Abstract
iASPP is one of the most evolutionarily conserved inhibitors of p53, whereas ASPP1 and ASPP2 are activators of p53. We show here that, in addition to the DNA-binding domain, the ASPP family members also bind to the proline-rich region of p53, which contains the most common p53 polymorphism at codon 72. Furthermore, the ASPP family members, particularly iASPP, bind to and regulate the activity of p53Pro72 more efficiently than that of p53Arg72. Hence, escape from negative regulation by iASPP is a newly identified mechanism by which p53Arg72 activates apoptosis more efficiently than p53Pro72.
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References
Slee, E.A., O'Connor, D.J. & Lu, X. To die or not to die: how does p53 decide? Oncogene 23, 2809–2818 (2004).
Samuels-Lev, Y. et al. ASPP proteins specifically stimulate the apoptotic function of p53. Mol. Cell 8, 781–794 (2001).
Bergamaschi, D. et al. iASPP oncoprotein is a key inhibitor of p53 conserved from worm to human. Nat. Genet. 33, 162–167 (2003).
Liu, Z.J., Zhang, Y., Zhang, X.B. & Yang, X. Abnormal mRNA expression of ASPP members in leukemia cell lines. Leukemia 18, 880 (2004).
Zhang, X., Wang, M., Zhou, C., Chen, S. & Wang, J. The expression of iASPP in acute leukemias. Leuk. Res. 29, 179–183 (2005).
Agirre, X. et al. ASPP1, a common activator of TP53, is inactivated by aberrant methylation of its promoter in acute lymphoblastic leukemia. Oncogene 25, 1862–1870 (2006).
Lossos, I.S., Natkunam, Y., Levy, R. & Lopez, C.D. Apoptosis stimulating protein of p53 (ASPP2) expression differs in diffuse large B-cell and follicular center lymphoma: correlation with clinical outcome. Leuk. Lymphoma 43, 2309–2317 (2002).
Vives, V. et al. ASPP2 is a haploinsufficient tumor suppressor that cooperates with p53 to suppress tumor growth. Genes Dev. 20, 1262–1267 (2006).
Gorina, S. & Pavletich, N.P. Structure of the p53 tumor suppressor bound to the ankyrin and SH3 domains of 53BP2. Science 274, 1001–1005 (1996).
Walker, K.K. & Levine, A.J. Identification of the novel p53 functional domain which is necessary for efficient growth suppression. Proc. Natl. Acad. Sci. USA 93, 15335–15340 (1996).
Zhu, J., Jiang, J., Zhou, W., Zhu, K. & Chen, X. Differential regulation of cellular target genes by p53 devoid of the PXXP motifs with impaired apoptotic activity. Oncogene 18, 2149–2155 (1999).
Baptiste, N., Friedlander, P., Chen, X. & Prives, C. The proline-rich domain of p53 is required for cooperation with anti-neoplastic agents to promote apoptosis of tumor cells. Oncogene 21, 9–21 (2002).
Venot, C. et al. The requirement for the p53 proline-rich functional domain for mediation of apoptosis is correlated with specific PIG3 gene transactivation and with transcriptional repression. EMBO J. 17, 4668–4679 (1998).
D'Erchia, A.M., Pesole, G., Tullo, A., Saccone, C. & Sbisa, E. Guinea pig p53 mRNA: identification of new elements in coding and untranslated regions and their functional and evolutionary implications. Genomics 58, 50–64 (1999).
Noma, C., Miyoshi, Y., Taguchi, T., Tamaki, Y. & Noguchi, S. Association of p53 genetic polymorphism (Arg72Pro) with estrogen receptor positive breast cancer risk in Japanese women. Cancer Lett. 210, 197–203 (2004).
Granja, F. et al. Proline homozygosity in codon 72 of p53 is a factor of susceptibility for thyroid cancer. Cancer Lett. 210, 151–157 (2004).
Agorastos, T. et al. P53 codon 72 polymorphism and correlation with ovarian and endometrial cancer in Greek women. Eur. J. Cancer Prev. 13, 277–280 (2004).
de Oliveira, W.R. et al. Association of p53 arginine polymorphism with skin cancer. Int. J. Dermatol. 43, 489–493 (2004).
Matakidou, A., Eisen, T. & Houlston, R.S. TP53 polymorphisms and lung cancer risk: a systematic review and meta-analysis. Mutagenesis 18, 377–385 (2003).
Cenci, M. et al. p53 polymorphism at codon 72 is not a risk factor for cervical carcinogenesis in central Italy. Anticancer Res. 23, 1385–1387 (2003).
Dumont, P., Leu, J.I., Della Pietra, A.C. III, George, D.L. & Murphy, M. The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. Nat. Genet. 33, 357–365 (2003).
Gostissa, M. et al. The transcriptional repressor hDaxx potentiates p53-dependent apoptosis. J. Biol. Chem. 279, 48013–48023 (2004).
Siddique, M.M. Evidence for selective expression of the p53 codon 72 polymorphs: implications in cancer development. Cancer Epidemiol. Biomarkers Prev. 14, 2245–2252 (2005).
Trigiante, G. & Lu, X. ASPPs and Cancer. Nat. Rev. Cancer 6, 217–226 (2006).
Sjalander, A., Birgander, R., Kivela, A. & Beckman, G. p53 polymorphisms and haplotypes in different ethnic groups. Hum. Hered. 45, 144–149 (1995).
Sjalander, A., Birgander, R., Saha, N., Beckman, L. & Beckman, G. p53 polymorphisms and haplotypes show distinct differences between major ethnic groups. Hum. Hered. 46, 41–48 (1996).
Iwabuchi, K., Li, B., Bartel, P. & Fields, S. Use of the two-hybrid system to identify the domain of p53 involved in oligomerization. Oncogene 8, 1693–1696 (1993).
Slee, E.A. et al. The N-terminus of a novel isoform of human iASPP is required for its cytoplasmic localization. Oncogene (2004).
Bergamaschi, D. et al. ASPP1 and ASPP2: common activators of p53 family members. Mol. Cell. Biol. 24, 1341–1350 (2004).
Bergamaschi, D. et al. p53 polymorphism influences response in cancer chemotherapy via modulation of p73-dependent apoptosis. Cancer Cell 3, 387–402 (2003).
Acknowledgements
We would like to thank the Ludwig Institute for Cancer Research for supporting the work, E. Slee and D. O'Connor for reading the manuscript and M. Murphy for the WM115 and WM278 cell lines. D.B. is funded by the Association for International Cancer Research. T.C. is a clinical research fellow of Cancer Research UK.
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Contributions
D.B. performed most of the work, including most of the immunoprecipitations of p53/ASPP interaction in vitro and in vivo, all apoptosis assays, part of the transactivation assays and chromatin immunoprecipitation (ChIP). Y.S. was involved in the initial observations and immunoprecipitation in RKO cells as well as part of the transactivation assays. A.S. performed immunoprecipitation of Thio-p53/ASPP interaction and of p53/ASPP complex in melanoma cell lines and performed RT-PCR. M.Z. performed the sequence alignment of SH3 domain-containing proteins and computer modeling of p53/ASPP interaction. H.B. constructed the iASPP and ASPP2 mutants iASPPY814L and ASPP2L1113Y. A.B. constructed the pCDNA3HATNV-Pr72R and pCDNA3HATNV-Pr72P plasmids. G.D.S. supervised the work of A.B. N.S. performed p53 sequence analysis and developed quantitative PCR assays for ASPP1, ASPP2 and iASPP. P.S. performed analysis of p53 arginine and proline polymorphisms and mutations. M.G. analyzed iASPP expression in the panel of human breast cancer samples using quantitative PCR. T.C. microdissected tumor sections, isolated genomic DNA and mRNA from these sections. X.L. was responsible for the overall project, in particular the ideas and strategies.
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The authors do not believe, or are unsure, whether they have competing financial interests as defined in the form “NPG_CFI_form.pdf”. However, in the interest of full disclosure, the authors declare that a patent application has been filed based on the results described in this publication in the name of the Ludwig Institute for Cancer Research, which funded this research.
Supplementary information
Supplementary Fig. 1
Computer modelling to illustrate the importance of Y814 of iASPP and L1113 of ASP2 in contacting codon 72 Pro or Arg of p53. (PDF 127 kb)
Supplementary Fig. 2
Wild-type iASPP preferentially binds to the proline-rich region of p53Pro72, whereas iASPPY814L and ASPP2 preferentially bind to the proline-rich region of p53Arg72. (PDF 27 kb)
Supplementary Table 1
mRNA expression of iASPP in human breast tumor samples expressing either wild-type or mutant p53. (PDF 23 kb)
Supplementary Table 2
Frequency of overexpression of iASPP in tumors with wild-type p53 homozygous for p53Pro72 versus those homozygous for p53Arg72 in the germ line. (PDF 597 kb)
Supplementary Table 3
Primer sequences used for the production of iASPP RNAi, CHIP assays, RT-PCR of various p53 targets and real-time RT-PCR of iASPP in breast tumor and matched normal samples. (PDF 14 kb)
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Bergamaschi, D., Samuels, Y., Sullivan, A. et al. iASPP preferentially binds p53 proline-rich region and modulates apoptotic function of codon 72–polymorphic p53. Nat Genet 38, 1133–1141 (2006). https://doi.org/10.1038/ng1879
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DOI: https://doi.org/10.1038/ng1879
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