A 3p21.3 region is preferentially eliminated from human chromosome 3/mouse microcell hybrids during tumor growth in SCID mice

Kholodnyuk, Irina; Kost‐Alimova, Marija; Kashuba, Vladimir I.; Gizatulin, Rinat; Szeles, Anna; Stanbridge, Eric J.; Zabarovsky, Eugene R.; Klein, George; Imreh, Stefan

doi:10.1002/(sici)1098-2264(199703)18:3<200::aid-gcc6>3.3.co;2-3

Cited by 12 publications

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“…In addition, LOH in a region syntenic with 3p21 is also found in many types of mouse cancers (22,70). When scid mouse tumors, which are induced by human chromosome 3-mouse microcell hybrids, were used to screen for a common eliminated region, one was often found at 3p21 (38,44), suggesting that loss of a tumor suppressor gene may be necessary for microcell hybrids to induce tumors in scid mice. The human mismatch repair gene (hMLH) also maps to 3p21, and loss of hMLH function is associated with microsatellite instability at one or more loci (51).…”

Section: Resultsmentioning

confidence: 99%

MCG10, a Novel p53 Target Gene That Encodes a KH Domain RNA-Binding Protein, Is Capable of Inducing Apoptosis and Cell Cycle Arrest in G₂-M

Zhu

Chen

2000

Molecular and Cellular Biology

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p53, a tumor suppressor, inhibits cell proliferation by inducing cellular genes involved in the regulation of the cell cycle. MCG10, a novel cellular p53 target gene, was identified in a cDNA subtraction assay with mRNA isolated from a p53-producing cell line. MCG10 can be induced by wild-type but not mutant p53 and by DNA damage via two potential p53-responsive elements in the promoter of the MCG10 gene. The MCG10 gene contains 10 exons and is located at chromosome 3p21, a region highly susceptible to aberrant chromosomal rearrangements and deletions in human neoplasia. The MCG10 gene locus encodes at least two alternatively spliced transcripts, MCG10 and MCG10as. The MCG10 and MCG10as proteins contain two domains homologous to the heterogeneous nuclear ribonucleoprotein K homology (KH) domain. By generating cell lines that inducibly express either wild-type or mutated forms of MCG10 and MCG10as, we found that MCG10 and MCG10as can suppress cell proliferation by inducing apoptosis and cell cycle arrest in G 2 -M. In addition, we found that MCG10 and MCG10as, through their KH domains, can bind poly(C) and that their RNA-binding activity is necessary for inducing apoptosis and cell cycle arrest. Furthermore, we found that the level of the poly(C) binding MCG10 protein is increased in cells treated with the DNA-damaging agent camptothecin in a p53-dependent manner. These results suggest that the MCG10 RNA-binding protein is a potential mediator of p53 tumor suppression.RNA-binding proteins are a large family of proteins with diverse functions which contain one or more RNA-binding domains (RBDs) and other auxiliary domains for protein-protein interaction and subcellular targeting (22,23,46,65,71,78). Several ribosomal proteins are RNA-binding proteins, for example, S6, S15, and L11, which are necessary for ribosome assembly and may be a target for translational regulation (23,82). Several groups of RNA-binding proteins have been shown to play an important role in alternate splicing, RNA editing, and alternate poly(A) site selection. Among these are the abundant heterogeneous nuclear ribonucleoproteins (hnRNPs), which shuttle between the nucleus and cytoplasm (48,74,82).Three major RNA-binding motifs have been found in hnRNPs, that is, the RBD, arginine/glycine-rich box (RGG), and hnRNP K homology (KH) domain. The consensus RBD structure is composed of 90 to 100 amino acids with a ␤␣␤␤␣␤ secondary structure (9). A majority of hnRNPs, such as A, B, C, D, F, G, and H, contain one or more RBDs, which are necessary for the ability of these hnRNPs in the regulation of splicing, RNA trafficking, and mRNA stability (48, 82). RNAbinding experiments demonstrate that RBD motif proteins can bind RNA with a wide range of affinities and specificities (9). The RGG box is composed of several closely spaced arginineglycine-glycine repeats with a ␤-spiral secondary structure (9). Several hnRNPs contain RGG boxes along with RBD or KH motifs. RNA-binding experiments have demonstrated that the RGG box has a relatively weak RNA-binding ...

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Section: Resultsmentioning

confidence: 99%

MCG10, a Novel p53 Target Gene That Encodes a KH Domain RNA-Binding Protein, Is Capable of Inducing Apoptosis and Cell Cycle Arrest in G₂-M

Zhu

Chen

2000

Molecular and Cellular Biology

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“…(2) 3p21.3-22 (AP20 region, Kashuba et al, 1995;between D3S1611 andD3S1260). This region is also involved in the common eliminated region (CER) in SCID mouse tumors derived from human chromosome 3-containing hybrid cell lines (Imreh et al, 1994;Kholodnyuk et al, 1996). The more restricted CER1 described in later studies is centromeric to AP20, however (Szeles et al, 1997).…”

Section: Most Frequently Affected 3p Regions In Rcc Biopsies and Linesmentioning

confidence: 88%

Combined LOH/CGH analysis proves the existence of interstitial 3p deletions in renal cell carcinoma

et al. 2000

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We have recently developed an allele titration assay (ATA) to assess the sensitivity and in¯uence of normal cell admixture in loss of heterozygosity (LOH) studies based on CA-repeat. The assay showed that these studies are biased by the size-dependent dierential sensitivity of allele detection. Based on these data, we have set up new criteria for evaluation of LOH. By combining these new rules with comparative genome hybridization (CGH) we have shown the presence of interstitial deletions in renal cell carcinoma (RCC) biopsies and cell lines. At least three out of 11 analysed RCC cell lines and three out of 37 biopsies contain interstitial deletions on chromosome 3. Our study suggests the presence of several regions on human chromosome 3 that might contribute to tumor development by their loss: (i) 3p25-p26, around the VHL gene (D3S1317); (ii) 3p21.3-p22 (between D3S1260 and D3S1611); (iii) 3p21.2 (around D3S1235 and D3S1289); (iv) 3p13-p14 (around D3S1312 and D3S1285). For the ®rst time, AP20 region (3p21.3-p22) was carefully tested for LOH in RCC. It was found that the AP20 region is the most frequently aected area. Our data also suggest that another tumor suppressor gene is located near the VHL gene in 3p25-p26.

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“…Functional studies, using transfection of P1 clones containing an 80-kb fragment of DNA from the 3p21.3 region and transfer of the same or similar chromosome 3 fragments via microcell fusion, have resulted in tumor suppression of the A9 mouse fibrosarcoma cell lines (44)(45)(46). Candidates for such a tumor suppressing activity include a number of genes including a member of the semaphorin family and BAP-1 (ref.…”

Section: Discussionmentioning

confidence: 99%

Functional evidence for a nasopharyngeal carcinoma tumor suppressor gene that maps at chromosome 3p21.3

Cheng

Poulos

Lung

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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Nasopharyngeal carcinoma is a malignancy that is prevalent among populations from Southeast Asia. Epidemiological studies indicate that genetic predisposition, Epstein-Barr virus, and environmental conditions may play a role in determining incidence. Molecular studies have implicated a tumor suppressor gene(s) on the short arm of chromosome 3. In this study we provide functional evidence, via monochromosome transfer, for a tumor suppressor gene(s) activity in chromosome 3p21.3.

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A 3p21.3 region is preferentially eliminated from human chromosome 3/mouse microcell hybrids during tumor growth in SCID mice

Cited by 12 publications

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MCG10, a Novel p53 Target Gene That Encodes a KH Domain RNA-Binding Protein, Is Capable of Inducing Apoptosis and Cell Cycle Arrest in G₂-M

MCG10, a Novel p53 Target Gene That Encodes a KH Domain RNA-Binding Protein, Is Capable of Inducing Apoptosis and Cell Cycle Arrest in G₂-M

Combined LOH/CGH analysis proves the existence of interstitial 3p deletions in renal cell carcinoma

Functional evidence for a nasopharyngeal carcinoma tumor suppressor gene that maps at chromosome 3p21.3

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A 3p21.3 region is preferentially eliminated from human chromosome 3/mouse microcell hybrids during tumor growth in SCID mice

Cited by 12 publications

References 0 publications

MCG10, a Novel p53 Target Gene That Encodes a KH Domain RNA-Binding Protein, Is Capable of Inducing Apoptosis and Cell Cycle Arrest in G2-M

MCG10, a Novel p53 Target Gene That Encodes a KH Domain RNA-Binding Protein, Is Capable of Inducing Apoptosis and Cell Cycle Arrest in G2-M

Combined LOH/CGH analysis proves the existence of interstitial 3p deletions in renal cell carcinoma

Functional evidence for a nasopharyngeal carcinoma tumor suppressor gene that maps at chromosome 3p21.3

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MCG10, a Novel p53 Target Gene That Encodes a KH Domain RNA-Binding Protein, Is Capable of Inducing Apoptosis and Cell Cycle Arrest in G₂-M

MCG10, a Novel p53 Target Gene That Encodes a KH Domain RNA-Binding Protein, Is Capable of Inducing Apoptosis and Cell Cycle Arrest in G₂-M