Thymocyte apoptosis induced by p53-dependent and independent pathways

Abstract

Death by apoptosis is characteristic of cells undergoing deletion during embryonic development, T- and B-cell maturation and endocrine-induced atrophy. Apoptosis can be initiated by various agents and may be a result of expression of the oncosuppressor gene p53 (refs 6-8). Here we study the dependence of apoptosis on p53 expression in cells from the thymus cortex. Short-term thymocyte cultures were prepared from mice constitutively heterozygous or homozygous for a deletion in the p53 gene introduced into the germ line after gene targeting. Wild-type thymocytes readily undergo apoptosis after treatment with ionizing radiation, the glucocorticoid methylprednisolone, or etoposide (an inhibitor of topoisomerase II), or after Ca(2+)-dependent activation by phorbol ester and a calcium ionophore. In contrast, homozygous null p53 thymocytes are resistant to induction of apoptosis by radiation or etoposide, but retain normal sensitivity to glucocorticoid and calcium. The time-dependent apoptosis that occurs in untreated cultures is unaffected by p53 status. Cells heterozygous for p53 deletion are partially resistant to radiation and etoposide. Our results show that p53 exerts a significant and dose-dependent effect in the initiation of apoptosis, but only when it is induced by agents that cause DNA-strand breakage.

Twenty years of p53 research: structural and functional aspects of the p53 protein

“…If p53 is mutated or inactivated in some manner, the apoptotic response is not activated and cell proliferation is allowed. Analysis of cells and tissues of p53-null mice has shown that functional p53 is necessary for DNA damage-induced apoptosis of cortical thymocytes (Clarke et al, 1993), myeloid progenitor cells (Lotem and Sachs, 1993), marrow preB cells (Strasser et al, 1994), quiescent peripheral B and T lymphocytes (Strasser et al, 1994), keratinocytes (Ziegler et al, 1994) and small intestine cells .…”

p53, Apaf-1, caspase-3, and -9 are dispensable for Cdk5 activation during cell death

“…We first examine the relationship of Cdk5 to the p53-mediated signaling pathway. [43][44][45] p53 may mediate mitochondrial cell death signaling through the elevation of the level of reactive oxygen species, 46 while oxidative stress can stimulate Cdk5 activity by inducing an upregulation of p35 in human neuroblastoma IMR-32 cells. 47 Reactive oxygen species (ROS) are instrumental in a number of neurodegenerative disorders where Cdk5 is activated.…”

Synergistic effects of adenovirus expressing wild-type p53 on chemosensitivity of non-small cell lung cancer cells

“…[7][8][9][10] This resistance is most likely due to the fact that cells without wt-p53 delay or are unable to initiate apoptosis. 7,11,12 In fact, administration of Ad-p53 with cis-diamminedichloroplatinum(II) (CDDP) induced tumor regression as well as apoptosis in p53-deleted human lung tumors that were grown as subcutaneous xenographs in nu/nu mice. 13 On the basis of these findings, gene therapy against p53-mutated NSCLC has started.…”