RESUMO
We demonstrated here the growth-suppressing effects of sodium butyrate (NaB) on human endometrial and ovarian cancer cells. The arrest of cells at the G1 checkpoint accounted for this effect. NaB-mediated p21 might arrest endometrial and ovarian cancer cells at the G0/G1 phase by eliciting pRb unphosphorylation. To demonstrate the role of pRb regulation by p21, we measured the sensitivity to NaB of cervical cancer cells in which pRb had been inactivated by HPV E7. The cervical cancer cells displayed a sensitivity in NaB-mediated G2/M arrest in addition to their sensitivity in G0/G1 arrest. Arrest at G0/G1 and G2/M accompanied induction of senescence-like phenotypes (SLPs). Most importantly, the effect of NaB on senescence induction was not coupled with the predominance of hypophosphorylated pRb forms in the cervical cancer cells. This suggested that NaB had the potential to elicit SLPs through p21-mediated withdrawal from cell cycle progression. The consequences of p21 induction were manifold. The effects of NaB on gynecologic cancer cell growth indicated its potential use in cancer treatment. NaB was effective even in the cancer cells with mutant p53 and/or Rb genes by eliciting cell senescence.
Assuntos
Butiratos/farmacologia , Neoplasias dos Genitais Femininos/tratamento farmacológico , Animais , Ciclo Celular/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21 , Ciclinas/biossíntese , Feminino , Neoplasias dos Genitais Femininos/patologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Fenótipo , Células Tumorais CultivadasRESUMO
Quartz crystal resonators, including electric twins, are investigated. Electric twins are artificially formed in the usual AT-cut quartz crystal resonantor before the deposition of electrodes. We have directly observed that vibrations generated at electrodes propagate into the outside region isotropically, but cannot propagate into the region of electric twin.
RESUMO
Hepatocyte growth factor (HGF) is a multifunctional growth factor which has pleiotrophic biological effects on epithelial cells such as proliferation, motogenesis, invasiveness and morphogenesis. Peritoneal dissemination is critical for the progression of ovarian cancer, and our study revealed that HGF induces migration and invasion of ovarian cancer cells. We also demonstrated that HGF stimulates autophosphorylation of its receptor, followed by activation of the Ras-MAP (mitogen-activated peptide) kinase cascade. Moreover, infection of ovarian cancer cells with Ras dominant-negative adenovirus reduced the HGF-induced motogenic and invasive activities. Additionally, both MEK and P13-kinase pathways downstream of Ras were involved in HGF-stimulated ovarian cancer cell invasiveness.
Assuntos
Fator de Crescimento de Hepatócito/fisiologia , Neoplasias Ovarianas/patologia , Proteínas ras/fisiologia , Feminino , Humanos , Sistema de Sinalização das MAP Quinases , Invasividade Neoplásica , Metástase Neoplásica , Transdução de Sinais/fisiologia , Células Tumorais CultivadasRESUMO
The WAF1 protein, which is a downstream mediator of p53, functions as a universal inhibitor of cyclin-dependent kinases. The functional link between p53 and WAF1 suggests the possibility that alteration in WAF1 function constitutes an alternative mechanism to p53 inactivation. However, there are few reports describing somatic mutations of the WAF1 gene in various human malignancies. A polymorphism in the WAF1 gene, a C-to-A transversion at codon 31 resulting in the change of a serine (Ser) to an arginine (Arg), is well known. We found this substitution in 42 of 54 endometrial carcinoma patients. Allele frequency was 0.44/0.56 for the codon 31 polymorphism (Ser/Arg), the difference of allele frequency between patients and normal controls being significant (0.59/0.41 in normal controls). In addition, individuals carrying the codon 31 Arg allele had a tendency to develop histologically high-grade (odds ratio, 6. 11) and clinically advanced tumors. We investigated the association of the Arg allele with the known risk factors of endometrial carcinomas. Statistical analyses of 42 cases and 32 controls carrying the codon 31 Arg allele identified hypertension (odds ratio, 4.33) and family history of cancer (odds ratio, 2.81) as positive risk factors. This implies that these two parameters may be associated with a tendency to develop endometrial carcinomas in individuals carrying the codon 31 Arg allele of the WAF1 gene.
Assuntos
Carcinoma Endometrioide/genética , Ciclinas/genética , Ciclinas/isolamento & purificação , Neoplasias do Endométrio/genética , Alelos , Sequência de Aminoácidos , Carcinoma Endometrioide/imunologia , Estudos de Casos e Controles , Códon/genética , Inibidor de Quinase Dependente de Ciclina p21 , Primers do DNA , Suscetibilidade a Doenças , Neoplasias do Endométrio/imunologia , Feminino , Frequência do Gene , Genótipo , Humanos , Immunoblotting , Dados de Sequência Molecular , Razão de Chances , Polimorfismo Genético , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de RiscoRESUMO
Estrogen has an important role in both the etiology and treatment of hormone-dependent endometrial cancers, although the mechanism remains elusive. To definethe role of estrogen-mediated signaling we investigated the biological significance of estrogen receptors (ER) in NIH3T3 cell transformation via the [ ¹2; Val ] K-Ras mutant. This mutant enhanced the steady state level and transcriptional activity of ER. In addition, overexpression of both wild type K-Ras and ER transformed NIH3T3 cells. Co-expression of the progesterone receptor (PR) with mutant K-Ras led to suppression of tumorigenicity and inhibition of ER activation. The antisense oligomers complementary to ER suppressed proliferation and transformed phenotypes of K12V cells. These observations support the importance of ER in Ras-mediated cell transformation. To address whether ER activation is also important in the development of human endometrial cancers, we investigated ER and PR expression levels in premalignant and malignant endometrial lesions. The results suggested the implication of ER abundance in endometrial hyperplasias, though modulation of PR expression by ER was retained. G1 adenocarcinoma also expressed higher levels of ER while PR modulation by ER was abrogated. These data implied the importance of ER activitiesin endometrial hyperplasia and G1 adenocarcinoma development.
RESUMO
Since the majority of endometrial carcinomas do not contain any detectable ras mutations, the precise contribution of aberrant Ras function, if any, to endometrial carcinoma development remains to be determined. Since there is considerable evidence that Ras transformation is associated with a decreased requirement for growth factors, we compared the growth response of endometrial carcinoma cells harbouring wild-type (Ishikawa cells) or mutated (HHUA cells) K-ras to epidermal growth factor (EGF). K-ras mutation did not significantly affect the level of the EGF receptor (EGFR) expressed in these carcinoma cells. EGF could stimulate the growth of Ishikawa, but not HHUA cells. Furthermore, EGF caused elevation of Ras-GTP levels in Ishikawa, but not HHUA cells. However, the introduction of mutated, but not normal, K-ras into Ishikawa cells rendered them non-responsive to EGF growth stimulation. Thus, the presence of mutated K-ras alone modulated the growth response of endometrial carcinoma cells to EGF. An inhibitor of the EGFR tyrosine kinase activity could prevent soft agar colony formation of Ishikawa cells, but not HHUA or mutant K-ras(12V)-transfected Ishikawa cells. Taken together, these results suggest that mutated K-ras causes a loss of responsiveness to EGF stimulation and that EGFR function is dispensable for the growth of mutant Ras-positive endometrial carcinoma cells.
Assuntos
Neoplasias do Endométrio/genética , Fator de Crescimento Epidérmico/genética , Receptores ErbB/metabolismo , Genes ras , Mutação , Apoptose/genética , Divisão Celular , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Inibidores Enzimáticos/farmacologia , Fator de Crescimento Epidérmico/metabolismo , Feminino , Humanos , Hidroquinonas/farmacologia , Transdução de Sinais , Fator de Crescimento Transformador alfa/metabolismo , Células Tumorais CultivadasRESUMO
To investigate regulation mechanisms of G2/M phase transition, we studied the association of cell cycle progression with p53-dependent p21/waf-1 and cyclinG expression. We used doxorubicin (DOX) and sodium butyrate (NaB) to accumulate p53 protein. DOX treatment resulted in an apparent increase of cells in the G2/M fraction, whereas NaB arrested cells at G1. P53 protein induction in response to DOX accompanied up-regulation of p21/waf-1 and cyclinG expression. However, cyclinG was undetectable in NaB-treated cells. These results implied a putative association between increases in the proportion of cells accumulating in the G2/M fraction and enhanced cyclinG expression. Antisense oligo DNAs (AS) complementary to cyclinG mRNA inhibited the cyclinG protein expression induced by DOX treatment. This inhibition resulted in a marked reduction in the number of cells arrested at G2/M and accumulating at G1. A role for cyclinG in G2/M phase transition control is implied.
Assuntos
Ciclo Celular/efeitos dos fármacos , Ciclinas/metabolismo , Dano ao DNA/genética , Proteína Supressora de Tumor p53/metabolismo , Animais , Butiratos/farmacologia , Ácido Butírico , Ciclina G , Ciclina G1 , Inibidor de Quinase Dependente de Ciclina p21 , DNA Antissenso/genética , DNA Antissenso/farmacologia , Doxorrubicina/farmacologia , Inibidores Enzimáticos/farmacologia , Fibroblastos , Fase G2/fisiologia , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Immunoblotting , Mitose/fisiologia , RNA Mensageiro/genética , RatosRESUMO
We investigated the biological significance of estrogen receptors (ER) in NIH3T3 cell transformation by the [12Val] K-Ras mutant. This mutant enhanced the steady state level of ER. Cells expressing mutant K-Ras (K12V cell) were tumorigenic. To determine the role of ER accumulation in Ras-transformed cells, we developed cells (KwtER cells) that overexpressed both wild-type (wt) K-Ras and ER, and found these cells were also tumorigenic. E2 stimulated the transcriptional activity by ER dominantly in K12V cells. However, only partial activation of ER by E2 was seen in KwtER cells. In the presence of 10% serum in media, the activation of ER appeared only in transformed KtwER and K12V cells, suggesting that two independently transmitted signals, the E2-ER binding and the ER-AF1 activation, are necessary for ER activation and that the dominant activation of ER might be involved in Ras-mediated cell transformation. Co-expression of progesterone receptor (PR) with mutant K-Ras led to suppression of tumorigenicity and inhibition of the activation of ER. The antisense oligomers complementary to the ER suppressed proliferation and transformed phenotypes of K12V cells. These observations support the importance of ER in Ras-mediated cell transformation.
Assuntos
Transformação Celular Neoplásica/genética , Genes ras/genética , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Ativação Transcricional , Células 3T3 , Animais , Divisão Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Camundongos , Mutação , Oligonucleotídeos Antissenso/farmacologia , Receptores de Estrogênio/efeitos dos fármacos , Receptores de Progesterona/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Regulação para Cima , Proteínas ras/metabolismoRESUMO
We report the first familial case of dominantly inherited aniridia with a cryptic inversion within band 11p13. High-resolution chromosome analysis gave a suspicion of a tiny constitutional aberration around band 11p13 and fluorescence in situ hybridization using 11p cosmids successfully confirmed that the aniridia patients of this family have an inversion within band 11p13. The distal breakpoint of the inversion is telomeric to a candidate aniridia gene (AN2) and suggests that more genes might be involved in the etiology of aniridia. In situ hybridization is a powerful tool to detect cryptic rearrangements in sporadic or familial patients with aniridia. This family indicated the importance of careful observation of the 11p13 region of aniridia patients, even if the aniridia was autosomal dominantly inherited.
Assuntos
Aniridia/genética , Inversão Cromossômica , Cromossomos Humanos Par 11 , Adulto , Idoso , Bandeamento Cromossômico , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , LinhagemRESUMO
We report on a boy with the blepharophimosis sequence and de novo, apparently balanced reciprocal translocation between 3q23 and 4p15.2 [46,XY,t(3;4)(q23;p15.2)de novo]. Possible assignment of this autosomal dominant disorder is discussed. A 3q23 band is a more preferable gene locus of the belpharophimosis sequence, based on the comparison of clinical manifestations between 4p- and 3q-syndromes.
Assuntos
Blefarofimose/genética , Cromossomos Humanos Par 3 , Genes Dominantes/genética , Translocação Genética/genética , Humanos , Lactente , Cariotipagem , MasculinoRESUMO
A 7-year-old girl with cytochrome c oxidase deficiency who had no neurologic deficits in infancy suddenly developed ophthalmoplegia, ptosis, and respiratory arrest. She recovered almost completely 80 days after onset, suggesting that acute onset and rapid remission are observed in patients with cytochrome c oxidase deficiency. It is also possible that early initiation of therapy in cytochrome c oxidase deficiency with coenzyme Q10 may hasten and enhance the therapeutic effect.
Assuntos
Blefaroptose/etiologia , Deficiência de Citocromo-c Oxidase , Oftalmoplegia/etiologia , Insuficiência Respiratória/etiologia , Doença Aguda , Ataxia Cerebelar/etiologia , Criança , Coenzimas , Feminino , Humanos , Músculos/enzimologia , Músculos/patologia , Indução de Remissão , Ubiquinona/uso terapêuticoRESUMO
In 7 cases with unilateral cerebellar vascular lesion, decreased perfusion was observed in the contralateral cerebral cortex by single photon emission computed tomography (SPECT) with I-123 labeled N-isopropyl-p-iodoamphetamine (IMP). These cases had symptoms due to cerebellar lesions but did not show any cerebral cortical symptoms. Reduction of cerebral cortical perfusion appeared on more than 25 days after the onset of CVA, did not correlate with morphological changes by cranial X-ray computed tomography and digital subtraction angiography in acute phase, and was persistent or irreversible later. We made a guess this phenomenon was due to the remote neuronal effect through cerebellothalamic projection.
Assuntos
Doenças Cerebelares/fisiopatologia , Circulação Cerebrovascular , Idoso , Anfetaminas , Doenças Cerebelares/diagnóstico por imagem , Feminino , Humanos , Radioisótopos do Iodo , Iofetamina , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
A 2-year-old boy underwent bone marrow transplantation for severe aplastic anemia. Eighteen months later he developed chronic lung disease and dryness of the eyes. Ophthalmologic examination revealed obstruction of the nasolacrimal ducts and marked dilatation of the lacrimal sacs bilaterally. It seems likely that the nasolacrimal duct obstruction was a manifestation of chronic graft-versus-host disease.