Post-translational modifications and activation of p53 by genotoxic stresses - PubMed (original) (raw)
Review
Post-translational modifications and activation of p53 by genotoxic stresses
E Appella et al. Eur J Biochem. 2001 May.
Free article
Abstract
In unstressed cells, the tumor suppressor protein p53 is present in a latent state and is maintained at low levels through targeted degradation. A variety of genotoxic stresses initiate signaling pathways that transiently stabilize the p53 protein, cause it to accumulate in the nucleus, and activate it as a transcription factor. Activation leads either to growth arrest at the G1/S or G2/M transitions of the cell cycle or to apoptosis. Recent studies point to roles for multiple post-translational modifications in mediating these events in response to genotoxic stresses through several potentially interacting but distinct pathways. The approximately 100 amino-acid N-terminal and approximately 90 amino-acid C-terminal domains are highly modified by post-translational modifications. The N-terminus is heavily phosphorylated while the C-terminus contains phosphorylated, acetylated and sumoylated residues. Antibodies that recognize p53 only when it has been modified at specific sites have been developed, and studies with these reagents show that most known post-translational modifications are induced when cells are exposed to genotoxic stresses. These recent results, coupled with biochemical and genetic studies, suggest 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. Modifications to the C-terminus inhibit the ability of this domain to negatively regulate sequence-specific DNA binding; additionally, they modulate the stability, the oligomerization state, the nuclear import/export process and the degree of ubiquitination of p53.
Similar articles
- Signaling to p53: breaking the posttranslational modification code.
Appella E, Anderson CW. Appella E, et al. Pathol Biol (Paris). 2000 Apr;48(3):227-45. Pathol Biol (Paris). 2000. PMID: 10858956 Review. - Post-translational modification of p53 and the integration of stress signals.
Meek DW. Meek DW. Pathol Biol (Paris). 1997 Dec;45(10):804-14. Pathol Biol (Paris). 1997. PMID: 9769944 Review. - DNA damage activates p53 through a phosphorylation-acetylation cascade.
Sakaguchi K, Herrera JE, Saito S, Miki T, Bustin M, Vassilev A, Anderson CW, Appella E. Sakaguchi K, et al. Genes Dev. 1998 Sep 15;12(18):2831-41. doi: 10.1101/gad.12.18.2831. Genes Dev. 1998. PMID: 9744860 Free PMC article. - p53 regulation by post-translational modification and nuclear retention in response to diverse stresses.
Jimenez GS, Khan SH, Stommel JM, Wahl GM. Jimenez GS, et al. Oncogene. 1999 Dec 13;18(53):7656-65. doi: 10.1038/sj.onc.1203013. Oncogene. 1999. PMID: 10618705 Review. - Functional analysis of the roles of posttranslational modifications at the p53 C terminus in regulating p53 stability and activity.
Feng L, Lin T, Uranishi H, Gu W, Xu Y. Feng L, et al. Mol Cell Biol. 2005 Jul;25(13):5389-95. doi: 10.1128/MCB.25.13.5389-5395.2005. Mol Cell Biol. 2005. PMID: 15964796 Free PMC article.
Cited by
- Surf the post-translational modification network of p53 regulation.
Gu B, Zhu WG. Gu B, et al. Int J Biol Sci. 2012;8(5):672-84. doi: 10.7150/ijbs.4283. Epub 2012 May 10. Int J Biol Sci. 2012. PMID: 22606048 Free PMC article. Review. - Exploring the Roles of HERC2 and the NEDD4L HECT E3 Ubiquitin Ligase Subfamily in p53 Signaling and the DNA Damage Response.
Mathieu NA, Levin RH, Spratt DE. Mathieu NA, et al. Front Oncol. 2021 Mar 31;11:659049. doi: 10.3389/fonc.2021.659049. eCollection 2021. Front Oncol. 2021. PMID: 33869064 Free PMC article. Review. - Transactivation specificity is conserved among p53 family proteins and depends on a response element sequence code.
Ciribilli Y, Monti P, Bisio A, Nguyen HT, Ethayathulla AS, Ramos A, Foggetti G, Menichini P, Menendez D, Resnick MA, Viadiu H, Fronza G, Inga A. Ciribilli Y, et al. Nucleic Acids Res. 2013 Oct;41(18):8637-53. doi: 10.1093/nar/gkt657. Epub 2013 Jul 26. Nucleic Acids Res. 2013. PMID: 23892287 Free PMC article. - Novel regulation of checkpoint kinase 1: Is checkpoint kinase 1 a good candidate for anti-cancer therapy?
Goto H, Izawa I, Li P, Inagaki M. Goto H, et al. Cancer Sci. 2012 Jul;103(7):1195-200. doi: 10.1111/j.1349-7006.2012.02280.x. Epub 2012 Apr 23. Cancer Sci. 2012. PMID: 22435685 Free PMC article. Review. - A pool of peptides extracted from wheat bud chromatin inhibits tumor cell growth by causing defective DNA synthesis.
Mancinelli L, Secca T, De Angelis PM, Mancini F, Marchesini M, Marinelli C, Barberini L, Grignani F. Mancinelli L, et al. Cell Div. 2013 Aug 6;8:11. doi: 10.1186/1747-1028-8-11. eCollection 2013. Cell Div. 2013. PMID: 23915323 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Research Materials
Miscellaneous