Expression of Mad1 in T cells leads to reduced thymic cellularity and impaired mitogen-induced proliferation.
To investigate Mad1 function in vivo, transgenic mice were generated that express a Mad1 transgene in T lineage cells under the control of the proximal lck promoter. Thymus size in lck-Mad1 transgenic mice is drastically reduced although representation of the various thymocyte sub populations appears normal. To investigate more closely any effects of Mad1 expression on thymocytes, we examined thymic selection using MHC class I-restricted H-Y-TCR transgenic mice. Mad1 expression in vivo reduces the efficiency of positive selection. Furthermore, thymocytes and splenic T cells from lck-Mad1 transgenic mice display a profound proliferative defect in response to activation with either PMA/Ionomycin or immobilized anti-CD3/CD28 antibody. This proliferative defect is not reversed by addition of exogenous IL-2 and is p53-independent. The growth inhibition caused by Mad1 is overcome by expression of active c-Myc.
Rudolph
B
B
Imperial Cancer Research Fund, PO Box 123, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
Hueber
A O
AO
Evan
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GI
D000818:Animals; D015703:Antigens, CD / Q000502:physiology; D015153:Blotting, Western; D018797:Cell Cycle Proteins; D017931:DNA Primers / Q000737:chemistry; D005260:Female; D016259:Genes, myc / Q000502:physiology; D006182:H-Y Antigen / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D007124:Immunoenzyme Techniques; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D008934:Mitogens / Q000494:pharmacology*; D009687:Nuclear Proteins; D010750:Phosphoproteins / Q000096:biosynthesis*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000096:biosynthesis*; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016196:S Phase / Q000187:drug effects; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D015703:Antigens, CD; D018797:Cell Cycle Proteins; D017931:DNA Primers; D006182:H-Y Antigen; D015395:Histocompatibility Antigens Class I; C501385:Mad1l1 protein, mouse; D008934:Mitogens; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53