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BID regulation by p53 contributes to chemosensitivity

Abstract

The role of the p53 protein (encoded by TP53) in tumour suppression relies partly on the ability of p53 to regulate the transcription of genes that are important in cell-cycle arrest and in apoptosis. But the apoptotic pathway mediated by p53 is not fully understood. Here we show that BID, a member of the pro-apoptotic Bcl-2 family of proteins, is regulated by p53. BID mRNA is increased in a p53-dependent manner in vitro and in vivo, with strong expression in the splenic red pulp and colonic epithelium of γ-irradiated mice. Both the human and the mouse BID genomic loci contain p53-binding DNA response elements that bind p53 and mediate p53-dependent transactivation of a reporter gene. In addition, BID-null mouse embryonic fibroblasts are more resistant than are wild-type fibroblasts to the DNA damaging agent adriamycin and the nucleotide analogue 5-fluorouracil, both of which stabilize endogenous p53. Our results indicate that BID is a p53-responsive 'chemosensitivity gene' that may enhance the cell death response to chemotherapy.

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Figure 1: Identification of BID as a p53 transcriptionally regulated gene.
Figure 2: Induction of BID mRNA in response to DNA damage.
Figure 3: EMSANI of potential p53-binding elements in BID genomic loci.
Figure 4: Luciferase and ChIP assays using BID genomic regions.
Figure 5: BID−/− MEFs show resistance to adriamycin and 5-FU.

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References

  1. Ryan, K. M., Phillips, A. C. & Vousden, K. H. Regulation and function of the p53 tumor suppressor protein. Curr. Opin. Cell Biol. 13, 332–337 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. El-Deiry, W. S. Insights into cancer therapeutic design based on p53 and TRAIL receptor signaling. Cell Death Differ. 8, 1066–1075 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. El-Deiry, W. S. et al. WAF1, a potential mediator of p53 tumor suppression. Cell 75, 817–825 (1993).

    Article  CAS  PubMed  Google Scholar 

  4. Attardi, L. D. et al. PERP, an apoptosis-associated target of p53, is a novel member of the PMP-22/gas3 family. Genes Dev. 14, 704–718 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Lin, Y., Ma, W. & Benchimol, S. Pidd, a new death-domain-containing protein, is induced by p53 and promotes apoptosis. Nature Genet. 26, 122–127 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Miyashita, T. & Reed, J. C. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 80, 293–299 (1995).

    Article  CAS  PubMed  Google Scholar 

  7. Nakano, K. & Vousden, K. H. PUMA, a novel proapoptotic gene, is induced by p53. Mol. Cell 7, 683–694 (2001).

    Article  CAS  PubMed  Google Scholar 

  8. Oda, E. et al. Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science 288, 1053–1058 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Yu, J., Zhang, L., Hwang, P. M., Kinzler, K. W. & Vogelstein, B. PUMA induces the rapid apoptosis of colorectal cancer cells. Mol. Cell 7, 673–682 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Wu, G. S. et al. KILLER/DR5 is a DNA damage-inducible p53-regulated death receptor gene. Nature Genet. 17, 141–143 (1997).

    Article  CAS  PubMed  Google Scholar 

  11. Wu, G. S., Burns, T. F., Zhan, Y., Alnemri, E. S. & El-Deiry, W. S. Molecular cloning and functional analysis of the mouse homologue of the KILLER/DR5 tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor. Cancer Res. 59, 2770–2775 (1999).

    CAS  PubMed  Google Scholar 

  12. Muller, M. et al. p53 activates the CD95 (APO-1/Fas) gene in response to DNA damage by anticancer drugs. J. Exp. Med. 188, 2033–2045 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Murphy, M. et al. Transcriptional repression by wild-type p53 utilizes histone deacetylases, mediated by interaction with mSin3a. Genes Dev. 13, 2490–2501 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hoffman, W. H., Biade, S., Zilfou, J. T., Chen, J. & Murphy, M. Transcriptional repression of the anti-apoptotic survivin gene by wild type p53. J. Biol. Chem. 277, 3247–3257 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Adams, J. M. & Cory, S. The Bcl-2 protein family: arbiters of cell survival. Science 281, 1322–1326 (1998).

    Article  CAS  PubMed  Google Scholar 

  16. Wang, K., Yin, X. M., Chao, D. T., Milliman, C. L. & Korsmeyer, S. J. BID: a novel BH3 domain-only death agonist. Genes Dev. 10, 2859–2869 (1996).

    Article  CAS  PubMed  Google Scholar 

  17. Li, H., Zhu, H., Xu, C. J. & Yuan, J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94, 491–501 (1998).

    Article  CAS  PubMed  Google Scholar 

  18. Luo, X., Budihardjo, I., Zou, H., Slaughter, C. & Wang, X. Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94, 481–490 (1998).

    Article  CAS  PubMed  Google Scholar 

  19. Zha, J., Weiler, S., Oh, K. J., Wei, M. C. & Korsmeyer, S. J. Posttranslational N-myristoylation of BID as a molecular switch for targeting mitochondria and apoptosis. Science 290, 1761–1765 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Wei, M. C. et al. tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev. 14, 2060–2071 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Wei, M. C. et al. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292, 727–730 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gross, A. et al. Caspase cleaved BID targets mitochondria and is required for cytochrome c release, while BCL-XL prevents this release but not tumor necrosis factor-R1/Fas death. J. Biol. Chem. 274, 1156–1163 (1999).

    Article  CAS  PubMed  Google Scholar 

  23. Yin, X. M. et al. Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosis. Nature 400, 886–891 (1999).

    Article  CAS  PubMed  Google Scholar 

  24. Scaffidi, C. et al. Two CD95 (APO-1/Fas) signaling pathways. EMBO J. 17, 1675–1687 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Scorrano, L. et al. A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis. Dev. Cell 2, 55–67 (2002).

    Article  CAS  PubMed  Google Scholar 

  26. Harvey, D. M. & Levine, A. J. p53 alteration is a common event in the spontaneous immortalization of primary BALB/c murine embryo fibroblasts. Genes Dev. 5, 2375–2385 (1991).

    Article  CAS  PubMed  Google Scholar 

  27. Chen, J., Wu, X., Lin, J. & Levine, A. J. mdm-2 inhibits the G1 arrest and apoptosis functions of the p53 tumor suppressor protein. Mol. Cell. Biol. 16, 2445–2452 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wang, Y. et al. Reconstitution of wild-type p53 expression triggers apoptosis in a p53-negative v-myc retrovirus-induced T-cell lymphoma line. Cell Growth Differ. 4, 467–473 (1993).

    CAS  PubMed  Google Scholar 

  29. Pritchard, D. M., Potten, C. S., Korsmeyer, S. J., Roberts, S. & Hickman, J. A. Damage-induced apoptosis in intestinal epithelia from bcl-2-null and bax-null mice: investigations of the mechanistic determinants of epithelial apoptosis in vivo. Oncogene 18, 7287–7293 (1999).

    Article  CAS  PubMed  Google Scholar 

  30. Lowe, S. W., Schmitt, E. M., Smith, S. W., Osborne, B. A. & Jacks, T. p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature 362, 847–849 (1993).

    Article  CAS  PubMed  Google Scholar 

  31. Midgley, C. A. et al. Coupling between gamma irradiation, p53 induction and the apoptotic response depends upon cell type in vivo. J. Cell Sci. 108, 1843–1848 (1995).

    CAS  PubMed  Google Scholar 

  32. Burns, T. F., Bernhard, E. J. & El-Deiry, W. S. Tissue specific expression of p53 target genes suggests a key role for KILLER/DR5 in p53-dependent apoptosis in vivo. Oncogene 20, 4601–4612 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Wang, K. et al. BID, a proapoptotic BCL-2 family member, is localized to mouse chromosome 6 and human chromosome 22q11. Genomics 53, 235–238 (1998).

    Article  CAS  PubMed  Google Scholar 

  34. El-Deiry, W. S., Kern, S. E., Pietenpol, J. A., Kinzler, K. W. & Vogelstein, B. Definition of a consensus binding site for p53. Nature Genet. 1, 45–49 (1992).

    Article  CAS  PubMed  Google Scholar 

  35. Vousden, K. H. & Lu, X. Live or let die: the cell's response to p53. Nature Rev. Cancer 2, 594–604 (2002).

    Article  CAS  Google Scholar 

  36. Kaeser, M. D. & Iggo, R. D. From the cover: chromatin immunoprecipitation analysis fails to support the latency model for regulation of p53 DNA binding activity in vivo. Proc. Natl Acad. Sci. USA 99, 95–100 (2002).

    Article  CAS  PubMed  Google Scholar 

  37. Oda, K. et al. p53AIP1, a potential mediator of p53-dependent apoptosis, and its regulation by Ser-46-phosphorylated p53. Cell 102, 849–862 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Costanzo, A. et al. DNA damage-dependent acetylation of p73 dictates the selective activation of apoptotic target genes. Mol. Cell 9, 175–186 (2002).

    Article  CAS  PubMed  Google Scholar 

  39. Bunz, F. et al. Disruption of p53 in human cancer cells alters the responses to therapeutic agents. J. Clin. Invest. 104, 263–269 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. MacLachlan, T. K. & El-Deiry, W. S. Apoptotic threshold is lowered by p53 transactivation of caspase-6. Proc. Natl Acad. Sci. USA 99, 9492–9497 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Moroni, M. C. et al. Apaf-1 is a transcriptional target for E2F and p53. Nature Cell Biol. 3, 552–558 (2001).

    Article  CAS  PubMed  Google Scholar 

  42. Zeng, Y. X. & El-Deiry, W. S. Regulation of p21WAF1/CIP1 expression by p53-independent pathways. Oncogene 12, 1557–1564 (1996).

    CAS  PubMed  Google Scholar 

  43. Sax, J. K., Dash, B. C., Hong, R., Dicker, D. T. & El-Deiry, W. S. The cyclin-dependent kinase inhibitor butyrolactone is a potent inhibitor of p21(WAF1/CIP1) expression. Cell Cycle 1, 90–96 (2002).

    CAS  PubMed  Google Scholar 

  44. Kadkol, S., Juang, J. & Wu, T. C. in Tumor Suppressor Genes: Regulations, Functions and Medicinal Applications Vol. 2 (ed. El-Deiry, W. S.) (Humana Press, Totowa, NJ, 2003).

    Google Scholar 

  45. Somasundaram, K. et al. Arrest of the cell cycle by the tumour-suppressor BRCA1 requires the CDK-inhibitor p21WAF1/CIP1. Nature 389, 187–190 (1997).

    Article  CAS  PubMed  Google Scholar 

  46. MacLachlan, T. K. et al. BRCA1 effects on the cell cycle and the DNA damage response are linked to altered gene expression. J. Biol. Chem. 275, 2777–2785 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Pietenpol, J. A. et al. Sequence-specific transcriptional activation is essential for growth suppression by p53. Proc. Natl Acad. Sci. USA 91, 1998–2002 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zeng, Y. X., Somasundaram, K., Prabhu, N. S., Krishnadasan, R. & El-Deiry, W. S. Detection and analysis of living, growth-inhibited mammalian cells following transfection. Biotechniques 23, 88–94 (1997).

    Article  CAS  PubMed  Google Scholar 

  49. Takimoto, R. & El-Deiry, W. S. Wild-type p53 transactivates the KILLER/DR5 gene through an intronic sequence-specific DNA-binding site. Oncogene 19, 1735–1743 (2000).

    Article  CAS  PubMed  Google Scholar 

  50. Szak, S. T., Mays, D. & Pietenpol, J. A. Kinetics of p53 binding to promoter sites in vivo. Mol. Cell. Biol. 21, 3375–3386 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank D. Dicker for assistance with flow cytometry. This work was supported by the Howard Hughes Medical Institute and by grants from the NIH.

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Correspondence to Wafik S. El-Deiry.

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Figure S1. Additional EMSANI of both the human and mouse p53 binding elements. (PDF 252 kb)

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Sax, J., Fei, P., Murphy, M. et al. BID regulation by p53 contributes to chemosensitivity. Nat Cell Biol 4, 842–849 (2002). https://doi.org/10.1038/ncb866

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