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PubMed1980

The relationship between cell killing, chromosome aberrations, spindle defects and mitotic delay in mouse lymphoma cells of differential sensitivity to X-rays.

The ultrasensitivity of a subline of L5178Y mouse lymphoma cells to X-rays was thought to result from chromosome structural aberrations which are much more frequent in these cells than in radiation-resistant cells derived from them (Scott, Fox and Fox 1974). However, Ehmann, Nagasawa, Peterson and Lett (1974) in time-lapse photography studies of the sensitive line, concluded that the induction of multipolar mitoses by X-rays might be a more important mechanism of cell killing than chromosome aberrations. We have now shown that at survival levels above about 20 per cent, chromosome structural aberrations which lead to bridges and fragments at anaphase are about four times more frequent than spindle defects. We have confirmed the higher frequency of structural aberrations and spindle defects, and the greater mitotic delay in the X-ray-sensitive than in the X-ray-resistant cell line and have proposed a model which causally relates these end-points to cell killing and DNA repair.

Anaphase↗
PubMed1996

The genomic structure and chromosomal localization of the mouse STAT3 gene.

A variety of cytokines induce the tyrosine phosphorylation of signal transducers and activators of transcription (STATs). Activation of the same STAT proteins by distinct cytokines and activation of different STAT proteins by each cytokine are thought to contribute to redundancy and pleiotropy of cytokine actions respectively. STAT3 is rapidly tyrosine phosphorylated in response to IL-6, ciliary neurotrophic factor, oncostatin M, leukemia inhibitory factor, IL-11, granulocyte colony stimulation factor and epidermal growth factor. In this report we have isolated and characterized the mouse genomic structure of STAT3. The mouse STAT3 gene consisted of 24 exons which spanned > 37 kb. The structure of the mouse STAT3 gene was almost identical to that of the human STAT2 gene, including the number and size of exons, indicating that the exon-intron organization had already been accomplished before these two genes duplicated, and then these genes evolved to respond to different ligands. By molecular linkage analysis with interspecific backcross mice the STAT3 gene mapped at 1.4 cM proximal to D11Mit59 on mouse chromosome 11. The promoter region contained potential regulatory elements such as GATA, NF-IL-6, PEBP2, Sp-1, AP-2 binding sites, cAMP response element, CAAT box and E-box. Transient expression of constructs harboring the 5' flanking region of the STAT3 gene fused to the luciferase gene showed that a 160 bp sequence upstream of the transcription start site conferred a basal and an IL-6-inducible promoter activity.

Animals↗
PubMed1987

Potentiating effect of caffeine on embryotoxicity of cyclophosphamide treatment in vivo during the preimplantation period.

Since it is unknown if chemicals which are generally safe in pregnancy can potentiate the embryotoxicity of cytotoxic drugs before implantation, the combined effects of cyclophosphamide (CPA) and caffeine (CF) were studied in the mouse (day 2) with CPA at 20 mg/kg, which induces a 18% resorption rate, and CF at 100 mg/kg, which does not increase embryolethality. The embryotoxicity of CPA did not increase when CF was either given 6 h before or simultaneously with CPA on day 2. However, when CF was given 6 h after CPA, a potentiated increase of embryolethality was observed at term and of structural chromosomal aberrations in embryos even before implantation, while sister chromatid exchange (SCE) frequency was less increased than after single CPA treatment. The results demonstrate the importance of pharmacokinetics in pregnancy even before implantation. Furthermore, since SCE may not only indicate DNA damage but also repair, the reduced SCE rate and the increase in structural chromosome aberrations suggest that CF can inhibit the repair of CPA-induced DNA damage in preimplantation embryos. Finally, for the first time the data are providing evidence that CF at subthreshold doses can potentiate the embryotoxicity of an alkylating agent in vivo even before implantation.

Animals↗
PubMed1999

cDNA cloning, genomic structure, and chromosomal localization of a novel murine epidermis-type lipoxygenase.

Using a combination of degenerate PCR technique and conventional screening procedures, we isolated a cDNA encoding a novel lipoxygenase, termed epidermis-type lipoxygenase-3 (e-LOX-3, gene symbol Aloxe3), from mouse skin. Aloxe3 mRNA is expressed in the stratified epithelia of skin, tongue, and forestomach. The cDNA encodes a protein of 711 amino acids with a calculated molecular mass of 80.6 kDa. The amino acid sequence shows approximately 54% identity to the recently identified 12(R)-lipoxygenase. Sequence comparison revealed a segment of 41 amino acid residues localized near the boundary between the N- and the C-terminal domain sequences of the molecule, a structural feature that is also characteristic of 12(R)-lipoxygenase, suggesting that these two epidermis-derived lipoxygenases may be members of a novel structural class of mammalian lipoxygenases. The novel lipoxygenase gene is divided into 15 exons and 14 introns, spanning 22.3 kb of genomic DNA. By interspecific backcross analysis, the novel gene was localized to the central region of mouse chromosome 11.

Amino Acid Sequence↗
PubMed1996

Protective role of soybean feeding against the cytogenetical and histopathological effects of dibutylamine and sodium nitrate on bone marrow and liver of mice.

The protective role of soybean feeding against the cytogenetic and histopathologic effects of the nitrosamine precursors sodium nitrate and dibutylamine was evaluated. Treated animals were killed every 3 months, over a period of 15 months, and bone marrow cells were prepared for cytogenetic studies and livers for histopathological observations. Structural chromosomal aberrations and mitotic indices increased after treatment with the nitrosamine precursors for all tested times. Livers were within the normal appearance during the first 6 months. After that a mild, moderate, marked dysplasia with lymphocytic infiltration, fatty vacuolation and liver atrophy was observed. Soybean coadministered with the nitrosamine precursors reduced the number of structural chromosomal aberrations. Mitotic indices decreased at all tested groups but still higher than the control level. A marked reduction in dysplastic features in the liver cells was observed. In conclusion, the cytogenetic and histopathologic results of this study strongly support the protective role of soybean against the genotoxic and carcinogenic action of nitrosomine formed in vivo from its precursors.

Animal Feed↗
PubMed2003

Cytogenetic effects of lambda-cyhalothrin on Wistar rat bone marrow.

In this study, the genotoxic and cytotoxic potential of lambda-cyhalothrin (LCT), a synthetic pyrethroid insecticide, was investigated in Wistar rat bone-marrow cells, using the structural chromosomal aberration (SCA) and micronucleus (MN) test systems. LCT was administrated to adult female albino rats as repeated i.p. doses of 6.12, 3.06, 0.8 mg/kg BW for 13 days at 48 h intervals. Mitomycin C (MMC) was used as a positive control (2 mg/kg BW). All the doses of LCT increased the number of structural chromosomal aberrations and the frequency of micronucleated erythrocytes, compared with the control group. It was also observed that LCT caused a significant decrease in the number of polychromatic erythrocytes. Our results demonstrate that LCT has a clastogenic/genotoxic potential as measured by the bone marrow SCA and MN tests in Wistar rats.

Animals↗
PubMed1998

Structure and chromosome mapping of the human small maf-genes MAFG and MAFK.

The newly emerged Maf family proteins possess a highly conserved basic leucine zipper (bZip) domain in common and are subdivided into large and small Maf proteins. The Maf family proteins appear to regulate cell differentiation processes and also cellular functions as partner molecules of CNC family proteins. To facilitate understanding of the function of small Maf proteins, we isolated the genes (MAFG and MAFK) encoding human small Maf proteins MafG and MafK and characterized their structures and organization by means of restriction enzyme mapping, Southern blot hybridization and nucleotide sequence analysis. Organization of the small maf genes are highly conserved in vertebrates, suggesting an important functional contribution of the gene products. We also examined the location of these genes within the human genome by fluorescence in situ hybridization (FISH) analysis. Human MAFG and MAFK are located at 17q25 and 7p22, respectively. Thus, small maf genes are not clustered in a single locus.

Chromosome Mapping↗
PubMed2003

Genetic pathways and genome-wide determinants of clinical outcome in colorectal cancer.

Various studies have suggested the existence of different pathways of tumor progression in colorectal cancer that associate with specific molecular, chromosomal, and clinicopathological features. We hypothesize that a comprehensive analysis of cumulated genomic damage in colorectal cancers would aid the characterization of different tumor progression pathways and identify the factors determining clinical outcome of tumors of each type. Genome-wide disruption was studied by DNA fingerprinting in a series of 129 sporadic colorectal carcinomas. These results, taken together with data for DNA ploidy, microsatellite instability, p53, and K-ras mutations and clinicopathological characteristics of the patients, have been used to classify colorectal carcinomas. The following five groups can be defined based on the type and level of cumulated genomic damage: (a) tumors with microsatellite instability, right location, and good prognosis; (b) diploid tumors lacking p53 mutations, left and right location, low subchromosomal damage, and bad prognosis; (c) diploid tumors with p53 mutations, left location, high levels of subchromosomal damage, and good prognosis; (d) high aneuploid tumors, p53 mutations, left location, high levels of numerical and structural chromosomal alterations, and bad prognosis; and finally (e) low aneuploid tumors, no p53 mutations, left and right location, low levels of structural chromosomal alterations, and good prognosis. We postulate that these groups represent alternative pathways of tumor progression, each with determinants of aggressiveness. This indicates a need for different prognostic assessments depending on which group the tumor belongs to.

Adult↗
PubMed2006

Stable expression of a heterogeneous gene introduced via gene targeting into the HPRT locus of human fibrosarcoma cells.

To obtain a cell line that maintains stability of gene expression is important for industrial production of therapeutic proteins from recombinant cells. In this study, we attempted to improve the stability of expression of an exogenous gene by using the gene-targeting method in cultured cells. In our gene-targeting system, the green fluorescent protein (GFP) gene was used as an exogenous reporter gene targeted to the locus of the endogenous hypoxanthine phosphoribosyl transferase (HPRT) gene, which is constitutively expressed. Cell lines selected using markers of the targeting DNA were cultivated for 129 days without any drug selection, and the expression levels of GFP protein and the chromosomal structure of the gfp gene in these cell lines were evaluated. Cell lines in which gfp genes were randomly integrated into the genome showed decreased GFP expression, which resulted from loss of genes or attenuation of transcription. In contrast, cell lines in which the gfp gene was targeted to the hprt locus maintained a stable chromosomal structure and stable expression of the gfp gene, even after prolonged cultivation. These results suggest that constitutively expressed endogenous gene loci may be suitable positions for stable expression of exogenous genes, and that the gene-targeting strategy presented here may be useful for generation of cell lines for industrial protein production.

Biotechnology↗
PubMed1995

Genotoxic effects of the alpha, beta-unsaturated aldehydes 2-trans-butenal, 2-trans-hexenal and 2-trans, 6-cis-nonadienal.

The genotoxic effects of the 2-alkenals crotonaldehyde, 2-trans-hexenal and 2-trans-6-cis-nonadienal were studied by cytogenetic methods, analyzing frequencies of sister-chromatid-exchanges, numerical and structural chromosome aberrations and micronucleus induction in human blood lymphocytes and cells of the permanent Namalva line. Crotonaldehyde and hexenal were tested in concentrations of 5 microM to 250 microM and nonadienal from 5 microM to 70 microM. Significant dose-related increases of sister-chromatid-exchanges and micronuclei were found for all three compounds. Structural chromosomal aberrations were significantly increased only by crotonaldehyde, but not by hexenal and nonadienal. In contrast numerical chromosome aberrations were not induced by crotonaldehyde whereas hexenal and nonadienal were potent inducers of aneuploidy. The micronuclei were classified by using a centromere-specific DNA probe in a fluorescence in situ hybridization assay. Hexenal and nonadienal increased the percentage of centromere-positive micronuclei, nonadienal being considerably more potent than hexenal. From these results it was concluded that crotonaldehyde acts more as a clastogen whereas hexenal and nonadienal preferentially show aneugenic effects.

Aldehydes↗
PubMed1987

cDNA sequence, protein structure, and chromosomal location of the human gene for poly(ADP-ribose) polymerase.

Recently we described a full-length cDNA for the human nuclear enzyme poly(ADP-ribose) polymerase. Here, we report the chromosomal localization and partial map of the human gene for this enzyme as well as the complete coding sequence for this protein. The nucleotide sequence reveals a single 3042-base open reading frame encoding a protein with a predicted Mr of 113,135. A comparison of this deduced amino acid sequence with the amino acid sequence of three peptides derived from human poly(ADP-ribose) polymerase revealed a match of 27 amino acid residues. A computer-derived structural analysis of the enzyme and a search for similarities with other proteins confirmed that the polymerase belongs to a subfamily of DNA/NAD-binding proteins and DNA-repair proteins. Possible Zn2+-binding "fingers," a nucleotide-binding fold, and a nuclear transport signal were noted. Additionally, chromosomal mapping has identified polymerase-hybridizing sequences on human chromosomes 1 (the active gene), 13, and 14 (processed pseudogenes). Using the polymerase cDNA as a probe, we also have detected several DNA restriction fragment length polymorphisms in normal humans.

Amino Acid Sequence↗
PubMed1990

Structure and chromosomal localization of the gene for the oligodendrocyte-myelin glycoprotein.

Utilizing a cDNA clone encoding the oligodendrocyte-myelin glycoprotein (OMgp) to screen a human genomic DNA library, we have obtained a clone that contains the OMgp gene. The genomic clone was restriction mapped and the OMgp gene and its 5' and 3' flanking regions were sequenced. A single intron is found in the 5' untranslated region of the gene, while the coding region is uninterrupted by an intron. This placement of a single intron in the OMgp gene is identical to that of the gene for the alpha-chain of platelet glycoprotein Ib, which, along with OMgp, belongs to a family of proteins sharing two distinct structural domains: an NH2-terminal cysteine-rich domain and an adjacent domain of tandem leucine-rich repeats. Hence, it is possible that this family of proteins is not only related in terms of primary structure, but also through similar gene structure. Sequence comparison of the 5' and 3' flanking regions did not reveal striking similarities to other DNA sequences, and no obvious promoter elements were noted. By hybridization of the genomic clone to metaphase cells, we have localized the human OMgp gene to chromosome 17 bands q11-12, a region to which the neurofibromatosis type 1 gene has been previously mapped.

Amino Acid Sequence↗
PubMed2001

Genomic structure and chromosomal mapping of the gene coding for ICBP90, a protein involved in the regulation of the topoisomerase IIalpha gene expression.

We have recently identified a novel CCAAT box binding protein (ICBP90) involved in the regulation of topoisomerase IIalpha gene expression. We have observed that it is expressed in non-tumoral proliferating human lung fibroblast cells whereas in HeLa cells, a tumoral cell line, ICBP90 was still present even when cells were at confluence. In the present study, we have determined the ICBP90 gene structure by screening of a human placenta genomic library and PCR analysis. We report that the ICBP90 gene spans about 35.8 kb and contains six coding exons named A to F. In the 5' upstream sequence of the region containing the coding exons, two additional exons (I and II) were found. Additionally, an internal splicing site was found in exon A. A promoter region, including three putative Sp1 binding sites between exons I and A, was identified by transient transfection. Northern blot analysis of several cancer cell lines revealed the existence of two ICBP90 mRNA species of 5.1 and 4.3 kb that are transcribed from the gene. The relative amounts of these mRNAs depended on the cell type. In MOLT-4 cells and Burkitt's lymphoma Raji cells, the 4.3 kb or the 5.1 kb transcripts were mainly observed, respectively. In other cell lines, such as HL-60 cells, chronic myelogenous leukaemia K-562, lung carcinoma A549, HeLa or colorectal SW480, both 4.3 and 5.1 kb forms of ICBP90 mRNA could be detected. Interestingly, western blot analysis showed several ICBP90 protein bands in HeLa but only a single band in MOLT-4 cell extracts. Taken together our results are consistent with the ICBP90 gene exhibiting alternative splicing and promoter usage in a cell-specific manner.

Alternative Splicing↗
PubMed1996

Human Cart-1: structural organization, chromosomal localization, and functional analysis of a cartilage-specific homeodomain cDNA.

Homeoproteins control cell fates during development, specifying pattern formation and the ontogeny of specific tissues and organs in embryogenesis. Cart-1 cDNA was recently cloned from a rat chondrosarcoma tumor and it encodes a protein containing a paired-like homeodomain that is selectively expressed in cartilage during early chondrocyte differentiation. Here we report the molecular cloning of the human Cart-1 cDNA from a HeLa cervical carcinoma cDNA library. The human Cart-1 cDNA sequence is 88% identical and the deduced amino acid sequence is 95% identical to the rat sequence, indicating that Cart-1 structure is highly conserved. Northern and reverse transcriptase polymerase chain reaction (RT-PCR) analysis revealed Cart-1 mRNA expression in HeLa cervical carcinoma cells and human cervical tissue, but Cart-1 mRNA was not detected in GH3 rat pituitary cells and murine 10T1/2 one-half fibroblast cells. The Cart-1 gene was localized to human chromosome 12 and regionally mapped to the 12q21.3-q22 by PCR analysis of rodent-X-human somatic cell hybrid DNA and the CEPH megabase-insert YAC DNA pools, respectively. The Holt-Oram syndrome, characterized by upper limb and atrial septal dysplasias, also maps to the 12q21.3-q22 region. Cotransfection studies show that Cart-1 inhibits the rat prolactin promoter and that this repression is mediated by footprint II, an AT-rich element that functions as an inhibitory site of prolactin gene expression in nonpituitary cells and which was used to clone Cart-1. Taken together, these data indicate that Cart-1 may also influence cervix development, identify a putative DNA binding site for Cart-1, and, begin to define its functional role as modulator of gene expression.

Amino Acid Sequence↗
PubMed1995

Structure and chromosomal localization of the human stromal cell-derived factor 1 (SDF1) gene.

Stromal cell-derived factors 1 alpha and 1 beta are small cytokines belonging to the intercrine CXC subfamily and originally isolated from a murine bone-marrow stroma cell line by the signal sequence trap method. cDNA and genomic clones of human SDF1 alpha and SDF1 beta (SDF1A and SDF1B) were isolated and characterized. cDNAs of SDF1 alpha and SDF1 beta encode proteins of 89 and 93 amino acids, respectively. SDF1 alpha and SDF1 beta sequences are more than 92% identical to those of the human counterparts. The genomic structure of the SDF1 gene revealed that human SDF1 alpha and SDF1 beta are encoded by a single gene and arise by alternative splicing. SDF1 alpha and SDF1 beta are encoded by 3 and 4 exons, respectively. Ubiquitous expression of the SDF1 gene, except in blood cells, was consistent with the presence of the GC-rich sequence in the 5'-flanking region of the SDF1 gene, as is often the case in the "housekeeping" genes. Although genes encoding other members of the intercrine family are localized on chromosome 4q or 17q, the human SDF1 gene was mapped to chromosome 10q by fluorescence in situ hybridization. Strong evolutionary conservation and unique chromosomal localization of the SDF1 gene suggest that SDF1 alpha and SDF1 beta may have important functions distinct from those of other members of the intercrine family.

Amino Acid Sequence↗
PubMed2003

Comparative analysis of the genetic structure and chromosomal mapping of the murine Gadd45g/CR6 gene.

Gadd45g/CR6, Gadd45b/MyD118, and Gadd45a/Gadd45 are members of a gene family that displays distinct patterns of gene expression in response to stimuli that induce differentiation, growth arrest, and/or apoptosis. All three of these highly conserved proteins interact with a number of critical cell cycle and cell survival regulatory proteins such as PCNA, p21(WAF1/CIP1), CDK1 (cdc2-p34), and MTK1/MEKK4, and have been reported to influence the activity of the p38 and JNK kinases. Species-blot analysis showed that Gadd45g is an evolutionarily conserved gene and sequence analysis showed that Gadd45g has a gene structure conserved with that of other members of its gene family. A comparison of the putative transcription factor binding sites found in the sequences of the gene family members suggests, that like Gadd45b, NF-kappaB and STATs may be responsible for the differences in regulation of expression observed between Gadd45g and Gadd45a. Analysis of the Gadd45b/MyD118 promoter shows that there are three different enhanceosome-like regions that may allow cell-type specific responses to TGF-beta1 by the Gadd45b/MyD118 promoter. Fluorescent in situ hybridization (FISH) confirmed the localization of the Gadd45g gene to mouse chromosome band 13A5-B, which has been reported to contain a quantitative trait locus that regulates body weight in mice. This suggests that alleles of the Gadd45g gene may function in the regulation of body weight, in addition to its currently recognized roles in differentiation and stress responses.

Animals↗
PubMed2000

Structure and chromosomal localization of the rat salivary Psp and Smgb genes.

SMGB and PSP are among the most abundant products of the immature acinar cells in developing rat parotid and submandibular glands and are also products of the sublingual gland serous demilunes. Previous analysis of Smgb and Psp cDNA clones demonstrated a high degree of sequence similarity between the signal peptide-encoding and 3' untranslated regions of these transcripts, although the secreted proteins themselves are more divergent. The current study reports the upstream sequences, genomic organization and localization of the Psp and Smgb genes. Both structural genes contain nine exons and are present at 3q41-3q42, where they are arranged in tandem and separated by 21kb. In addition to the previously observed sequence similarity, Psp and Smgb are highly homologous throughout exon 1 and at 365 of 600bp immediately upstream of the transcription start site. These findings indicate that the Psp and Smgb genes arose by tandem duplication and divergence. The similar neonatal submandibular and parotid gland expression patterns observed for these genes are likely to be due to closely conserved or shared enhancer(s).

Animals↗
PubMed1994

Cytogenetic study of two cases with lymphoma of mucosa-associated lymphoid tissue.

Cytogenetic studies have been reported in fewer than 20 patients with lymphoma of mucosa associated lymphoid tissue (MALT). Two patients with this disease at the Clinical Center, National Institutes of health had numerical and structural chromosome abnormalities, including +12 in both cases. The clonal karyotypes observed were 48-49,XX,t(2;8)(q33;p23), +3, -10,del(10)(q23), +12, +18 [cp] and 47,X,-X,i(6p), +7, +inv(12)(p13q13). Review of cytogenetic studies from published data showed that all cases of MALT lymphoma reported to date also have both numerical and structural chromosome abnormalities, the most frequent being numerical involvement of chromosomes 3, 7, and 12. Identification of a clonal abnormality can help establish the diagnosis when differential diagnosis includes atypical hyperplasia. Although trisomy 12 has been associated with a poor prognosis in B-cell chronic lymphocytic lymphoma (B-CLL), both these patients with MALT lymphoma have had long survival: 8 and 11 years, respectively.

Chromosome Aberrations↗