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PubMed1987

Cytogenetic alterations associated with the acquisition of doxorubicin resistance: possible significance of chromosome 7 alterations.

Cytogenetic abnormalities associated with the acquisition of doxorubicin (DOX) resistance (DOXR) were examined in two cell lines (HT1080 fibrosarcoma and LoVo colon adenocarcinoma) which were selected in the presence of increasing concentrations of DOX over a 2-year period. Karyotypes of both tumor lines were initially near-diploid although they differed significantly in their intrinsic sensitivities to DOX (DOX 50% inhibiting concentrations: LoVo, 0.10 micrograms/ml; HT1080, 0.006 microgram/ml). Chromosome banding analysis of DOXR sublines of the LoVo and HT1080 cell lines demonstrated a strikingly different response to DOX selection with regard to both numeric and structural chromosome alterations. DOXR LoVo cells maintained the parental modal chromosomal number of 49 despite a 285-fold increase in the level of resistance, with minimal structural chromosome changes observed. In contrast, the development of DOXR in HT1080 cells was accompanied by marked aneuploidy, including a significant increase in the complexity of the tumor karyotype with increasing levels of DOXR. Cytogenetic evidence suggestive of gene amplification (double minutes and homogeneously staining regions) was also observed in the DOXR HT1080 cell line. Examination of chromosome alterations common to both resistant lines revealed alterations of chromosomes 1, 5, 7, and 11, with chromosome 7q the most frequent site of chromosome change. Reversion of DOXR in both the HT1080 and LoVo cell lines (by continuous in vitro passage once off drug) resulted in an accompanying loss in structurally altered No. 7 chromosomes. Our data suggest that alterations of chromosome 7 are a common and perhaps significant feature of DOXR tumor cells.

Adenocarcinoma↗
PubMed1987

Chromosome damage induced in human lymphocytes by 5-methoxypsoralen and 8-methoxypsoralen plus UV-A.

The induction of structural chromosome aberrations and sister chromatid exchanges (SCE) was studied in human lymphocytes in vitro after treatment with the two bifunctional furocoumarins 5-methoxypsoralen (5-MOP) and 8-methoxypsoralen (8-MOP) in the presence of UV-A. The results show that both psoralens induce a dose-dependent increase in the SCE rate as well as in structural chromosome aberrations. 5-MOP was 2.0-2.5 times more effective for the induction of chromosome breaks and had a slightly stronger effect with respect to SCE induction. A significant influence on proliferation kinetics could be observed only with 5-MOP plus UV-A.

5-Methoxypsoralen↗
PubMed1996

Structure and chromosomal location of the mouse interleukin-12 p35 and p40 subunit genes.

Interleukin-12 (IL-12) is a heterodimeric cytokine composed of p35 and p40 subunits and is required for induction of T helper 1 (Th1) responses. Knowledge of how the IL-12 gene is regulated will permit an understanding of susceptibility and resistance to pathogenic microbes and to autoiummune diseases. In this report, we provide the gene structures, nucleotide sequences and chromosomal assignment for the p35 and p40 subunits of mouse IL-12. The p35 and p40 subunit genes are distributed over 8 kb and 14 kb, and map to chromosomes 3 and 11, respectively. The p35 subunit gene consists of eight exons, including a 5'-noncoding exon that was defined by sequence comparison of genomic DNA with the 5'ends of novel cDNA molecules. Transcription of p35 mRNA can start from the first exon but can also initiate further downstream. Potential transcription regulatory elements, AP1, AP2, AP3, NF-kB and GATA recognition sequences, are located within 523 bp upstream of the p35 gene; however, no TATA box was identified. The p40 subunit gene consists of eight exons. A TATA box is located 30 bp upstream from the transcription start site, and AP1, AP3, GATA, and Pu.1 recognition sequences are located within 690 bp upstream of the p40 gene. An AGTTTCTACTTT sequence, which acts as an interferon-gamma response element in the promoter of the major histocompatibility complex class I gene, was also found upstream of the p40 gene.

Animals↗
PubMed1999

De novo complete trisomy 5p: clinical report and FISH studies.

We describe a de novo trisomy 5p in a 1-year-old severely retarded boy. The complete short arm of chromosome 5 segregated as an additional marker chromosome in all metaphases. The marker was identified as 5p by conventional cytogenetic techniques (GTG, GBG, CBG) and molecular cytogenetic techniques (whole chromosome-painting probe, probes for the cri-du-chat region and the centromere, and additionally high-resolution multicolor banding using a chromosome 5-specific DNA probe cocktail). The clinical findings were similar to the established trisomy 5p phenotype including macrocephaly, facial abnormalities, tracheobronchial defects with subsequent respiratory infections, hypotonia, and psychomotor retardation. To the best of our knowledge this is the first description of an isolated complete 5p trisomy without involvement of the aberrant chromosome in any structural chromosomal rearrangements.

Centromere↗
PubMed1994

Isolation and characterization of conditionally immortalized astrocyte cell lines derived from adult human spinal cord.

As an approach to develop both oligodendrocytic and astrocytic cell lines from adult human spinal cord, a cellular preparation of highly enriched oligodendrocytes and their precursors was infected with a replication-deficient retrovirus containing DNA sequences encoding the temperature-sensitive mutant of SV40 large T antigen. Six immortal cell lines were obtained. At both permissive (33 degrees C) and non-permissive (38.5 degrees C) temperatures, all cell lines were positive for vimentin, two demonstrated glial fibrillary acidic protein (GFAP) immunoreactivity, and none expressed oligodendrocyte or microglial markers. The 2 GFAP-positive cell lines [human spinal cord (HSC)2 and HSC6] were further characterized. Karyotype analysis revealed that both HSC2 and HSC6 cells showed gain of chromosomal material and structural chromosomal abnormalities. However, at non-permissive temperature both cell lines were indistinguishable from primary human astrocytes by a number of criteria. These properties included glutamine synthetase activity, Na(+)-dependent glutamate uptake, K+ flux, purine-evoked Ca2+ mobilization and entry, and the ability to support neurite outgrowth from embryonic rat retinal explants. The HSC2 and HSC6 cell lines may prove to be valuable models for studying the physiological properties of adult human astrocytes.

Adult↗
PubMed1997

Chromosome localization and structure of the murine cyclin G1 gene promoter sequence.

Cyclins play an essential role in the control of the cell cycle. In this study the murine cyclin G1 gene expression, structure, and chromosomal localization were examined. Genes with high homology to murine cyclin G1 were detected in various mammals, including human, monkey, rat, dog, cow, and rabbit, but not in yeast or chicken. Cyclin G1 gene was expressed in all murine tissues examined, with the highest levels in cardiac and skeletal muscle. A 10,366-bp genomic DNA fragment encompassing the promoter region and the 5'-flanking region of the gene was cloned and sequenced. Three putative binding sites for the myocyte enhancer factor-2 family of transcription factors were revealed. Furthermore, an upstream p53-binding site was localized to nucleotides -252 to -233 and a new putative p53-binding site was identified in the first intronic region at nucleotides 275 to 294. By fluorescence in situ hybridization, the cyclin G1 gene was mapped to mouse chromosome 11B1.1. This region is homologous with human chromosome 5q31-q32, consistent with the recent mapping of the human cyclin G1 gene to chromosome 5q32-q34. Localization of murine cyclin G1 will facilitate determination of gene linkage and the identification of synteny groups in mammals and of DNA elements in or near this gene that mediate its tissue expression or development-specific pattern of expression.

Amino Acid Sequence↗
PubMed1985

The involvement of nucleosomes in Giemsa staining of chromosomes. A new hypothesis on the banding mechanism.

A new hypothesis is proposed on the involvement of nucleosomes in Giemsa banding of chromosomes. Giemsa staining as well as the concomitant swelling can be explained as an insertion of the triple charged hydrophobic dye complex between the negatively-charged super-coiled helical DNA and the denatured histone cores of the nucleosomes still present in the fixed chromosomes. New cytochemical data and recent results from biochemical literature on nucleosomes are presented in support of this hypothesis. Chromosomes are stained by the Giemsa procedure in a purple (magenta) colour. Giemsa staining of DNA and histone (isolated or in a simple mixture) in model experiments results in different colours, indicating that a higher order configuration of these chromosomal components lies at the basis of the Giemsa method. Cytophotometry of Giemsa dye absorbance of chromosomes shows that the banding in the case of saline pretreatment is due to a relative absence of the complex in the faintly coloured bands (interbands). Pretreatment with trypsin results in an increase in Giemsa dye uptake in the stained bands. Cytophotometric measurements of free phosphate groups before and after pretreatment with saline, reveal a blocking of about half of the free phosphate groups indicating that a substantial number of free amino groups is still present in the fixed chromosomes. Glutaraldehyde treatment inhibited Giemsa-banding irreversibly while the formaldehyde-induced disappearance of the bands could be restored by a washing procedure. These results correlate with those of biochemical nucleosome studies using the same aldehydes. Based on these findings and on the known properties of nucleosomes, a mechanism is proposed that explains the collapse of the chromosome structure when fixed chromosomes are transferred to aqueous buffer solutions. During homogeneous Giemsa staining reswelling of the unpretreated chromosome is explained by insertion of the hydrophobic Giemsa complex between the hydrophobic nucleosome cores and the superhelix DNA. Selective Giemsa staining of the AT-enriched bands after saline pretreatment is thought to be due to the, biochemically well-documented, higher affinity of arginine-rich proteins present in the core histones for GC-enriched DNA, which prevents the insertion of the Giemsa complex in the interbands. Production of Giemsa bands by trypsin pretreatment can be related to the action of this enzyme on the H1 histones and subsequent charge rearrangements.(ABSTRACT TRUNCATED AT 400 WORDS)

Azure Stains↗
PubMed2005

The neurobeachin gene spans the common fragile site FRA13A.

Common fragile sites are normal constituents of chromosomal structure prone to chromosomal breakage. In humans, the cytogenetic locations of more than 80 common fragile sites are known. The DNA at 11 of them has been defined and characterized at the molecular level. According to the Genome Database, the common fragile site FRA13A maps to chromosome band 13q13.2. Here, we identify the precise genomic position of FRA13A, and characterize the genetic complexity of the fragile DNA sequence. We show that FRA13A breaks are limited to a 650 kb region within the neurobeachin (NBEA) gene, which genomically spans approximately 730 kb. NBEA encodes a neuron-specific multidomain protein implicated in membrane trafficking that is predominantly expressed in the brain and during development.

Autistic Disorder↗
PubMed1990

Cytogenetic studies of endometrial malignancies.

Thirty cases of endometrial malignancy were successfully studied cytogenetically. Twenty-four of the cases were endometrial adenocarcinomas. Twenty-three of these were stage I tumors, and the twenty-fourth was a stage IV tumor. Fourteen of the stage I adenocarcinomas had abnormal chromosomes, and nine had apparently normal chromosomes. No two tumors had an identical chromosomal rearrangement. Trisomy 1q was common however; 10 of the 14 tumors with abnormal chromosomes had a chromosome 1 abnormality. Clinical and pathologic data were available for 17 of these patients. There appeared to be no relationship between prognostic indicators and the tumor karyotype except for uterine size. Six cases of endometrial malignant mixed müllerian tumor (MMMT) of the homologous type were also analyzed cytogenetically. Three of these tumors had very abnormal karyotypes, and the remaining three had apparently normal chromosomes. Structural abnormalities of chromosome 1, 3, and 5 were present in all three tumors with abnormal karyotypes, but identical breakpoints or rearrangements were not observed.

Adenocarcinoma↗
PubMed2004

Comprehensive conventional and molecular cytogenetic characterization of B-CPAP, a human papillary thyroid carcinoma-derived cell line.

Cell lines derived from different thyroid tumor histotypes are useful for the in vitro study of both the phenotypic and genetic features of these cancers. Although karyotypic changes are known to be associated with thyroid lesions, the chromosome patterns of only a few cell lines have been published. Herein, we report an extensive conventional and molecular cytogenetic investigation of the human papillary thyroid carcinoma derived cell line B-CPAP. Morphological studies and expression of tumor markers in this cell line have been reported previously, but no detailed characterization on the origin of the chromosome markers is available. B-CPAP cells have a rather stable hypertriploid karyotype, with chromosome polysomies and structural chromosome abnormalities featuring whole chromosome arm imbalances. Chromosome banding revealed a main clone with nine chromosome markers, and fluorescence in situ hybridization (FISH) with whole chromosome paint (wcp), partial chromosome paint (pcp), and centromeric probes clarified their origin. The use of centromeric probes provided accurate refinement of the rearrangements classified as whole-arm translocations by banding and FISH with wcp probes. Both chromosomal and array-based comparative genomic hybridization experiments confirmed the cytogenetic characterization of this cell line. Moreover, the use of fluorescence immunophenotyping and interphase cytogenetics as a tool for the investigation of neoplasms (FICTION) technique, which simultaneously shows nuclear ploidy and cytoplasmic immunofluorescence, detailed the oncocytic feature of the cells. Intriguingly, despite their origin, they lack most of the features expressed in papillary thyroid tumor cells and have a chromosomal pattern reminiscent of that of a subgroup of oncocytic malignant thyroid tumors.

Carcinoma, Papillary↗
PubMed2005

Chromosome morphogenesis: condensin-dependent cohesin removal during meiosis.

During meiosis, segregation of homologous chromosomes necessitates the coordination of sister chromatid cohesion, chromosome condensation, and recombination. Cohesion and condensation require the SMC complexes, cohesin and condensin, respectively. Here we use budding yeast Saccharomyces cerevisiae to show that condensin and Cdc5, a Polo-like kinase, facilitate the removal of cohesin from chromosomes prior to the onset of anaphase I when homologs segregate. This cohesin removal is critical for homolog segregation because it helps dissolve the recombination-dependent links between homologs that form during prophase I. Condensin enhances the association of Cdc5 with chromosomes and its phosphorylation of cohesin, which in turn likely stimulates cohesin removal. Condensin/Cdc5-dependent removal of cohesin underscores the potential importance of crosstalk between chromosome structural components in chromosome morphogenesis and provides a mechanism to couple chromosome morphogenesis with other meiotic events.

Adenosine Triphosphatases↗
PubMed2004

Structural biochemistry of ATP-driven dimerization and DNA-stimulated activation of SMC ATPases.

Structural maintenance of chromosome (SMC) proteins play a central role in higher-order chromosome structure in all kingdoms of life. SMC proteins consist of a long coiled-coil domain that joins an ATP binding cassette (ABC) ATPase domain on one side and a dimerization domain on the other side. SMC proteins require ATP binding or hydrolysis to promote cohesion and condensation, which is suggested to proceed via formation of SMC rings or assemblies. To learn more about the role of ATP in the architecture of SMC proteins, we report crystal structures of nucleotide-free and ATP bound P. furiosus SMC ATPase domains. ATP dimerizes two SMC ATPase domains by binding to opposing Walker A and signature motifs, indicating that ATP binding can directly assemble SMC proteins. DNA stimulates ATP hydrolysis in the engaged SMC ABC domains, suggesting that ATP hydrolysis can be allosterically regulated. Structural and mutagenesis data identify an SMC protein conserved-arginine finger that is required for DNA stimulation of the ATPase activity and directly connects a putative DNA interaction site to ATP. Our results suggest that stimulation of the SMC ATPase activity may be a specific feature to regulate the ATP-driven assembly and disassembly of SMC proteins.

Adenosine Triphosphatases↗
PubMed2004

Genetic aspects of human male infertility: the frequency of chromosomal abnormalities and Y chromosome microdeletions in severe male factor infertility.

OBJECTIVE: The main purpose of this study is to detect the frequency and type of both chromosomal abnormalities and Y chromosome microdeletions in patients with severe male factor infertility and fertile control subjects. The association between the genetic abnormality and clinical parameters was also evaluated. METHODS: This study was carried out in 208 infertile and 20 fertile men. Results of 208 patients, 119 had non-obstructive azoospermia and 89 had severe oligoasthenoteratozoospermia (OAT). Seventeen out of 119 (14.3%) azoospermic patients and two out of 89 (2.2%) patients with OAT had Y chromosome microdeletions. In total, 19 cases with deletions were detected in 208 infertile men, with a frequency of 9.1%. The AZFc locus, mainly DAZ gene cluster was the most frequently deleted region. Five other cases with azoospermia (4.2%) and two cases with OAT (2.2%) had a chromosomal abnormality, with a total number of seven (3.4%). Including Y chromosome deletions and structural chromosome abnormalities, the rate of genetic abnormalities was 12.5% (26/208) in our patients. On the other hand, 20 men with proven fertility and fathers of five cases with microdeletions were genetically normal. Y chromosome deletions and chromosomal abnormalities were associated with various histological alterations in testis. Sertoli cell-only (SCO) syndrome and maturation arrest predominated in these cases, whereas hypospermatogenesis occurred more frequently in genetically normal patients. CONCLUSION: Various chromosomal abnormalities and deletions of Y chromosome can cause spermatogenic breakdown resulting in chromosomally derived infertility. All these findings strongly support the recommendation of genetic screening of infertile patients.

Chromosome Deletion↗
PubMed2004

Prenatal karyotypes of fetuses conceived by intracytoplasmic sperm injection.

OBJECTIVE: To evaluate the rate of chromosomal abnormalities in babies conceived by intracytoplasmic sperm injection (ICSI). DESIGN: Retrospective case-control analysis. SETTING: Private IVF center. PATIENT(S): One thousand one hundred thirty-six karyotype results obtained from fetuses conceived by ICSI. INTERVENTION(S): Amniocentesis and prenatal karyotyping. MAIN OUTCOME MEASURE(S): Presence of normal and abnormal chromosomal configurations. RESULT(S): Abnormal karyotypes were detected in 17 (1.5%) of 1,136 fetuses. Eight (0.7%) of these were from singleton and nine (0.8%) from twin pregnancies. There was no difference in the autosomal chromosome structure or the number or structure of sex chromosomes in karyotyped fetuses of singleton and twin pregnancies. However, abnormal numbers of autosomal chromosomes were more frequent in singletons (2.3%) than in twins (1.1%). There was also no difference in the frequency of chromosomal aberrations between ICSI groups in which ejaculated spermatozoa (1.9%) and testicular spermatozoa (1.5%) were used. There was no difference in the frequency of chromosomal aberrations between fetuses for whom ICSI was used because of male factors (1.8%) compared with babies for whom ICSI was also the choice of assisted fertilization method for other types of infertility factors (0.9%). CONCLUSION(S): Sperm source does not influence the karyotype of babies conceived by ICSI. By comparing our results with previously reported data from natural pregnancies, we show that ICSI babies carry a significantly increased risk of an abnormal karyotype. However, the increased risk is similar among the different infertility groups.

Amniocentesis↗
PubMed1992

Telomere-proximal DNA in Saccharomyces cerevisiae is refractory to methyltransferase activity in vivo.

Genes located near telomeres in Saccharomyces cerevisiae undergo position-effect variegation; their transcription is subject to reversible but mitotically heritable repression. This position effect and the finding that telomeric DNA is late replicating suggest that yeast telomeres exist in a heterochromatin-like state. Mutations in genes that suppress the telomeric position effect suggest that a special chromatin structure exists near chromosomal termini. Thus transcriptional repression may be explained by the inability of DNA binding proteins to access the DNA near telomeres. To test this hypothesis, the Escherichia coli Dam DNA methyltransferase, which modifies the sequence GATC, was introduced into S. cerevisiae cells. DNA sequences near the telomere were highly refractive to Dam methylation but were modified when located at positions more internal on the chromosome. Telomeric sequences were accessible to methyltransferase activity in strains that contained a mutation that suppressed the telomeric position effect. These data support the model that sequence-specific DNA binding proteins are excluded from telomere-proximal sequences in vivo and show that expression of DNA methyltransferase activity may serve as a useful tool for mapping chromosomal structural domains in vivo.

Chromatin↗
PubMed2002

In vivo dissection of the chromosome condensation machinery: reversibility of condensation distinguishes contributions of condensin and cohesin.

The machinery mediating chromosome condensation is poorly understood. To begin to dissect the in vivo function(s) of individual components, we monitored mitotic chromosome structure in mutants of condensin, cohesin, histone H3, and topoisomerase II (topo II). In budding yeast, both condensation establishment and maintenance require all of the condensin subunits, but not topo II activity or phospho-histone H3. Structural maintenance of chromosome (SMC) protein 2, as well as each of the three non-SMC proteins (Ycg1p, Ycs4p, and Brn1p), was required for chromatin binding of the condensin complex in vivo. Using reversible condensin alleles, we show that chromosome condensation does not involve an irreversible modification of condensin or chromosomes. Finally, we provide the first evidence of a mechanistic link between condensin and cohesin function. A model discussing the functional interplay between cohesin and condensin is presented.

Adenosine Triphosphatases↗
PubMed1988

Cytogenetic study of 105 children with acute lymphoblastic leukemia.

Cytogenetic analysis was performed on 105 children with acute lymphoblastic leukemia (ALL). Adequate mitoses for study were obtained in 79 of the cases (71%). A normal karyotype was found in 18 patients (23%), while clonal chromosomal abnormalities were detected in 61 patients (77%). The karyotypes fell into five categories according to modal number: normal (18 patients), pseudodiploid (27 patients), hypodiploid (3 patients), hyperdiploid with 47-50 chromosomes (11 patients), and hyperdiploid with greater than or equal to 51 chromosomes (20 patients). Structural chromosome changes were found in 50 patients (63%); translocations were encountered in 15 of these patients (19%). The chromosome most often participating in translocations was number 19. Modal number was found to be an independent prognostic factor. Modal numbers 47-50 were associated with the poorest prognosis. The hyperdiploid clone with more than 50 chromosomes and the normal karyotype had the best prognosis.

Adolescent↗
PubMed2000

Discrepancies in cytogenetic results between different tissues in two fetuses with Wolf- Hirschhorn syndrome.

Discrepant unbalanced structural chromosome aberrations between placental and fetal tissue, both involving the short arm of chromosome 4, were found in two human fetuses affected with Wolf-Hirschhorn syndrome. In the first instance, placental chromosome examination revealed a del(4) (p14), whereas fetal fibroblast chromosomes showed an unbalanced der(4)t(4;13)(p14;q11) translocation. In the second instance, placental karyotyping revealed a 4p+ chromosome, while amniocytes showed a submicroscopic deletion at 4p16.3. Since confirmation of structural aberrations from placental tissue is mostly not sought if the phenotype of the fetus is abnor- mal, discrepancies between karyotypes obtained from placental tissue and amniocytes or fetal tissues might be more frequent than the rare reports published so far would suggest. It is unclear whether the simple deletion or the more complex rearrangement is the primary aberration from which the other derived. Structural chromosome aberrations often have a much more complex mechanism of formation than the end product would suggest, and secondary rearrangements of a given aberration in the zygote are more frequent than expected.

Abnormalities, Multiple↗