytogenetic aberrations in OS (43,44). Likewise, previous studies have shown an association of deletion 8p with disease progression in hepatocellular carcinoma (45) and colon cancer (46).…”

Section: Discussionmentioning

confidence: 83%

Identification of chromosomal aberrations associated with disease progression and a novel 3q13.31 deletion involving LSAMP gene in osteosarcoma

Yen

Chen

et al. 2009

Int J Oncol

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Abstract. Five osteosarcoma (OS) cell lines, 37 OS tumors and 9 corresponding non-neoplastic samples were genotyped by Affymetrix 10 K 2.0 SNP array. Regions of high level amplification and homozygous deletion were identified and validated by quantitative PCR and FISH. Certain recurrent cytogenetic alterations were more frequent in recurrent/ metastatic than in primary OS. These included deletion of 6q14.1, 6q16.2-q22.31, and 8p23.2-p12, amplification of 8q21.12, 8q22.3-q24.3 and 17p12, and loss of heterozygosity (LOH) at 2q24.3-q31.2, 5q11.2, 6p21.31-p21.1, 6q14.1-q16.2, 8p22-p12, 9q22.1, 10q21.1-q22.1, 10q23.31-q24.1, 12q15-q21.1 and 21q21.2-q21.3. Most of the LOH calls were associated with deletion, but a subset of them was associated with normal or increased copy number (CN). A consensus 3q13.31 deletion localized to a region within the limbic systemassociated membrane protein (LSAMP) gene was also identified. The FISH evaluations demonstrated highlylocalized homozygous or heterozygous LSAMP deletions in 6 of 11 primary OS. qRT-PCR evaluations of the two major alternative LSAMP transcripts demonstrated reduced expression of 1b isoform transcript in each of three OS with LSAMP exon 1b deletion. Further, the 1a isoform transcripts in these same OS had either reduced expression or a premature termination codon in LSAMP exon 2. This SNP genotyping study identified chromosomal aberrations associated with disease progression in OS and disclosed LSAMP as a novel tumor suppressor gene in OS. The study also demonstrated that CN and LOH analyses were able to detect distinct subsets of genetic abnormalities in OS.

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Section: Discussionmentioning

confidence: 83%

Identification of chromosomal aberrations associated with disease progression and a novel 3q13.31 deletion involving LSAMP gene in osteosarcoma

Yen

Chen

et al. 2009

Int J Oncol

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“…The eEF1A1gene, EEF1A1, maps to 6q14.1. This region is not frequently amplified in any malignancy and is deleted in squamous cell carcinoma, osteosarcoma and prostate cancer (Nathrath et al, 2002;Verhagen et al, 2002;Fitzsimmons et al, 2003). This suggests that 6q14.1 contains a tumor suppressor.…”

Section: Eef1a2 Activates Akt and Actin Remodelingmentioning

confidence: 82%

eEF1A2 activates Akt and stimulates Akt-dependent actin remodeling, invasion and migration

et al. 2006

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eEF1A2 (eukaryotic protein elongation factor 1 alpha 2) is a protein translation factor that is likely a human oncogene by virtue of its capacity to transform mammalian cells and its high expression in tumors of the ovary, breast and lung. Here, we show that expression of eEF1A2 is sufficient to stimulate the formation of filopodia in BT549 human breast cancer cells and non-transformed Rat2 cells. Filopodia formation in eEF1A2-expressing cells is dependent on the activity of phosphatidylinositol-3 kinase (PI3K), and the ROCK and Akt kinases. Furthermore, eEF1A2 expression is sufficient to activate Akt in a PI3K-dependent fashion and inactivation of eEF1A2 by short interfering RNA reduces Akt activity. Using breast cancer cell line BT 549, we show that eEF1A2 expression stimulates cell migration and invasion in a largely PI3K-and Akt-dependent manner. These results suggest that eEF1A2 regulates oncogenesis through Akt and PI3K-dependent cytoskeletal remodeling.

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“…The 15q21 locus (Figure 3c) that contains the Leo1 gene is amplified in colorectal cancer and malignant fibrous histiocytoma of bone (Camps et al, 2006;Tarkkanen et al, 2006). This region has a potential osteosarcoma suppressor gene identified by a hPAF complex in cancer K Chaudhary et al combination of synteny and microsatellite mapping (Nathrath et al, 2002). Interestingly, the interaction of Leo1 with nuclear b-catenin suggests an alternate role of this protein in cancer development.…”

Section: Leo1: Interacts With B-catenin During Wnt Signaling Cascadementioning

confidence: 99%

Human RNA polymerase II-associated factor complex: dysregulation in cancer

et al. 2007

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Genetic instabilities are believed to be one of the major causes of developing a cancer phenotype in humans. During the progression of cancer, aberrant expression of proteins, either owing to genetic (amplification, mutation and deletion) or epigenetic modifications (DNA methylation and histone deacetylation), contributes in different ways to the development of cancer. By differential screening analysis, an amplification of the 19q13 locus containing a novel pancreatic differentiation 2 (PD2) gene was identified. PD2 is the human homolog of the yeast RNA polymerase II-associated factor 1 (yPaf1) and is part of the human RNA polymerase II-associated factor (hPAF) complex. hPAF is comprised of five subunits that include PD2/hPaf1, parafibromin, hLeo1, hCtr9 and hSki8. This multifaceted complex was first identified in yeast (yPAF) and subsequently in Drosophila and human. Recent advances in the study on PAF have revealed various functions of the complex in human, which are similar to yPAF, including efficient transcription elongation, mRNA quality control and cell-cycle regulation. Although the precise function of this complex in cancer is not clearly known, some of its subunits have been linked to a malignant phenotype. Its core subunit, PD2/hPaf1, is amplified and overexpressed in many cancers. Further, an overexpression of PD2/hPaf1 results in the induction of a transformed phenotype, suggesting its possible involvement in tumorigenesis. The parafibromin subunit of the hPAF complex is a product of the HRPT-2 (hereditary hyperparathyroidism type 2) tumor suppressor gene, which is mutated in the germ line of hyperparathyroidismjaw tumor patients. This review focuses on the functions of the PAF complex and its individual subunits, the interaction of the subunits with each other and/or with other molecules, and dysregulation of the complex, providing an insight into its potential involvement in the development of cancer.

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Two novel tumor suppressor gene loci on chromosome 6q and 15q in human osteosarcoma identified through comparative study of allelic imbalances in mouse and man

Cited by 18 publications

References 36 publications

Identification of chromosomal aberrations associated with disease progression and a novel 3q13.31 deletion involving LSAMP gene in osteosarcoma

Identification of chromosomal aberrations associated with disease progression and a novel 3q13.31 deletion involving LSAMP gene in osteosarcoma

eEF1A2 activates Akt and stimulates Akt-dependent actin remodeling, invasion and migration

Human RNA polymerase II-associated factor complex: dysregulation in cancer

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