Analysis Tools
mortality/aging
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• homozygotes were viable, fertile and outwardly healthy; however, several mutants succumbed to malignant B-cell lymphomas at approximately 1 year of age
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neoplasm
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• following weekly topical application of the carcinogen DMBA over a 25-wk observation period, only 35% of homozygotes survived and remained tumor-free relative to 75% of wild-type controls
• the major tumor types observed in DMBA-treated mice were squamous cell carcinoma of the skin and malignant lymphoma
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cellular
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• following low-density seeding, mutant MEFs displayed increased ability to generate actively growing colonies of clonal origin
• mutant MEFs showed a 3- to 5-fold increase in foci formation by myc/Ras relative to wild-type MEFs
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• the extent of 3H-thymidine incorporation was consistently increased in homozygous mutant cultures after stimulation with anti-CD3 plus anti-CD28 antibodies but not with LPS
• mutant samples exhibited an increase in exit from the G1 phase of the cell cycle that was proportional to the increase in 3H-thymidine incorporation (overall 10% decrease in G1 population of anti-CD3/CD28-treated mutant cells)
• no changes in the percentage of apoptotic cells were observed
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endocrine/exocrine glands
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• at 1 year of age, homozygotes exhibited an increase in the total number of prostatic glands (atrophic + acinar) relative to age-matched controls
• mutant prostates contained microscopic foci of enlarged and elaborate glandular structures, some of which contained hypercellular acini and dysplastic cells, with mitotic figures in epithelial cells located in suprabasal layers of the acini
• however, mutant prostatic tissues displayed no overt neoplastic transformation
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• immunohistochemical assessment of cellular proliferation in prostatic epithelium suggested that prostatic hyperplasia probably results from aberrant entry into the S-phase of the cell cycle
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hematopoietic system
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• the extent of 3H-thymidine incorporation was consistently increased in homozygous mutant cultures after stimulation with anti-CD3 plus anti-CD28 antibodies but not with LPS
• mutant samples exhibited an increase in exit from the G1 phase of the cell cycle that was proportional to the increase in 3H-thymidine incorporation (overall 10% decrease in G1 population of anti-CD3/CD28-treated mutant cells)
• no changes in the percentage of apoptotic cells were observed
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• mutant spleens were slightly enlarged relative to those in age-matched controls
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• in some instances, lymphocytic precursor cells displayed dysplastic morphology; however, FACS analysis revealed no changes in the splenic subpopulation profiles relative to wild-type controls
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• spleen enlargement correlated with a cellular expansion of the white pulp, initiated by fusion of white-pulp follicles and followed by mild to severe extramedullary hematopoietic changes
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immune system
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• the extent of 3H-thymidine incorporation was consistently increased in homozygous mutant cultures after stimulation with anti-CD3 plus anti-CD28 antibodies but not with LPS
• mutant samples exhibited an increase in exit from the G1 phase of the cell cycle that was proportional to the increase in 3H-thymidine incorporation (overall 10% decrease in G1 population of anti-CD3/CD28-treated mutant cells)
• no changes in the percentage of apoptotic cells were observed
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• mutant spleens were slightly enlarged relative to those in age-matched controls
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• in some instances, lymphocytic precursor cells displayed dysplastic morphology; however, FACS analysis revealed no changes in the splenic subpopulation profiles relative to wild-type controls
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• spleen enlargement correlated with a cellular expansion of the white pulp, initiated by fusion of white-pulp follicles and followed by mild to severe extramedullary hematopoietic changes
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renal/urinary system
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• at 7 months or older, homozygotes displayed dilation of the Bowman's space
• overall, renal dysmorphology resulted in cystic spaces similar to those observed in human glomerulocystic diseases
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• at 7 months or older, homozygotes exhibited focal atrophic changes in the glomeruli, including partial to total loss of the glomerular tufts
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• homozygotes displayed progressive degenerative changes in the cortical region of the kidney
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• younger homozygotes displayed renal alterations including cytoplasmic vacuolization of proximal tubular epithelial cells; these changes resembled the focal dilations observed in the precystic phase of polycystic kidney disease
• at 7 months or older, homozygotes showed atrophy of proximal tubules and foci of regenerating proximal convoluted tubules
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reproductive system
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• at 1 year of age, homozygotes exhibited an increase in the total number of prostatic glands (atrophic + acinar) relative to age-matched controls
• mutant prostates contained microscopic foci of enlarged and elaborate glandular structures, some of which contained hypercellular acini and dysplastic cells, with mitotic figures in epithelial cells located in suprabasal layers of the acini
• however, mutant prostatic tissues displayed no overt neoplastic transformation
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• immunohistochemical assessment of cellular proliferation in prostatic epithelium suggested that prostatic hyperplasia probably results from aberrant entry into the S-phase of the cell cycle
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homeostasis/metabolism
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• following weekly topical application of the carcinogen DMBA over a 25-wk observation period, only 35% of homozygotes survived and remained tumor-free relative to 75% of wild-type controls
• the major tumor types observed in DMBA-treated mice were squamous cell carcinoma of the skin and malignant lymphoma
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growth/size/body
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• mutant spleens were slightly enlarged relative to those in age-matched controls
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