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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p53 Mutations as a possible predictor of response to chemotherapy in metastatic colorectal carcinomas
TL;DR: The data suggest that mutated p53 colorectal tumors had a weak response, or even no response, to chemotherapeutic treatment, and routine assessment of p53 status would be helpful in selecting patients with only wild‐type p53 gene who have a predictably better response to chemotherapy.
Journal ArticleDOI
Protein kinase C involvement in apoptosis
TL;DR: The uncoupling of timing for p34cdc2 activation and the completion of DNA replication results in the so-called "mitotic catastrophe" that shares some features with apoptosis.
Journal ArticleDOI
The p53 gene is a potent determinant of chemosensitivity and radiosensitivity in gastric and colorectal cancers.
Madoka Hamada,Toshiyoshi Fujiwara,Akio Hizuta,Akira Gochi,Yoshio Naomoto,Norihisa Takakura,Kenji Takahashi,Jack A. Roth,Noriaki Tanaka,Kunzo Orita +9 more
TL;DR: p53 mutations are associated with the poor response of chemotherapy and radiotherapy, and thep53-inducible WAF1/CIP1 protein was immunohistochemically observed in wild-type- p53-containing tumors, where-as mutant-p 53-expressing tumors expressed no detectable WAF 1/C IP1.
Journal ArticleDOI
The p53 pathway in hematopoiesis: lessons from mouse models, implications for humans
TL;DR: P53-dependent cell cycle control, senescence, and apoptosis functions are actively involved in maintaining hematopoietic homeostasis under normal and stress conditions, and their relevance to human disease is summarized.
Journal ArticleDOI
Nuclear accumulation and activation of p53 in embryonic stem cells after DNA damage.
TL;DR: In embryonic stem cells where (anti-proliferative) p53 activity is not necessary, or even unfavorable, p53 is retained in the cytoplasm and prevented from activating its target genes, however, if its activity is beneficial or required, it is allowed to accumulate in the nucleus and activates itstarget genes, even in embryonic stem Cells.
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.