Research / Clinical
Summary
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Diseases/Research Topics
Cancer, Genetics, Mouse, Mouse Cancer Genetics, Responses to Extracellular Stimuli and Stress
Ser15 is phosphorylated by ATM family kinases and might play a role in p53 responses to genotoxic stresses. We have introduced the ser15 to ala missense mutation into both alleles of the endogenous p53 gene of ES cells, therefore, these ES cells will express a p53 identical to the germline one except that ser15 is mutated to ala and thus it can not be phosphorylated any more. We analyzed the p53 responses to DNA damage induced by ionizing radiation or UV in these mutant ES cells and these studies provide compelling evidence that phosphorylation of p53 at ser15 is required for efficient p53 upregulation following DNA damage.
In addition, we are using the same strategy to study the importance of a number of other phosphorylation events of p53 in the p53 responses to cellular and genotoxic stresses.
The defective T cell development in ATM-/- mice, including an average three-fold reduction of total thymocyte number and an average 10-fold reduction in mature thymocyte number, could be due to two possibilities. The primary cause for the reduction of thymocytes in ATM-/- mice could be due to defects in cellular proliferation, as has been observed in ATM-/- fibroblasts, or disrupted V(D)J recombination or both. To test these two possibilities, a functional TCRab double transgene is being introduced into the ATM mutant mice. If the T cell defects are due to disrupted V(D)J recombination in ATM-/- mice, the transgenic TCRab chain should rescue the T cell developmental defects in ATM-/- mice. In addition, ATM-/- mice are also impaired in the T-dependent immune responses. This could be due to reduced T cell number or intrinsically defective T cell function or both. These two possibilities can also be tested in the TCRab+ATM-/- mice because most T cells in these mice should express the monospecific transgenic TCRab chain. Our data indicated that the T cell developmental defects are due to both impaired V(D)J recombination and defective thymocyte proliferation. In addition, ATM-/- T cells are functionally normal. Therefore, the T cell developmental defects in A-T patients and ATM-/- mice are likely due to greatly reduced T cell numbers. We are also testing the potential role of ATM in V(D)J recombination. We have used the cell-sorting facility of Cancer Center extensively.
Keywords: DNA damage, ATM, p53, cell cycle arrest, apoptosis, tumorigenesis, V(D)j recombination, enhancer
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