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1.
Cancer Res ; 66(8): 4041-8, 2006 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-16618723

RESUMO

Hexavalent chromium [Cr(VI)] compounds are established human lung carcinogens. The carcinogenicity of Cr(VI) is related to its solubility, with the most potent carcinogens being the insoluble particulate Cr(VI) compounds. However, it remains unknown why particulate Cr(VI) is more carcinogenic than soluble Cr(VI). One possible explanation is that particulates may provide more chronic exposures to chromate over time. We found that aneuploid cells increased in a concentration- and time-dependent manner after chronic exposure to lead chromate. Specifically, a 24-hour lead chromate exposure induced no aneugenic effect, whereas a 120-hour exposure to 0.5 and 1 microg/cm2 lead chromate induced 55% and 60% aneuploid metaphases, respectively. We also found that many of these aneuploid cells were able to continue to grow and form colonies. Centrosome defects are known to induce aneuploidy; therefore, we investigated the effects of chronic lead chromate exposure on centrosomes. We found that centrosome amplification in interphase and mitotic cells increased in a concentration- and time-dependent manner with 0.5 and 1 microg/cm2 lead chromate for 120 hours, inducing aberrant centrosomes in 18% and 21% of interphase cells and 32% and 69% of mitotic cells, respectively; however, lead oxide did not induce centrosome amplification in interphase or mitotic cells. There was also an increase in aberrant mitosis after chronic exposure to lead chromate with the emergence of disorganized anaphase and mitotic catastrophe. These data suggest that one possible mechanism for lead chromate-induced carcinogenesis is through centrosome dysfunction, leading to the induction of aneuploidy.


Assuntos
Aneuploidia , Centrossomo/efeitos dos fármacos , Cromatos/toxicidade , Chumbo/toxicidade , Pulmão/efeitos dos fármacos , Linhagem Celular , Centrossomo/fisiologia , Humanos , Pulmão/fisiologia , Pulmão/ultraestrutura , Mitose/efeitos dos fármacos
2.
PLoS One ; 6(6): e21291, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21731694

RESUMO

Aurora A is an oncogenic serine/threonine kinase which can cause cell transformation and centrosome amplification when over-expressed. Human breast tumors show excess Aurora A and phospho-centrin in amplified centrosomes. Here, we show that Aurora A mediates the phosphorylation of and localizes with centrin at the centrosome, with both proteins reaching maximum abundance from prophase through metaphase, followed by their precipitous loss in late stages of mitosis. Over-expression of Aurora A results in excess phospho-centrin and centrosome amplification. In contrast, centrosome amplification is not seen in cells over-expressing Aurora A in the presence of a recombinant centrin mutant lacking the serine phosphorylation site at residue 170. Expression of a kinase dead Aurora A results in a decrease in mitotic index and abrogation of centrin phosphorylation. Finally, a recombinant centrin mutation that mimics centrin phosphorylation increases centrin's stability against APC/C-mediated proteasomal degradation. Taken together, these results suggest that the stability of centrin is regulated in part by Aurora A, and that excess phosphorylated centrin may promote centrosome amplification in cancer.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Ciclossomo-Complexo Promotor de Anáfase , Aurora Quinases , Proliferação de Células , Centrossomo/metabolismo , Células HeLa , Humanos , Mitose , Mutação/genética , Fosforilação , Ligação Proteica , Estabilidade Proteica , Transporte Proteico , Serina/metabolismo , Complexos Ubiquitina-Proteína Ligase/metabolismo
3.
J Biol Chem ; 280(1): 768-76, 2005 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-15509582

RESUMO

In normal cells, cyclin D1 is induced by growth factors and promotes progression through the G(1) phase of the cell cycle. Cyclin D1 is also an oncogene that is thought to act primarily by bypassing the requirement for mitogens during the G(1) phase. Studies of clinical tumors have found that cyclin D1 overexpression is associated with chromosome abnormalities, although a causal effect has not been established in experimental systems. In this study, we found that transient expression of cyclin D1 in normal hepatocytes in vivo triggered dysplastic mitoses, accumulation of supernumerary centrosomes, abnormalities of the mitotic spindle, and marked chromosome changes within several days. This was associated with up-regulation of checkpoint genes p53 and p21 as well as hepatocyte apoptosis in the liver. Transient transfection of cyclin D1 also induced centrosome and mitotic spindle abnormalities in breast epithelial cells, suggesting that this may be a generalized effect. These results indicate that cyclin D1 can induce deregulation of the mitotic apparatus and aneuploidy, effects that could contribute to the role of this oncogene in malignancy.


Assuntos
Aneuploidia , Centrossomo/metabolismo , Ciclina D1/genética , Fuso Acromático/metabolismo , Animais , Transformação Celular Neoplásica , Células Cultivadas , Ciclina D1/biossíntese , Regulação da Expressão Gênica , Hepatócitos/metabolismo , Hepatócitos/ultraestrutura , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fuso Acromático/ultraestrutura
4.
Proc Natl Acad Sci U S A ; 99(4): 1978-83, 2002 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-11830638

RESUMO

Earlier studies of invasive breast tumors have shown that 60-80% are aneuploid and approximately 80% exhibit amplified centrosomes. In this study, we investigated the relationship of centrosome amplification with aneuploidy, chromosomal instability, p53 mutation, and loss of differentiation in human breast tumors. Twenty invasive breast tumors and seven normal breast tissues were analyzed by fluorescence in situ hybridization with centromeric probes to chromosomes 3, 7, and 17. We analyzed these tumors for both aneuploidy and unstable karyotypes as determined by chromosomal instability. The results were then tested for correlation with three measures of centrosome amplification: centrosome size, centrosome number, and centrosome microtubule nucleation capacity. Centrosome size and centrosome number both showed a positive, significant, linear correlation with aneuploidy and chromosomal instability. Microtubule nucleation capacity showed no such correlation, but did correlate significantly with loss of tissue differentiation. Centrosome amplification was detected in in situ ductal carcinomas, suggesting that centrosome amplification is an early event in these lesions. Centrosome amplification and chromosomal instability occurred independently of p53 mutation, whereas p53 mutation was associated with a significant increase in centrosome microtubule nucleation capacity. Together, these results demonstrate that independent aspects of centrosome amplification correlate with chromosomal instability and loss of tissue differentiation and may be involved in tumor development and progression. These results further suggest that aspects of centrosome amplification may have clinical diagnostic and/or prognostic value and that the centrosome may be a potential target for cancer therapy.


Assuntos
Neoplasias da Mama/genética , Centrossomo/química , Cromossomos/fisiologia , Aneuploidia , Neoplasias da Mama/ultraestrutura , Núcleo Celular/metabolismo , Aberrações Cromossômicas , Análise Mutacional de DNA , Genes p53/genética , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Microscopia de Fluorescência , Microtúbulos/metabolismo , Microtúbulos/ultraestrutura , Mutação , Ploidias , Células Tumorais Cultivadas
5.
Breast Cancer Res Treat ; 75(1): 25-34, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12500932

RESUMO

Molecular mechanisms leading to genomic instability and phenotypic variation during tumor development and progression are poorly understood. Such instability represents a major problem in the management of breast cancer because of its contribution to more aggressive phenotypes as well as chemoresistance. In this study we analyzed breast carcinomas and tumor-derived cell lines to determine the relationship between centrosome amplification and established prognostic factors. Our results show that centrosome amplification can arise independent of ER or p53 status and is a common feature of aneuploid breast tumors. Centrosome amplification is associated with mitotic spindle abnormalities in breast carcinomas and thus may contribute to genomic instability and the development of more aggressive phenotypes during tumor progression.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinoma/genética , Carcinoma/patologia , Centrossomo , Invasividade Neoplásica , Progressão da Doença , Humanos , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Fuso Acromático , Células Tumorais Cultivadas
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