Journal ArticleDOI
Thymocyte apoptosis induced by p53-dependent and independent pathways
Alan Richard Clarke,Colin A. Purdie,Colin A. Purdie,David J. Harrison,R. G. Morris,Colin C. Bird,Martin L. Hooper,Andrew H. Wyllie +7 more
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TLDR
The 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.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.read more
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A Surface Groove Essential for Viral Bcl-2 Function During Chronic Infection In Vivo
Joy Loh,Qiulong Huang,Andrew M. Petros,David G. Nettesheim,Linda F. van Dyk,Lucia Labrada,Samuel H. Speck,Beth Levine,Edward T. Olejniczak,Herbert W. Virgin +9 more
TL;DR: An essential functional role for amino acids in the BH3 peptide binding groove of a viral Bcl-2 family member during chronic infection is demonstrated.
Journal ArticleDOI
Acute overexpression of wt p53 facilitates anticancer drug-induced death of cancer and normal cells
TL;DR: It is concluded that exogenous wt p53 accelerates cell death induced by DNA damaging agents in both normal and cancer cells and offers no protection from anticancer drugs.
Journal ArticleDOI
Cell and tissue responses to genotoxic stress
TL;DR: Tumour susceptibility after endogenous or exogenous genotoxic stress represents a balance between cell‐intrinsic responses of target cells and changes to the microenvironment and could lead to novel prevention and therapeutic strategies for common forms of human malignancy.
Journal ArticleDOI
Small molecule antagonists of the MDM2 oncoprotein as anticancer agents.
John K. Buolamwini,James K. Addo,Shantaram Kamath,Shivaputra A. Patil,Darius Mason,Marian Ores +5 more
TL;DR: Three compounds have been discovered that are effective in inhibiting the E3 ligase activity of MDM2 towards p53, and should serve as leads for drug discovery targeting this aspect of the p53-MDM2 interaction.
Journal ArticleDOI
Importance of changes in epithelial cell turnover during Helicobacter pylori infection in gastric carcinogenesis
TL;DR: It seems that cagA status influences the effect of H pylori on epithelial apoptosis in infected patients, and an association of in vitro H pylonori induced apoptosis with changes in the expression of pro- and anti-apoptotic genes is reported in the literature.
References
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Journal ArticleDOI
Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation
TL;DR: It is shown here that this morphological change is closely associated with excision of nucleosome chains from nuclear chromatin, apparently through activation of an intracellular, but non-lysosomal, endonuclease.
Journal ArticleDOI
A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia
Michael B. Kastan,Qimin Zhan,Wafik S. El-Deiry,Tyler Jacks,William V. Walsh,Beverly Plunkett,Bert Vogelstein,Albert J. Fornace +7 more
TL;DR: Three participants are identified (AT gene(s), p53, and GADD45) in a signal transduction pathway that controls cell cycle arrest following DNA damage; abnormalities in this pathway probably contribute to tumor development.
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Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6
TL;DR: In this article, wild-type p53 protein has many properties consistent with its being the product of a tumour suppressor gene, which could be involved in promoting cell differentiation as well as in mediating growth arrest by growthinhibitory cytokines.
Journal ArticleDOI
Wild-type p53 is a cell cycle checkpoint determinant following irradiation.
TL;DR: Participation of p53 in this pathway suggests a mechanism for the contribution of abnormalities in p53 to tumorigenesis and genetic instability and provides a useful model for studies of the molecular mechanisms of p 53 involvement in controlling the cell cycle.
Journal ArticleDOI
Chromatin cleavage in apoptosis: association with condensed chromatin morphology and dependence on macromolecular synthesis.
TL;DR: The data confirm that the condensed chromatin which characterizes apoptosis morphologically consists of endogenously digested chromatin fragments, and provide support for the view that at least some cells enter apoptosis by a process dependent upon macromolecular synthesis.