Effect of p21(waf1/cip1) transgene on radiation induced apoptosis in T cells

The cyclin kinase inhibitor p21(WAF1/Cip1) is upregulated by the tumor supp ressor p53. While p21 is central for the G-1 arrest mediated by p53, it is still unclear if p21 also functions as a downstream effector of p53 depende nt apoptosis. Apoptosis induced by DNA damage but not dexamethasone is p53 dependent in thymocytes. To investigate the physiological role of p21 in ap optosis, we have generated transgenic mice in which the p21 transgene is ta rgeted for restricted expression in the T cell lineage. Thymocytes from p21 transgenic mice were hypersensitive to cell death induced by DNA damaging agents such as ionizing radiation and UV, but not be dexamethasone. Irradia ted p21 transgenic thymocytes had approximately twofold more apoptotic cell s as compared to irradiated age matched littermate control mice. Radiation induced death is comparable in thymocytes from p21 + Bcl2 + double transgen ic mice and age matched littermate controls, indicating that the Bcl2 trans gene rescues the radiation hypersensitivity imposed by p21. However, thymoc ytes from p53-/- mice even when they expressed the p21 transgene, were resi stant to death induced by radiation. Together these results show that thymo cytes from p21 transgenic mice are hypersensitive to radiation induced prog rammed cell death and suggest that the radiation hypersensitivity of p21 tr ansgenic thymocytes involves p53 dependent pathway and signals in addition to p21.