p53 is required for radiation-induced apoptosis in mouse thymocytes

Abstract

The p53 tumour suppressor gene is the most widely mutated gene in human tumorigenesis. p53 encodes a transcriptional activator whose targets may include genes that regulate genomic stability, the cellular response to DNA damage, and cell-cycle progression. Introduction of wild-type p53 into cell lines that have lost endogenous p53 function can cause growth arrest or induce a process of cell death known as apoptosis. During normal development, self-reactive thymocytes undergo negative selection by apoptosis, which can also be induced in immature thymocytes by other stimuli, including exposure to glucocorticoids and ionizing radiation. Although normal negative selection involves signalling through the T-cell receptor, the induction of apoptosis by other stimuli is poorly understood. We have investigated the requirement for p53 during apoptosis in mouse thymocytes. We report here that immature thymocytes lacking p53 die normally when exposed to compounds that may mimic T-cell receptor engagement and to glucocorticoids but are resistant to the lethal effects of ionizing radiation. These results demonstrate that p53 is required for radiation-induced cell death in the thymus but is not necessary for all forms of apoptosis.

Chk1 complements the G2/M checkpoint defect and radiosensitivity of ataxia-telangiectasia cells

“…A-T cells are also characterized by extreme radiosensitivity but since all checkpoints are defective in these cells there remains some doubt about the importance of individual checkpoints in cell survival post-irradiation. It is unlikely that the failure of A-T cells to mount an e ective p53 response to radiation accounts for any of the radiosensitivity since no correlation has been observed between propensity to radiation sensitivity and either the absence or mutation in p53 (Clarke et al, 1993;Lee and Bernstein, 1993;Lowe et al, 1993;Slichenmyer et al, 1993). In addition, while enforced expression of wild type p53 in A-T cells activated the G1/S checkpoint, it failed to alter the radiosensitivity in these cells .…”

Death-associated protein kinase 2 is a new calcium/calmodulin-dependent protein kinase that signals apoptosis through its catalytic activity

“…Mutant mice lacking the caspase family member revealed its essential role for execution of apoptosis in vivo (Kuida et al, 1996(Kuida et al, , 1998Hakem et al, 1998). In addition to the activation of caspases, apoptosis is known to be mediated by activation of c-Myc, p53 and protein kinases (Askew et al, 1991;Evan et al, 1992;Lowe et al, 1993;Anderson, 1997). Evidence has been presented that certain protein kinases have an ability to induce apoptosis, or are activated by various apoptotic stimuli.…”

A novel gene transfer strategy that combines promoter and transgene activities for improved tumor cell inhibition

“…21 P53 is known to be a key regulator of apoptosis following radiation or treatment of cells with chemotherapeutic agents such as doxorubicin. 22,23 Replacement of p53 activity in tumor cells has been shown repeatedly to halt cell proliferation as well as increase sensitivity to traditional cancer-fighting treatments.…”