DNA damage, p14ARF, Nucleophosmin (NPM/B23), and cancer
- 436 Downloads
The p53/p14ARF/mdm2 stress response pathway plays a central role in mediating cellular responses to oncogene activation, genome instability, and therapy-induced DNA damage. Abrogation of the pathway occurs in most if not all cancers, and may be essential for tumor development. The high frequency with which the pathway is disabled in cancer and the fact that the pathway appears to be incompatible with tumor cell growth, has made it an important point of focus in cancer research and therapeutics development. Recently, Nucleophosmin (NPM, B23, NO38 and numatrin), a multifunctional nucleolar protein, has emerged as a p14ARF binding protein and regulator of p53. While complex formation between ARF and NPM retains ARF in the nucleolus and prevents ARF from activating p53, DNA damaging treatments promote a transient subnuclear redistribution of ARF to the nucleoplasm, where it interacts with mdm2 and promotes p53 activation. The results add support to a recently proposed model in which the nucleolus serves as a p53-uspstream sensor of stress, and where ARF links nucleolar stress signals to nucleoplasmic effectors of the stress response. A better understanding of ARF’s nucleolar interactions could further elucidate the regulation of the p53 pathway and suggest new therapeutic approaches to restore p53 function.
Keywordsp53 p14ARF DNA damage NPM Nucleophosmin B23 Nucleolus
Unable to display preview. Download preview PDF.
Our laboratory is supported by the NCI/NIH (CA111868) and the California Tobacco-Related Disease Research Program (11RT-0074). We apologize to the many authors who we were unable to cite due to space limitations.
- Falini B, Mecucci C, Tiacci E, Alcalay M, Rosati R, Pasqualucci L, La Starza R, Diverio D, Colombo E, Santucci A, Bigerna B, Pacini R, Pucciarini A, Liso A, Vignetti M, Fazi P, Meani N, Pettirossi V, Saglio G, Mandelli F, Lo-Coco F, Pelicci PG, Martelli MF (2005) Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med 352:254–266PubMedGoogle Scholar
- Feuerstein N, Mond JJ (1987a) Identification of a prominent nuclear protein associated with proliferation of normal and malignant B cells. J Immunol 139:1818–1822Google Scholar
- Feuerstein N, Mond JJ (1987b) “Numatrin,” a nuclear matrix protein associated with induction of proliferation in B lymphocytes. J Biol Chem 262:11389–11397Google Scholar
- O’Connor PM, Jackman J, Bae I, Myers TG, Fan S, Mutoh M, Scudiero DA, Monks A, Sausville EA, Weinstein JN, Friend S, Fornace AJ Jr, Kohn KW (1997) Characterization of the p53 tumor suppressor pathway in cell lines of the National Cancer Institute anticancer drug screen and correlations with the growth-inhibitory potency of 123 anticancer agents. Cancer Res 57:4285–4300PubMedGoogle Scholar
- Olson MO (2004) Sensing cellular stress: another new function for the nucleolus? Sci STKE 2004:pe10Google Scholar
- Rizos H, Darmanian AP, Holland EA, Mann GJ, Kefford RF (2001) Mutations in the INK4a/ARF melanoma susceptibility locus functionally impair p14ARF. J Biol Chem 276:41424–41434Google Scholar
- Saadatmandi N, Wilson DR, Gjerset RA (2002) p53 gene therapy. In: Encyclopedia of cancer, Vol 3. Academic Press, pp 425–432Google Scholar
- Zhang Y, Xiong Y (1999) Mutations in human ARF exon 2 disrupt its nucleolar localization and impair its ability to block nuclear export of MDM2 and p53. Mol Cell 3:579–591Google Scholar