Mice lacking the p53-effector gene Gadd45a develop a lupus-like syndrome.
This study addresses the biological function of the p53-effector genes Gadd45a and p21 in the immune system. We find that Gadd45a is a negative regulator of T cell proliferation because, compared to wild-type cells, Gadd45a(-/-) T cells have a lower threshold of activation and proliferate to a greater extent following primary T cell receptor stimulation. Gadd45a(-/-) mice develop an autoimmune disease, similar to human systemic lupus erythematosus (SLE), characterized by high titers of anti-dsDNA, anti-ssDNA, and anti-histone autoantibodies, severe hematological disorders, autoimmune glomerulonephritis, and premature death. Here we show that the lack of both Gadd45a and p21 dramatically accelerates the development of autoimmunity observed in each individual single-gene disruption mutant, demonstrating that these genes play nonredundant roles in the immune response.
Salvador
Jesus M
JM
Gene Response Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Hollander
M Christine
MC
Nguyen
Anh Thu
AT
Kopp
Jeffrey B
JB
Barisoni
Laura
L
Moore
Jodene K
JK
Ashwell
Jonathan D
JD
Fornace
Albert J
AJ
D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D018797:Cell Cycle Proteins; D002455:Cell Division; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D005260:Female; D005921:Glomerulonephritis / Q000235:genetics / Q000276:immunology; D006405:Hematology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013577:Syndrome; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D016159:Tumor Suppressor Protein p53 / Q000276:immunology*; D000097642:GADD45 Proteins
D000974:Antibodies, Antinuclear; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; C493957:Cdkn1a protein, mouse; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins