RESUMEN
MDM-2 is a cellular oncoprotein that binds to the p53 protein and abrogates its growth-suppressing function. At least seven MDM-2 mRNAs and five proteins (p90, p85, p76, p74, and p57) have been reported in tissue culture. MDM-2 gene amplification occurs in human sarcomas and high-grade gliomas. MDM-2 overexpression without gene amplification has been reported in leukemias and lymphomas. Here we report MDM-2 mRNA overexpression in 24 (73%) out of 33 cases of human breast carcinoma as compared with normal breast tissue. The MDM-2 overexpression was seen in the absence of MDM-2 gene amplification. MDM-2 protein expression was studied by western blot analysis in 21 of these cases of carcinoma. We found complete concordance between MDM-2 mRNA overexpression and MDM-2 protein levels. MDM-2 proteins were overexpressed in 15 of 21 breast carcinoma tissue samples but not in normal breast tissue controls. Ten of these fifteen cases overexpressed MDM-2 p57 protein, two cases overexpressed both p57 and p90, and three cases overexpressed only p90. MDM-2 overexpression was confirmed by immunohistochemistry. p53 overexpression was also studied by immunohistochemistry, 69% of breast carcinomas that overexpressed the MDM-2 mRNA had detectable nuclear p53 protein. These findings demonstrate that MDM-2 oncoprotein expression is altered in primary human breast carcinomas at both mRNA and protein levels. In addition, our results suggest that MDM-2 p57 protein represents the main MDM-2 protein altered in breast carcinomas.
Asunto(s)
Neoplasias de la Mama/metabolismo , Carcinoma/metabolismo , Proteínas Nucleares , Proteínas Proto-Oncogénicas/metabolismo , ARN Mensajero/metabolismo , Western Blotting , Femenino , Humanos , Inmunohistoquímica , Metástasis Linfática , Pronóstico , Proteínas Proto-Oncogénicas c-mdm2 , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
The human homologue of the mouse double minute 2 (MDM-2) gene codes for a cellular protein that forms a complex with the mutant and wild-type p53 protein and modulates its trans-activation activity. Overexpression of the MDM-2 gene in cells increases their tumorigenic potential and overcomes the growth-suppressive activity of p53. Previous reports have shown that the MDM-2 gene is amplified in approximately one third of human sarcomas. To examine the role of MDM-2 in leukemia, we analyzed MDM-2 gene amplification and mRNA expression in various types of leukemias. We did not detect gene amplification in any of the 48 cases of leukemia that we examined. In contrast, we observed significant MDM-2 mRNA overexpression in 34 of 64 cases (53%). The level of mRNA overexpression in some cases of leukemias was comparable to that observed in some cases of sarcomas, which demonstrate more than 50-fold MDM-2 gene amplification. Furthermore, we divided these cases into different prognostic groups according to their karyotypic abnormalities. MDM-2 overexpression seemed to be associated with unfavorable chromosomal abnormalities. These findings suggest that the expression of the MDM-2 gene is altered in a significant fraction of human leukemias and MDM-2 may play a significant role in leukemogenesis. In addition, these results suggest that mechanisms other than gene amplification may play a significant role in deregulating the MDM-2 expression.
Asunto(s)
Regulación Leucémica de la Expresión Génica , Leucemia/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares , Oncogenes , Proteínas Proto-Oncogénicas , Secuencia de Bases , Aberraciones Cromosómicas , Amplificación de Genes , Genes p53 , Humanos , Datos de Secuencia Molecular , Proteínas Proto-Oncogénicas c-mdm2 , ARN Mensajero/análisis , ARN Neoplásico/análisis , Células Tumorales CultivadasRESUMEN
Hip fractures on 117 patients treated surgically and followed up for an average of 10.2 months are reviewed. Among the parameters analyzed were complications, mortality, clinical follow-up by the operating surgeon, and the ability to ambulate after surgery. Postoperative surgical complications occurred in 36% and medical complications in 18% of the patients. Mortality was 25% within the first year after surgery. Sixty-one percent of the patients returned at least once to the surgeon's office for follow-up; only 38% were followed for more than six months. In the surviving patients who were good ambulators before hip fracture, 60% to 70% became good ambulators postoperatively. Only 20% to 30% of the surviving patients who were poor ambulators preoperatively ever walked again.