Inhibition of RNA polymerase II as a trigger for the p53 response
Reads0
Chats0
TLDR
The results suggest that the induction of the p53 response by certain toxic agents is not triggered by DNA strand breaks but rather, may be linked to inhibition of mRNA synthesis either directly by the poisoning of RNA polymerase II or indirectly byThe induction of elongation-blocking DNA lesions.Abstract:
The mechanisms by which the p53 response is triggered following exposure to DNA-damaging agents have not yet been clearly elucidated. We and others have previously suggested that blockage of RNA polymerase II may be the trigger for induction of the p53 response following exposure to ultraviolet light. Here we report on the correlation between inhibition of mRNA synthesis and the induction of p53, p21 WAF1 and apoptosis in diploid human fibroblasts treated with either UV light, cisplatin or the RNA synthesis inhibitors actinomycin D, DRB, H7 and a-amanitin. Exposure to ionizing radiation or the proteasome inhibitor LLnL, however, induced p53 and p21 WAF1 without aAecting mRNA synthesis. Importantly, induction of p53 by the RNA synthesis or proteasome inhibitors did not correlate with the induction of DNA strand breaks. Furthermore, cisplatin-induced accumulation of active p53 in repair-deficient XP-A cells occurred despite the lack of DNA strand break induction. Our results suggest that the induction of the p53 response by certain toxic agents is not triggered by DNA strand breaks but rather, may be linked to inhibition of mRNA synthesis either directly by the poisoning of RNA polymerase II or indirectly by the induction of elongation-blocking DNA lesions.read more
Citations
More filters
Journal ArticleDOI
Post-translational modifications and activation of p53 by genotoxic stresses
Ettore Appella,Carl W. Anderson +1 more
TL;DR: It is suggested that N-terminal phosphorylations are important for stabilizing p53 and are crucial for acetylation of C- terminal sites, which in combination lead to the full p53-mediated response to genotoxic stresses.
Journal ArticleDOI
Awakening guardian angels: drugging the p53 pathway
TL;DR: Several original approaches to drug discovery that could have wide applications to drug development are being used, including molecules that activate p53 by blocking protein–protein interactions with MDM2 and p53-binding molecules that can rescue the function of certain p53 mutants.
Journal ArticleDOI
Disruption of the nucleolus mediates stabilization of p53 in response to DNA damage and other stresses
Carlos P. Rubbi,Jo Milner +1 more
TL;DR: It is proposed that the nucleolus is a stress sensor responsible for maintenance of low levels of p53, which are automatically elevated as soon as nucleolar function is impaired in response to stress.
Journal ArticleDOI
Ribosomal Protein L23 Activates p53 by Inhibiting MDM2 Function in Response to Ribosomal Perturbation but Not to Translation Inhibition
TL;DR: Ectopic expression of L23 reduced MDM2-mediated p53 ubiquitination and also induced p53 activity and G1 arrest in p 53-proficient U2OS cells but not in p53-deficient Saos-2 cells, revealing that L23 is another regulator of the p53 -MDM2 feedback regulation.
Journal ArticleDOI
Inhibition of transcription by platinum antitumor compounds
Ryan C. Todd,Stephen J. Lippard +1 more
TL;DR: A detailed review of the structural investigations of various Pt-DNA adducts and the effects of these lesions on global DNA geometry and a mechanistic analysis of how DNA structural distortions induced by platinum damage may inhibit RNA synthesis in vivo are presented.
References
More filters
Journal ArticleDOI
p53, the Cellular Gatekeeper for Growth and Division
TL;DR: The author regrets the lack of citations for many important observations mentioned in the text, but their omission is made necessary by restrictions in the preparation of review manuscripts.
Journal ArticleDOI
The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53
TL;DR: It is demonstrated that the E6 proteins of the oncogenic HPVs that bind p53 stimulate the degradation of p53, which results in selective degradation of cellular proteins such as p53 with negative regulatory functions provides a novel mechanism of action for dominant-acting oncoproteins.
Journal Article
Participation of p53 Protein in the Cellular Response to DNA Damage
TL;DR: A role for the wild-type p53 protein in the inhibition of DNA synthesis that follows DNA damage is suggested and a new mechanism for how the loss of wild- type p53 might contribute to tumorigenesis is suggested.
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.
Journal ArticleDOI
p53 is required for radiation-induced apoptosis in mouse thymocytes
TL;DR: It is demonstrated 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.