The mouse telomerase holoenzyme, which synthesizes telomeric DNA de novo, is a ribonucleoprotein complex that includes the mouse telomerase RNA component (mTERC), mouse telomerase-associated protein (mTEP1) and mouse telomerase reverse transcriptase (mTERT). To determine the role of telomerase in urethane-induced lung tumorigenesis in A/J mice we examined telomerase activity and the expression of each telomerase subunit in 20 tumor samples, harvested at 16, 28, 40 and 50 weeks after urethane treatment. The telomeric repeat amplification protocol assay showed that statistically significant telomerase activation occurred both early and late in tumorigenesis. Semi-quantitative reverse transcription-polymerase chain reaction analysis revealed that mRNA expression levels of mTEP1 and mTERT were up-regulated during tumor progression, while mTERC expression was not significantly different between tumors and normal lung. We further examined mTEP1 protein expression in normal lung tissue and lung tumors; western blot analysis showed preferential expression of mTEP1 protein in lung tumors compared with normal lung and immunohistochemistry revealed that a majority of the adenoma cells were positively stained in the nucleus, whereas only a few of the adjacent normal alveolar cells were immunoreactive. In addition, we investigated DNAs of the 20 tumor samples by single strand conformation polymorphism and sequencing analyses to examine whether alterations of the p53 gene in exons 5-8 were associated with telomerase activity. Although we found one nonsense, two missense, two silent and one simultaneous double mutation at different codons in six late stage tumors, there was no apparent correlation between telomerase activity and p53 mutations. Collectively, these results suggest that mTEP1 as well as mTERT may be involved in the regulation of telomerase activity and that telomerase activation may contribute to lung tumorigenesis in A/J mice independently of p53 gene alterations.
A cerebral infarction of the left occipital lobe developed in a 6 5-year-old man with squamous cell carcinoma of the right lung. Neurological examinations and brain CT showed findings typical of ordinary infarction. Postmortem examination revealed a tumor embolus within the posterior cerebral artery. Such spontaneous tumor emboli large enough to obstruct a larger-sized artery are rare.
Maternal and fetal metabolism of vitamin D was examined in term pregnant rabbits fed a normal diet and in those supplemented with a large amount of vitamin D3. Term pregnant rabbits (27--30 days of gestation) fed the normal diet showed lower levels of plasma calcium, 25-hydroxyvitamin D3 (250HD3), and 24,25-dihydroxyvitamin D3 [24,25-(OH)2D3] and higher plasma 1 alpha, 25-dihydroxyvitamin D3 [1 alpha, 25-(OH)2D3] levels than age-matched nonpregnant female rabbits. Kidney homogenates from pregnant rabbits produced mainly 1 alpha 25-(OH)2D3, while those from nonpregnant animals produced 24,25-(OH)2D3 primarily. Plasma concentrations of calcium and phosphorus were significantly higher in fetuses than in mothers. Plasma levels of 250HD3 and 24,25-(OH)2D3 in fetuses were almost identical to those in mothers, whereas 1 alpha,25-(OH)2D3 levels in plasma were significantly higher in mothers than in their fetuses. A daily administration of 650 nmol vitamin D3 for 3 days to term pregnant rabbits caused a significant increase in calcium, phosphorus, 25OHD3, and 24,25-(OH)2D3 in maternal plasma, and in 25OHD3 and 24,25-(OH)2D3, but not calcium and phosphorus in fetal plasma. Treatment with large amounts of vitamin D3 also induced a marked suppression of 1 alpha-hydroxylase activity and a concomitant increase of 24-hydroxylase activity in the maternal but not in the fetal kidney. Plasma concentrations of 1 alpha,25-(OH)2D3 were not affected by treatment with large amounts of vitamin D3 in either the fetuses or the mothers. These results clearly indicate that the renal 25OHD3 metabolism in the fetus is regulated independently of that in the mother.
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