ABSTRACT
Mutant Cu/Zn superoxide dismutase (SOD1) associated with familial amyotrophic lateral sclerosis (FALS) causes selective motor neuron loss through unknown mechanisms of cell damage. Damaged neurons frequently undergo apoptosis mediated by the p53 cell survival regulator. We therefore studied whether motor neuron disease (MND) in mice expressing the human SOD1 mutant G93A is dependent on p53 by crossing G93A mice with p53-knockout mice. Since p53-/- mice's life expectance is usually shorter (160+/-49 days, n=11) than the time at which the G93A mice die from MND (212+/-50 days, n=7), only a few of the G93A/p53-/- double transgenics were expected to live to experience MND. Nevertheless, four of the 22 G93A/p53-/- mice succumbed to MND after 160+/-28 days, as expected under these conditions of competing death risks if the absence of p53 fails to protect from MND. Thus, MND in mice expressing G93A does not require p53. This conclusion is supported by histology: pre-symptomatic G93A mice display disease-associated vacuoles within the dendrites of motor neurons regardless of p53 status.
Subject(s)
Genes, p53 , Motor Neuron Disease/pathology , Motor Neurons/pathology , Spinal Cord/pathology , Superoxide Dismutase/genetics , Tumor Suppressor Protein p53/physiology , Aging , Amino Acid Substitution , Animals , Crosses, Genetic , Disease Models, Animal , Humans , Lumbar Vertebrae , Mice , Mice, Knockout , Mice, Transgenic , Motor Neuron Disease/genetics , Superoxide Dismutase/deficiency , Tumor Suppressor Protein p53/deficiency , Tumor Suppressor Protein p53/geneticsABSTRACT
Follicular neoplasms of oncocytic type in the thyroid gland frequently cause diagnostic problems and prognostic uncertainties. To identify numerical chromosomal aberrations of possible pathogenetic importance, we determined chromosome copy numbers in situ in interphase nuclei of 31 oncocytic adenomas and 25 oncocytic carcinomas. Archival formaldehyde-fixed, paraffin-embedded tumor samples and normal control thyroid tissues were arranged in arrays and analyzed by fluorescence in situ hybridization (FISH). We used pericentromeric or locus specific probes for chromosomes 1, 7, 8, 9, 11, 12, 17, 18, 22, and X as well as for the oncogenes Her2/neu, cyclin D1, N-myc, and c-myc. The average number of aneusomies per nucleus was significantly higher in carcinomas than in adenomas, and in both, monosomies were more frequent than polysomies. Loss of chromosome 22 was found in 8 of 21 (38%) carcinomas; in 5 cases, it was associated with chromosome 2 monosomy. Conversely, chromosome 2 aberrations were not found in adenomas. Monosomies for chromosome 8 and X were detected in most adenomas and carcinomas. The most common gains in adenomas and carcinomas were for chromosome 7 (13.8% and 32.0% of the cases, respectively), chromosome 12 (9.6% and 12.0%), and chromosome 17 (19.3% and 32.0%). None of the adenomas with trisomy 17 was associated with gains for chromosomes 7 and 12. None of the analyzed oncogenes was found to be amplified by FISH analysis. Our results indicate that numerical chromosomal aberrations in oncocytic follicular tumors of the thyroid gland are common findings and suggest that different patterns of aberrations may occur in these neoplasms.
