How does p53 cause apoptosis

Nunez, University of Michigan, Ann Arbor. MEFs grown on polylysine-coated glass coverslips were transfected with expression constructs using Fugene 6 as described above.

Transfected cells were immunostained 24—48 hr after transfection, as described previously Attardi et al. To detect mitochondria, Mito-Tracker Molecular Probes was used according to the manufacturer's instructions.

To detect p53, human p53 monoclonal antibody ; Oncogene Science was used. FITC-coupled anti-mouse antibodies and rhodamine-coupled anti-rabbit antibodies Cappel, were used to visualize monoclonal and polyclonal antibodies, respectively.

Cell death was assessed by examining the morphology of positively staining cells. We thank Dan Chasman for help with sequence analysis programs and Matt Petitt for assistance with graphics. We thank Annemieke deVries for assistance with the UV-induced apoptosis assays. We appreciate the advice of Andy Samuelson and Marisol Soengas on retroviral infections. This work has been supported by grant CA to S. The publication costs of this article were defrayed in part by payment of page charges.

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Download references. We thank all of our current and past colleagues at The Walter and Eliza Hall Institute and elsewhere. You can also search for this author in PubMed Google Scholar. Correspondence to Andreas Strasser. Reprints and Permissions. Aubrey, B. How does p53 induce apoptosis and how does this relate to pmediated tumour suppression?. Cell Death Differ 25, — Download citation. Received : 29 May Revised : 05 September Accepted : 08 September Published : 17 November More upstream regulators and downstream effectors of p53 will undoubtedly be described, but the real challenge is to determine how contextual factors influence the network and how tumor heterogeneity can be understood and exploited for therapeutic purposes.

Ideally, this increased understanding will permit the p53 network to be manipulated in more selective ways. Clearly, one avenue is to restore apoptosis by reintroducing a specific p53 activity, either through gene therapy or the rational design of small molecules. At the same time, the effects of p53 in normal tissues must be taken into account, including the role of pdependent apoptosis in producing toxic side effects from chemotherapy, as well as the potential for blocking pmediated apoptosis for acute or chronic diseases involving excessive cell death Komarova and Gudkov, ; Tyner et al.

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We also thank the Laurie Strauss Leukemia Foundation for their support. You can also search for this author in PubMed Google Scholar. Correspondence to Scott W Lowe. Reprints and Permissions. Fridman, J.

Control of apoptosis by p Oncogene 22, — Download citation. Published : 08 December Issue Date : 08 December Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Nature Communications Nature Microbiology Biological Trace Element Research Journal of Gastrointestinal Cancer Cellular and Molecular Life Sciences Advanced search.

Skip to main content Thank you for visiting nature. Download PDF. Abstract The p53 tumor suppressor acts to integrate multiple stress signals into a series of diverse antiproliferative responses. Main Tumor suppressors act to maintain tissue homeostasis, that is, to control the number and behavior of cells in a particular tissue within an organism Hussain and Harris, The apoptotic program Apoptosis is a complex process that proceeds through at least two main pathways extrinsic and intrinsic , each of which can be regulated at multiple levels.

Figure 1. Full size image. Downstream effectors of p53 in apoptosis p53 is a transcription factor capable of binding DNA in a sequence-specific fashion Ko and Prives, Transcriptional control of the Bcl-2 family The most intuitive link between pmediated transactivation and apoptosis comes from its ability to control transcription of proapoptotic members of the Bcl-2 family. Transcriptional control of the apoptotic machinery A body of work indicates that pmediated apoptosis proceeds primarily through the intrinsic apoptotic program e.

Transcriptional control of the extrinsic pathway The extrinsic apoptotic pathway is also regulated by p53, although the overall contribution of this regulation to pmediated cell death is poorly understood.

Other transcriptional targets Beyond the core constituents of the intrinsic and extrinsic apoptotic pathways, p53 transcriptionally activates other genes that have been linked to apoptosis. Redox metabolism Induction of p53 has also been shown to produce changes in REDOX metabolism, leading to increases in reactive oxygen species ROS prior to the onset of apoptotic cell death Polyak et al.

Pmediated transrepression While most studies investigating the action of p53 in apoptosis have focused on its transactivation functions, p53 also has transrepression capabilities that may contribute to apoptosis Mack et al. Nontranscriptional modes of action Although p53 can up- and downregulate gene transcription, its influence on apoptosis may not end there.

Coordination of the apoptotic program by p53 Why would a transcription factor evolve to use so many distinct mechanisms to produce the same biological end point? Regulation of pdependent apoptosis: deciding cell fate In addition to its ability to promote apoptosis, p53 can also induce cell cycle arrest, cellular senescence, and directly influence DNA repair.

Quantity vs quality How might p53 interpret contextual factors and respond accordingly? Which post modifications might influence p53 activity?