ABSTRACT
The mdm2 oncogene encodes p90(MDM2), which binds to and inactivates the p53 tumor suppressor protein. p90(MDM2) inhibits p53 by blocking the transcriptional activation domain of p53 as well as by stimulating its degradation. Recently, we showed that another product of the wild-type mdm2 gene, p76(MDM2), lacks the first 49 amino acids of p90(MDM2) and cannot bind p53. Here, we report that, like p90(MDM2), p76(MDM2) is expressed in both the nuclear and cytoplasmic compartments. Overexpression of p76(MDM2) antagonizes the ability of p90(MDM2) to stimulate the degradation of p53 and leads to an increase in the levels and activity of p53. Seven murine tissues express an alternatively spliced mdm2 mRNA that can encode p76(MDM2) but not p90(MDM2), as well as the normally spliced mdm2 mRNA that encodes both MDM2 proteins. All seven tissues express both MDM2 proteins. p90(MDM2) is much more abundant than p76(MDM2) in the testis, brain, heart, and kidney. However, in those tissues known to undergo p53-mediated apoptosis in response to gamma-irradiation, the thymus, spleen, and intestine, the levels of the MDM2 proteins are roughly equivalent. Our results indicate that the ratio of the two MDM2 proteins may regulate the response of tissues to DNA damage.
Subject(s)
Nuclear Proteins , Proto-Oncogene Proteins/physiology , Tumor Suppressor Protein p53/metabolism , 3T3 Cells , Alternative Splicing , Animals , Calcium Phosphates/metabolism , Fibroblasts , Fluorescent Antibody Technique , Humans , Male , Mice , Mice, Inbred C57BL , Precipitin Tests , Protein Binding , Protein Structure, Tertiary , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins c-mdm2 , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Testis/metabolism , Tissue Distribution , Transcriptional Activation , Tumor Cells, CulturedABSTRACT
The effects of the cerebral cortex gangliosides have been studied in fifteen patients with peripheral neuropathies through the results of electromyographic examination. The patients were divided into two groups: A--peripheral neuropathy of alcoholic etiology (seven patients); D--peripheral neuropathy of diabetes etiology (eight patients). The medication has been administered 20 mg/day intramuscularly during twenty days. At the end of that period it was verified: 1) a discrete increase of the motor conduction velocity in the patients of the group A; 2) the sensitive conduction velocity was inaltered in both groups; 3) a favourable therapeutic response (global evaluation) in three patients of group A, and in three of group D; they represent 40% of the total number of patients studied. For the control of therapeutical effects of the medication the authors suggest a more prolonged period of administration of the medication in hospitalized patients submitted to periodic electromyographic examinations.
Subject(s)
Gangliosides/therapeutic use , Neural Conduction/drug effects , Peripheral Nervous System Diseases/drug therapy , Adult , Aged , Electromyography , Female , Gangliosides/administration & dosage , Humans , Male , Middle Aged , Peripheral Nervous System Diseases/physiopathologyABSTRACT
Foram estudados atraves de exame eletromiografico os efeitos dos gangliosideos do cortex cerebral em 15 pacientes com neuropatia periferica, divididos em dois grupos A (etiologia alcoolica) e D (etiologia diabetica). Apos 20 dias de administracao por via intramuscular (20 mg/dia) do farmaco foi verificado: 1) que houve aumento discreto da velocidade de conducao motora nos pacientes do grupo A; 2) que a velocidade de conducao sensitiva nao se alterou em qualquer dos grupos e para o total dos pacientes observados; 3) resposta favoravel a terapeutica (avaliacao global) em tres dos 7 pacientes do grupo A, em tres dos 8 pacientes do grupo D e, portanto, em 40% do total de pacientes estudados.Os autores sugerem administracao do farmaco por tempo mais prolongado, em pacientes hospitalizados e submetido a avaliacao eletromiografica periodica, para verificar a eventual atuacao terapeutica do medicamento
