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iASPP inhibits p53-independent apoptosis by inhibiting transcriptional activity of p63/p73 on promoters of proapoptotic genes

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Abstract

The ability to induce apoptosis is the most important tumor-suppression function of p53. Inhibitory member of apoptosis-stimulating protein of p53 family (iASPP) is an apoptotic-specific regulator of p53. iASPP suppresses apoptosis by inhibiting the transactivation function of p53 on the promoters of proapoptotic genes; however, the mechanism whereby iASPP influences apoptosis in tumor cells with mutant or deficient p53 has not been completely defined. In this study, we investigated the role of iASPP in the p63/p73 apoptosis pathway. iASPP inhibited apoptosis independently of p53 in tumor cells, mainly by inhibiting the transcriptional activity of p63/p73 on the promoters of proapoptotic genes. Because p63 and p73 are rarely mutated in human cancers, inhibiting the expression of endogenous iASPP may provide a useful strategy for restoring the apoptotic activity of p63 and p73 in human tumors with p53 loss or mutation. These results represent a promising new strategy for the treatment of cancers with non-wild-type p53.

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Abbreviations

ASPP:

Apoptosis-stimulating protein of p53

iASPP:

Inhibitory member of the ASPP family

ChIP:

Chromatin immunoprecipitation

FCM:

Flow cytometry

References

  1. Vousden KH, Lu X (2002) Live or let die: the cell’s response to p53. Nat Rev Cancer 2:594–604

    Article  PubMed  CAS  Google Scholar 

  2. Vousden KH (2005) P53 and PUMA: a deadly duo. Science 309:1685–1686

    Article  PubMed  CAS  Google Scholar 

  3. Lu X (2005) p53: a heavily dictated dictator of life and death. Curr Opin Genet Dev 15:27–33

    Article  PubMed  CAS  Google Scholar 

  4. Samuels-Lev Y, O’Connor DJ, Bergamaschi D, Trigiante G, Hsieh JK, Zhong S et al (2001) ASPP proteins specifically stimulate the apoptotic function of p53. Mol Cell 8:781–794

    Article  PubMed  CAS  Google Scholar 

  5. Bergamaschi D, Samuels Y, O’Neil NJ, Trigiante G, Crook T, Hsieh JK et al (2003) iASPP oncoprotein is a key inhibitor of p53 conserved from worm to human. Nat Genet 33:162–167

    Article  PubMed  CAS  Google Scholar 

  6. Bergamaschi D, Samuels Y, Jin B, Duraisingham S, Crook T, Lu X (2004) ASPP1 and ASPP2: common activators of p53 family members. Mol Cell Biol 24:1341–1350

    Article  PubMed  CAS  Google Scholar 

  7. Bergamaschi D, Samuels Y, Sullivan A, Zvelebil M, Breyssens H, Bisso A et al (2006) iASPP preferentially binds p53 proline-rich region and modulates apoptotic function of codon 72-polymorphic p53. Nat Genet 38:1133–1141

    Article  PubMed  CAS  Google Scholar 

  8. Liu ZJ, Lu X, Zhong S (2005) ASPP—Apoptotic specific regulator of p53. Biochim Biophys Acta 1756:77–80

    PubMed  CAS  Google Scholar 

  9. Sullivan A, Lu X (2007) ASPP: a new family of oncogenes and tumour suppressor genes. Br J Cancer 96:196–200

    Article  PubMed  CAS  Google Scholar 

  10. Slee EA, Gillotin S, Bergamaschi D, Royer C, Llanos S, Ali S et al (2004) The N-terminus of a novel isoform of human iASPP is required for its cytoplasmic localization. Oncogene 23:9006–9016

    Google Scholar 

  11. Bell HS, Ryan KM (2008) iASPP inhibition: increased options in targeting the p53 family for cancer therapy. Cancer Res 68:4959–4962

    Article  PubMed  CAS  Google Scholar 

  12. Chen J, Xie F, Zhang L, Jiang WG (2010) iASPP is over-expressed in human non-small cell lung cancer and regulates the proliferation of lung cancer cells through a p53 associated pathway. BMC Cancer 10:694

    Article  PubMed  CAS  Google Scholar 

  13. Laska MJ, Vogel UB, Jensen UB, Nexo BA (2010) p53 and PPP1R13L(alias iASPP or RAI) form a feedback loop to regulate genotoxic stress responses. Biochim Biophys Acta 1800:1231

    Article  PubMed  CAS  Google Scholar 

  14. Hollstein M, Sidransky D, Vogelstein B, Harris CC (1991) p53 mutations in human cancers. Science 253:49–53

    Article  PubMed  CAS  Google Scholar 

  15. p53 mutation database. Available from: http://p53.free.fr/. Accessed 25 Mar 2012

  16. Slee EA, O’Connor DJ, Lu X (2004) To die or not to die: how does p53 decide. Oncogene 23:2809–2818

    Article  PubMed  CAS  Google Scholar 

  17. Chikh A, Matin RN, Senatore V, Hufbauer M, Lavery D, Raimondi C et al (2011) iASPP/p63 autoregulatory feedback loop is required for the homeostasis of stratified epithelia. EMBO J 30:4261

    Article  PubMed  CAS  Google Scholar 

  18. Liu ZJ, Gao X, Cai Y, Yang X, Fu XL, Chen J et al (2009) Construction of a full-length iASPP Expression plasmid pcDNA3.1(+)/iASPP and its biological activity. Plasmid 62:10–15

    Article  PubMed  CAS  Google Scholar 

  19. Liu ZJ, Cai Y, Hou L, Gao X, Xin HM, Lu X et al (2008) Effect of RNA interference of iASPP on the apoptosis in MCF-7 breast cancer cells. Cancer Invest 26:878–882

    Article  PubMed  CAS  Google Scholar 

  20. Liu ZJ, Xin HM, Chen J, Lu X, Zhong S, Gu SZ et al (2007) A new strategy to resume the apoptosis activity of p53 in leukemia cell lines retaining wild-type p53. Leukemia Res 31:1156–1158

    Article  CAS  Google Scholar 

  21. Jost CA, Marin MC, Kaelin WG Jr (1997) p73 is a human p53-related protein that can induce apoptosis. Nature 389:191–194

    Article  PubMed  CAS  Google Scholar 

  22. Yang A, Kaghad M, Wang Y, Gillett E, Fleming MD, Dotsch V et al (1998) p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol Cell 2:305–316

    Article  PubMed  CAS  Google Scholar 

  23. Robinson RA, Lu X, Jones EY, Siebold C (2008) Biochemical and structural studies of ASPP proteins reveal differential binding to p53, p63 and p73. Structure 16:259–268

    PubMed  CAS  Google Scholar 

  24. Flores ER, Tsai KY, Crowley D, Sengupta S, Yang A, McKcon F et al (2002) p63 and p73 are required for p53-dependent apoptosis in response to DNA damage. Nature 416:560–564

    Article  PubMed  CAS  Google Scholar 

  25. Murray-Zmijewski F, Lane DP, Bourdon JC (2006) P53/p63/p73 isoforms: an orchestra of isoforms to harmonise cell differentiation and response to stress. Cell Death Differ 13:962–972

    Article  PubMed  CAS  Google Scholar 

  26. Patel S, George R, Autore F, Fraternali F, Ladbury JE, Nikolova PV (2008) Molecular interactions of ASPP1 and ASPP2 with the p53 protein family and the apoptotic promoters PUMA and Bax. Nucleic Acids Res 36:5139–5151

    Article  PubMed  CAS  Google Scholar 

  27. Liu ZJ, Zhang Y, Zhang XB, Yang X (2004) Abnormal mRNA expression of ASPP members in leukemia cell lines. Leukemia 18:880

    Article  PubMed  Google Scholar 

  28. Zhang X, Wang M, Zhou C, Chen S, Wang J (2005) The expression of iASPP in acute leukemias. Leukemia Res 29:179–183

    Article  CAS  Google Scholar 

  29. Lu B, Guo H, Zhao J, Wang C, Wu G, Pang M et al (2010) Increased expression of iASPP, regulated by hepatitis B virus X protein-mediated NF-κB activation, in hepatocellular carcinoma. Gastroenterology 139:2183–2194

    Article  PubMed  CAS  Google Scholar 

  30. Liu WK, Jiang XY, Ren JK, Zhang ZX (2010) Expression pattern of the ASPP family members in endometrial endometrioid adenocarcinoma. Onkologie 33:500–503

    Article  PubMed  Google Scholar 

  31. Pinto EM, Musolino NR, Cescato VA, Soares IC, Wakamatsu A, de Oliveira E et al (2010) iASPP: a novel protein involved in pituitary tumorigenesis? Front Horm Res 38:70–76

    Article  PubMed  CAS  Google Scholar 

  32. Olivier M, Hollstein M, Hainaut P (2010) TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol 2:a001008

    Article  PubMed  Google Scholar 

  33. Soussi T, Kato S, Levy PP, Ishioka C (2005) Reassessment of the TP53 mutation database in human disease by data mining with a library of TP53 missense mutations. Hum Mutat 25:6–17

    Article  PubMed  CAS  Google Scholar 

  34. Berglind H, Pawitan Y, Kato S, Ishioka C, Soussi T (2008) Analysis of p53 mutation status in human cancer cell lines: a paradigm for cell line cross-contamination. Cancer Biol Ther 7:699–708

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Takara Biotechnology (Dalian) Co. Ltd., GeneChem Co. Ltd., and KangChen Bio-tech Inc. for technical assistance. This work was supported by the National Natural Science Foundation of China (30971140) and Natural Science Foundation Project of CQ CSTC, 2008BA5003.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, People’s Republic of China

    Yun Cai, Shi Qiu, Xing Gao, Shou-Zhi Gu & Ze-Jun Liu

  2. School of Rehabilitation Sciences, Seirei Christopher University, Hamamatsu, 433-8558, Japan

    Shou-Zhi Gu

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  1. Yun Cai
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  2. Shi Qiu
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  3. Xing Gao
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  4. Shou-Zhi Gu
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Correspondence to Ze-Jun Liu.

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Cai, Y., Qiu, S., Gao, X. et al. iASPP inhibits p53-independent apoptosis by inhibiting transcriptional activity of p63/p73 on promoters of proapoptotic genes. Apoptosis 17, 777–783 (2012). https://doi.org/10.1007/s10495-012-0728-z

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  • DOI: https://doi.org/10.1007/s10495-012-0728-z

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