RESUMEN
The insulin receptor susbtrate-3 (IRS-3) is a member of a family of intermediate adapter proteins that function as major intracellular targets for phosphorylation by the activated insulin and IGF-I receptors. Among the four IRS proteins identified so far, IRS-3 exhibits a rather peculiar expression pattern during both the embryonic development and adult life, suggesting a different mechanism of regulation of its expression. In this study, we cloned the 5' flanking region of the mIRS-3 gene and analyzed its promoter activity. The mIRS-3 promoter is inhibited by wild-type p53, and this effect is completely abolished by cotransfection of a dominant negative p53. Tumor-derived p53 mutants show variable, but lower suppressing capability than wt p53. In addition, treatment with doxorubicin inhibits endogenous expression of mIRS-3 mRNA in C2C12 and 3T3-L1 cells. The DNA region spanning from nucleotides -287 and -178 in the mIRS-3 promoter is responsible for a 32.2% reduction of the mouse double minute 2 (MDM2) promoter activity, suggesting its involvement in the p53-mediated inhibitory effect. In conclusion, our study demonstrates that the mIRS-3 promoter is regulated by p53 at the transcriptional level. The inhibition of mIRS-3 promoter by wild-type p53, and its de-repression by tumor-derived p53 mutants, appears to be similar to that previously reported for the IGF-I receptor promoter, suggesting a common role of these two genes in p53-mediated cell growth and differentiation.
Asunto(s)
Proteínas Nucleares , Fosfoproteínas/genética , Regiones Promotoras Genéticas , Proteína p53 Supresora de Tumor/metabolismo , Región de Flanqueo 5' , Animales , Antineoplásicos/farmacología , Secuencia de Bases , Células Cultivadas , Clonación Molecular , Doxorrubicina/farmacología , Regulación de la Expresión Génica , Humanos , Proteínas Sustrato del Receptor de Insulina , Riñón/citología , Riñón/embriología , Ratones , Datos de Secuencia Molecular , Mutación , Fosfoproteínas/efectos de los fármacos , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-mdm2 , Proteína p53 Supresora de Tumor/genéticaRESUMEN
The aim of the study is to evaluate if occupational exposure to urban stressors could cause alterations in luteinizing hormone (LH) plasma levels in male traffic policemen vs. administrative staff of Municipal Police.After excluding the subjects with the main confounding factors, male traffic police and administrative staff of Municipal Police were matched by age, working life, body mass index (BMI), alcohol drinking habit, cigarette smoking habit and habitual consumption of Italian coffee.In 166 male traffic police mean LH values were significantly higher compared to 166 male administrative employees. The distribution of LH values in traffic police and in administrative employees was statistically significant.Our results suggest that recent exposure to urban stressors (chemical, physical and psycho-social) can alter the plasma concentration of LH. In agreement with our previous research, levels of plasma LH may be used as early biological markers, valuable for the group, used in occupational set before the appearance of the disease.