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Query: UNIPROT:P50583 (asymmetrical)
 12,197 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using hamster-human hybrid cells and methods for differential staining of the hamster and human chromosomes, the relative proportion of induced chromosome-type symmetrical and asymmetrical interchange aberrations was measured after a 6.5-Gy dose of gamma radiation. The ratio of these aberration types was not significantly different from 1:1, i.e., the proportion of such interchanges that are symmetrical is very near 0.5, in agreement with the conclusion of others (J.A. Heddle, Genetics 52, 1329-1334, 1965; M. Holmberg and J. Jonasson, Hereditas 74, 57-68, 1973; J.R.K. Savage and D.G. Papworth, Mutat. Res. 95, 7-18, 1983). This proportion is important because virtually all estimates of radiation-induced chromosome-type exchange aberrations are based on measurement of the easily observed but unstable and lethal asymmetrical types, while some of the biological effects of concern from the point of view of oncogenesis and mutagenesis are thought to result from production of stable and nonlethal symmetrical types.
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PMID:Measurement of the relative proportion of symmetrical and asymmetrical chromosome-type interchanges induced by gamma radiation in human-hamster hybrid cells. 237 75

Genomic instability has been proposed to be the earliest step in radiation-induced tumorigenesis. It follows from this hypothesis that individuals highly susceptible to induction of tumors by radiation should exhibit enhanced radiation-induced instability. BALB/c white mice are considerably more sensitive to radiation-induced mammary cancer than C57BL/6 black mice. In this study, primary mammary epithelial cell cultures from these two strains were examined for the "delayed" appearance of chromosomal aberrations after exposure to 137Cs gamma radiation, as a measure of radiation-induced genomic instability. As expected, actively dividing cultures from both strains showed a rapid decline of initial asymmetrical aberrations with time postirradiation. However, after 16 population doublings, cells from BALB/c mice exhibited a marked increase in the frequency of chromatid-type breaks and gaps which remained elevated throughout the time course of the experiment (28 doublings). No such effect was observed for the cells of C57BL/6 mice; after the rapid clearance of initial aberrations, the frequency of chromatid-type aberrations in the irradiated population remained at or near those of nonirradiated controls. These results demonstrate a correlation between the latent expression of chromosomal damage in vitro and susceptibility for mammary tumors, and provide further support for the central role of radiation-induced instability in the process of tumorigenesis.
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PMID:Radiation-induced chromosomal instability in BALB/c and C57BL/6 mice: the difference is as clear as black and white. 900 2

Two distinct bidirectional selective breedings for quantitative traits were initiated from identical genetically heterogeneous mouse populations. The resulting lines are characterized by maximal or minimal acute inflammatory responsiveness (AIR): AIRmax and AIRmin lines, respectively, and by resistance or susceptibility to chemical skin tumorigenesis: Car-R and Car-S lines, respectively. The AIR response to s.c. injection of polyacrylamide microbeads, measured by cell content in the local exudate, was 10 times higher in AIRmax than in AIRmin mice. The response to selection was asymmetrical: the realized heritability was 0.26 in AIRmax and 0.008 in AIRmin, and resulted from the additive effect of 7-11 quantitative trait loci (QTL). Low responsiveness was globally dominant in F1 and 48% of F2 segregant variance was found to be due to genetic factors. These findings are the first demonstration of innate regulation of AIR by germ line genes. Susceptibility to skin tumorigenesis induced by a two-stage initiation (DMBA)-promotion (TPA) protocol was lower in AIRmax mice than in AIRmin mice, a 6-fold difference in tumor induction rate. Intense AIR was found to be associated with resistance, and low AIR with susceptibility to tumorigenesis, in F2 segregants chosen for extreme AIR phenotypes. At least some of the AIR QTLs therefore contain genes controlling tumorigenesis. Tumor phenotypes differed more in Car-R and Car-S than in AIRmax and AIRmin lines, indicating that QTLs unrelated to AIR, contribute to the host response to tumorigenesis. The extreme phenotypes/genotypes of the four selected lines and the known genetic constitution of their foundation population, offer new possibilities to discriminate the genes/mechanisms controlling two important traits: AIR and response to chemical tumorigenesis. Collaborative projects will be favorably considered. The description of tumor resistance genes in AIRmax and Car-R mice may be helpful for epidemiology and therapy of human cancer.
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PMID:Effect of genetic modification of acute inflammatory responsiveness on tumorigenesis in the mouse. 949 86

Cancer is now known to be a genetic disease. In tumor development, cell nuclei undergo mutations, which can result in cytologically visible chromosome aberrations. The aneuploid errors may involve amplification or deletion of whole chromosomes or segments thereof. David Hansemann [1858-1920] and Theodor Boveri [1862-1915] were major contributors to early debates on the relationship between chromosomal defects, tumorigenesis and malignancies. In 1890, Hansemann observed asymmetrical nuclear divisions in human epithelial cancers. In these abnormal, but bipolar, divisions, a fraction of the chromosomes fails to segregate properly. Hansemann carefully documented the occurrence of asymmetric divisions in a wide variety of tumors. However, he remained a lifelong skeptic with regard to whether such events could be considered the underlying cause of tumors. Almost a quarter of a century after Hansemann's initial observations, Boveri considered the origin of tumors based on his earlier recognition of the functional specificity of each chromosome. He also explicitly drew on Hansemann's observations in proposing a model for tumorigenesis. Its central tenet was that a tumor typically originates from a single cell that has inherited a defined, but incorrectly combined, set of chromosomes. The rare occurrence of a pluripolar spindle represented Boveri's paradigm for a type of abnormal mitosis that can produce a host of random chromosomal combinations. He suggested that some of these combinations will induce tumorous transformation, and will inevitably arise occasionally. Since pluripolar and unbalanced bipolar divisions fail to distribute the hereditary chromatic material correctly, both of these mechanisms can give rise to tumor progenitors.
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PMID:Reappraisal of the Hansemann-Boveri hypothesis on the origin of tumors. 1631 17

Stem cells possess the capacity to expand and self-renew and do so by dividing in either a symmetrical or an asymmetrical manner. Under particular circumstances, some stem cell populations can undergo prolonged cell cycle arrest or quiescence, until they are triggered to divide by a given stimulus. In cancer treatment, these populations represent a significant roadblock to efficient therapies as their non-dividing state renders them refractory to most commonly used cytotoxic interventions. In certain organisms, germline stem cells undergo quiescence if animals experience inappropriate growth conditions, and recent studies have determined that the level of insulin signaling is key in the regulation of their proliferation rate, and that it functions through at least two tumor suppressor genes, PTEN and LKB1. These gene products regulate both growth and polarity in diverse cellular contexts, while it remains unclear how they can modulate cell division and prevent tumorigenesis through each of these functions, and whether indeed these functions are separable. We hope that understanding how these tumor suppressor genes impinge on quiescent stem cell populations could provide us with a means of designing more effective therapies to reduce the frequency of stem cell-derived tumor growth that occurs following treatment.
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PMID:Genes that affect both cell growth and polarity mediate stem cell quiescence. 1798 6

Centrosomes are essential protagonists during cell division through microtubule nucleation and spindle formation which are key to the harmonious distribution of sister chromatids in the two daughter cells. However, during the past decade, a wealth of new observations has extended their role beyond mitosis, particularly in the asymmetrical partition of cell fate determinants. Remarkably, asymmetric centrosome inheritance per se, through the segregation of differently aged mother -centrioles, seems to regulate the differential behaviour of daughter cells, in part through asynchronous expression of primary cilia, governing the response to environmental signals. It is thus understandable why any quantitative or qualitative dysfunction of centrioles contributes to genomic -instability and thus -tumorigenesis.
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PMID:[Centrosomes, mitotic spindle and cancer: find the odd one out!]. 2041 42

Aurora-A is involved in chromosome alignment, centrosome maturation, mitotic spindle assembly and regards to an oncogene. Aurora-A is also known to bind to several other proteins affecting its up-regulation or down-regulation and localization. However, how these different binding signals work together to regulate Aurora-A is not properly known. To explore more Aurora-A interacting proteins, the low-copy yeast two-hybrid screening using Aurora-A as bait protein was performed. One novel gene, AIBp, was demonstrated to associate with Aurora-A by the yeast two-hybrid method and in vitro GST pull-down assay. Molecular characterization showed that AIBp possessed a binding site at the C-terminal with Aurora-A (kinase domain). Interestingly, AIBp also interacts with hNinein at the N-terminal, which overlaps with a previously reported hNinein and GSK3beta binding site. Using a kinase assay, AIBp interacts with the Aurora-A kinase domain functions as a positive regulator, whereas AIBp binding to hNinein appears to block the phosphorylation of hNinein by both Aurora-A and GSK3beta. siRNA-mediated elimination of AIBp from HeLa cells, results in a doughnut-like shape, asymmetrical spindle pole and multiple spindle pole formation. We also demonstrated that both AIBp and Aurora-A are co-overexpressed in various brain tumors. These studies demonstrate that AIBp may not only be required for the dynamic movement of Aurora-A at the centrosomes and spindle apparatus during the cell cycle, but may also be important during brain tumorigenesis.
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PMID:Functional characterization of AIBp, a novel Aurora-A binding protein in centrosome structure and spindle formation. 2059 70

Chlamydia trachomatis infection has been suggested to induce host genome duplication and is linked to increased risks of cervical cancer. We describe here the mechanism by which Chlamydia causes a cleavage furrow defect that consistently results in the formation of multinucleated host cells, a phenomenon linked to tumorigenesis. Host signaling proteins essential for cleavage furrow initiation, ingression, and stabilization are displaced from one of the prospective furrowing cortices after Chlamydia infection. This protein displacement leads to the formation of a unique asymmetrical, unilateral cleavage furrow in infected human cells. The asymmetrical distribution of signaling proteins is caused by the physical presence of the Chlamydia inclusion at the cell equator. By using ingested latex beads, we demonstrate that the presence of a large vacuole at the cell equator is sufficient to cause furrow ingression failure and can lead to multinucleation. Interestingly, internalized latex beads of similar size do not localize to the cell equator as efficiently as Chlamydia inclusions; moreover, inhibition of bacterial protein synthesis with antibiotic reduces the frequency at which Chlamydia localizes to the cell equator. Together, these results suggest that Chlamydia effectors are involved in strategic positioning of the inclusion during cell division.
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PMID:Chlamydia trachomatis inclusions induce asymmetric cleavage furrow formation and ingression failure in host cells. 2196 6

Heparanase has been implicated in cancer but its contribution to the early stages of cancer development is uncertain. In this study, we utilized nontransformed human MCF10A mammary epithelial cells and two genetic mouse models [Hpa-transgenic (Hpa-Tg) and knockout mice] to explore heparanase function at early stages of tumor development. Heparanase overexpression resulted in significantly enlarged asymmetrical acinar structures, indicating increased cell proliferation and decreased organization. This phenotype was enhanced by coexpression of heparanase variants with a mutant H-Ras gene, which was sufficient to enable growth of invasive carcinoma in vivo. These observations were extended in vivo by comparing the response of Hpa-Tg mice to a classical two-stage 12-dimethylbenz(a)anthracene (DMBA)/12-o-tetradecanoylphorbol-13-acetate (TPA) protocol for skin carcinogenesis. Hpa-Tg mice overexpressing heparanase were far more sensitive than control mice to DMBA/TPA treatment, exhibiting a 10-fold increase in the number and size of tumor lesions. Conversely, DMBA/TPA-induced tumor formation was greatly attenuated in Hpa-KO mice lacking heparanase, pointing to a critical role of heparanase in skin tumorigenesis. In support of these observations, the heparanase inhibitor PG545 potently suppressed tumor progression in this model system. Taken together, our findings establish that heparanase exerts protumorigenic properties at early stages of tumor initiation, cooperating with Ras to dramatically promote malignant development.
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PMID:Heparanase cooperates with Ras to drive breast and skin tumorigenesis. 2497 Apr 82

Melanoma is the most malignant cutaneous cancer and causes over 9000 deaths annually. Because fatality rates from malignant melanoma (MM) increase dramatically upon metastasis, we investigated tumorigenesis and metastasis of MM in transcriptome analyses of three distinct cell lines that correspond with the stages of MM pathogenesis: the normal stage (HEMn-LP), the onset of MM (A375), and the metastasis stage (A2058). Using next-generation sequencing (NGS) technology, we detected asymmetrical expression of genes among the three cell lines, notably on chromosomes 9, 11, 12, and 14, suggesting their involvement in tumorigenesis and metastasis of MM. These genes were clustered into 41 categories based on their expression patterns, and their biological functions were analyzed using Ingenuity Pathway Analysis. In the top cancer-associated category, HIF1A, IL8, TERT, ONECUT1, and FOXA1 directly interacted with either transcription factors or cytokines that are known to be involved in the tumorigenesis or metastasis of other malignant tumors. The present data suggest that cytokine regulatory pathways in macrophages predominate over other pathways during the pathogenesis of MM. This study provides new targets for the downstream mechanistic studies of the tumorigenesis and metastasis of MM and demonstrates a new strategy for studies of the progression of other malignant cancers.
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PMID:Whole transcriptome RNA-seq analysis: tumorigenesis and metastasis of melanoma. 2503 61


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