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Article

Wilms' tumor gene 1 enhances nutlin-3-induced apoptosis

  • Authors:
    • Sun-Young Lee
    • Yun-Jeong Choe
    • Jik Young Park
    • Sang Sun Lee
    • Yoon-Hyoung Kim
    • Seok Joon Shin
    • Yeun Jun Chung
    • Ho-Shik Kim
  • View Affiliations / Copyright

    Affiliations: Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea, Seegene Institute of Life Science, Seegene, Inc., Seoul 138-050, Republic of Korea, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea, Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea
  • Pages: 131-136
    |
    Published online on: November 1, 2013
       https://doi.org/10.3892/or.2013.2832
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Abstract

Nutlin-3, a human double minute 2 (HDM2) antagonist, induces cell cycle arrest or apoptosis by upregulating p53 in cancer cells. WT1, the product of Wilms' tumor gene 1, has been shown to interact with p53, but the effect of WT1 on nutlin-3-induced apoptosis has yet to be examined. To address this issue, we analyzed the inhibitory effect of nutlin-3 on cell growth as a function of Wt1 expression status using a Wt1-inducible U2OS cell line. In the absence of Wt1 expression, nutlin-3 induced cell cycle arrest with marginal cytotoxicity. Furthermore, upon Wt1 expression, nutlin-3 exerted a marked degree of cell death, as evidenced by the accumulation of hypo-diploid cells and LDH release. During cell death induction, cytochrome c was released into the cytosol, and caspase-9 and -3 were activated, suggesting that an intrinsic apoptotic pathway may be involved in this cell death. Consistent with this, z-VAD-Fmk, a pan-caspase inhibitor and the overexpression of BCL-XL attenuated the cell death. Nutlin-3 caused an increase in the mRNA levels of both BCL-XL and BAK, as well as their corresponding protein levels in mitochondria. In the presence of Wt1, nutlin-3-induced BCL-XL expression was attenuated while the expression of nutlin-3-induced BAK was potentiated. Collectively, these results suggest that WT1 potentiates nutlin-3-induced apoptosis by downregulating the expression of BCL-XL while upregulating that of BAK, which leads to the activation of an intrinsic apoptotic pathway.
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1 

Hastie ND: Wilms’ tumour gene and function. Curr Opin Genet Dev. 3:408–413. 1993.

2 

Call KM, Glaser T, Ito CY, et al: Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms’ tumor locus. Cell. 60:509–520. 1990.

3 

Kreidberg JA, Sariola H, Loring JM, et al: WT-1 is required for early kidney development. Cell. 74:679–691. 1993. View Article : Google Scholar : PubMed/NCBI

4 

Herzer U, Crocoll A, Barton D, Howells N and Englert C: The Wilms tumor suppressor gene wt1 is required for development of the spleen. Curr Biol. 9:837–840. 1999. View Article : Google Scholar : PubMed/NCBI

5 

Lee SB and Haber DA: Wilms tumor and the WT1 gene. Exp Cell Res. 264:74–99. 2001. View Article : Google Scholar : PubMed/NCBI

6 

Mayo MW, Wang CY, Drouin SS, et al: WT1 modulates apoptosis by transcriptionally upregulating the bcl-2 proto-oncogene. EMBO J. 18:3990–4003. 1999. View Article : Google Scholar : PubMed/NCBI

7 

Algar EM, Khromykh T, Smith SI, Blackburn DM, Bryson GJ and Smith PJ: A WT1 antisense oligonucleotide inhibits proliferation and induces apoptosis in myeloid leukaemia cell lines. Oncogene. 12:1005–1014. 1996.PubMed/NCBI

8 

Menke AL, Shvarts A, Riteco N, van Ham RC, van der Eb AJ and Jochemsen AG: Wilms’ tumor 1-KTS isoforms induce p53-independent apoptosis that can be partially rescued by expression of the epidermal growth factor receptor or the insulin receptor. Cancer Res. 57:1353–1363. 1997.

9 

Morrison DJ, English MA and Licht JD: WT1 induces apoptosis through transcriptional regulation of the proapoptotic Bcl-2 family member Bak. Cancer Res. 65:8174–8182. 2005. View Article : Google Scholar : PubMed/NCBI

10 

Maheswaran S, Park S, Bernard A, et al: Physical and functional interaction between WT1 and p53 proteins. Proc Natl Acad Sci USA. 90:5100–5104. 1993. View Article : Google Scholar : PubMed/NCBI

11 

Maheswaran S, Englert C, Zheng G, et al: Inhibition of cellular proliferation by the Wilms tumor suppressor WT1 requires association with the inducible chaperone Hsp70. Genes Dev. 12:1108–1120. 1998. View Article : Google Scholar : PubMed/NCBI

12 

Maheswaran S, Englert C, Bennett P, Heinrich G and Haber DA: The WT1 gene product stabilizes p53 and inhibits p53-mediated apoptosis. Genes Dev. 9:2143–2156. 1995. View Article : Google Scholar : PubMed/NCBI

13 

Vassilev LT, Vu BT, Graves B, et al: In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science. 303:844–848. 2004. View Article : Google Scholar : PubMed/NCBI

14 

Shangary S and Wang S: Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy. Annu Rev Pharmacol Toxicol. 49:223–241. 2009. View Article : Google Scholar : PubMed/NCBI

15 

Lee K, Lee MH, Kang YW, Rhee KJ, Kim TU and Kim YS: Parkin induces apoptotic cell death in TNF-α-treated cervical cancer cells. BMB Rep. 45:526–531. 2012.PubMed/NCBI

16 

Wang Z, Zhang Z, Wu Y, et al: Effects of echinomycin on endothelin-2 expression and ovulation in immature rats primed with gonadotropins. Exp Mol Med. 44:615–621. 2012. View Article : Google Scholar : PubMed/NCBI

17 

Lee SY, Shin SJ and Kim HS: ERK1/2 activation mediated by the nutlin-3-induced mitochondrial translocation of p53. Int J Oncol. 42:1027–1035. 2013.PubMed/NCBI

18 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCt method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

19 

Haber DA, Sohn RL, Buckler AJ, Pelletier J, Call KM and Housman DE: Alternative splicing and genomic structure of the Wilms tumor gene WT1. Proc Natl Acad Sci USA. 88:9618–9622. 1991. View Article : Google Scholar : PubMed/NCBI

20 

Green DR and Kroemer G: The pathophysiology of mitochondrial cell death. Science. 305:626–629. 2004. View Article : Google Scholar : PubMed/NCBI

21 

Zhao R, Gish K, Murphy M, et al: Analysis of p53-regulated gene expression patterns using oligonucleotide arrays. Genes Dev. 14:981–993. 2000.PubMed/NCBI

22 

Leu JI, Dumont P, Hafey M, Murphy ME and George DL: Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1 complex. Nat Cell Biol. 6:443–450. 2004. View Article : Google Scholar : PubMed/NCBI

23 

Chipuk JE, Kuwana T, Bouchier-Hayes L, et al: Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science. 303:1010–1014. 2004. View Article : Google Scholar : PubMed/NCBI

24 

Mihara M, Erster S, Zaika A, et al: p53 has a direct apoptogenic role at the mitochondria. Mol Cell. 11:577–590. 2003. View Article : Google Scholar : PubMed/NCBI

25 

Vajjhala PR, Macmillan E, Gonda T and Little M: The Wilms’ tumour suppressor protein, WT1, undergoes CRM1-independent nucleocytoplasmic shuttling. FEBS Lett. 554:143–148. 2003.

26 

Niksic M, Slight J, Sanford JR, Caceres JF and Hastie ND: The Wilms’ tumour protein (WT1) shuttles between nucleus and cytoplasm and is present in functional polysomes. Hum Mol Genet. 13:463–471. 2004.

27 

Tovar C, Rosinski J, Filipovic Z, et al: Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy. Proc Natl Acad Sci USA. 103:1888–1893. 2006. View Article : Google Scholar : PubMed/NCBI

28 

Moreno CS, Matyunina L, Dickerson EB, et al: Evidence that p53-mediated cell-cycle-arrest inhibits chemotherapeutic treatment of ovarian carcinomas. PLoS One. 2:e4412007. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Lee S, Choe Y, Park JY, Lee SS, Kim Y, Shin SJ, Chung YJ and Kim H: Wilms' tumor gene 1 enhances nutlin-3-induced apoptosis. Oncol Rep 31: 131-136, 2014.
APA
Lee, S., Choe, Y., Park, J.Y., Lee, S.S., Kim, Y., Shin, S.J. ... Kim, H. (2014). Wilms' tumor gene 1 enhances nutlin-3-induced apoptosis. Oncology Reports, 31, 131-136. https://doi.org/10.3892/or.2013.2832
MLA
Lee, S., Choe, Y., Park, J. Y., Lee, S. S., Kim, Y., Shin, S. J., Chung, Y. J., Kim, H."Wilms' tumor gene 1 enhances nutlin-3-induced apoptosis". Oncology Reports 31.1 (2014): 131-136.
Chicago
Lee, S., Choe, Y., Park, J. Y., Lee, S. S., Kim, Y., Shin, S. J., Chung, Y. J., Kim, H."Wilms' tumor gene 1 enhances nutlin-3-induced apoptosis". Oncology Reports 31, no. 1 (2014): 131-136. https://doi.org/10.3892/or.2013.2832
Copy and paste a formatted citation
x
Spandidos Publications style
Lee S, Choe Y, Park JY, Lee SS, Kim Y, Shin SJ, Chung YJ and Kim H: Wilms' tumor gene 1 enhances nutlin-3-induced apoptosis. Oncol Rep 31: 131-136, 2014.
APA
Lee, S., Choe, Y., Park, J.Y., Lee, S.S., Kim, Y., Shin, S.J. ... Kim, H. (2014). Wilms' tumor gene 1 enhances nutlin-3-induced apoptosis. Oncology Reports, 31, 131-136. https://doi.org/10.3892/or.2013.2832
MLA
Lee, S., Choe, Y., Park, J. Y., Lee, S. S., Kim, Y., Shin, S. J., Chung, Y. J., Kim, H."Wilms' tumor gene 1 enhances nutlin-3-induced apoptosis". Oncology Reports 31.1 (2014): 131-136.
Chicago
Lee, S., Choe, Y., Park, J. Y., Lee, S. S., Kim, Y., Shin, S. J., Chung, Y. J., Kim, H."Wilms' tumor gene 1 enhances nutlin-3-induced apoptosis". Oncology Reports 31, no. 1 (2014): 131-136. https://doi.org/10.3892/or.2013.2832
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