Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Short Report
  • Published:

A serine 37 mutation associated with two missense mutations at highly conserved regions of p53 affect pro-apoptotic genes expression in a T-lymphoblastoid drug resistant cell line

Oncogene volume 19, pages 5098–5105 (2000)Cite this article

Abstract

The p53 protein accumulates rapidly through post-transcriptional mechanisms following cellular exposure to DNA damaging agents and is also activated as a transcription factor leading to growth arrest or apoptosis. Phosphorylation of p53 occurs after DNA damage thereby modulating its activity and impeding the interaction of p53 with its negative regulator oncogene Mdm2. The serines 15 and 37 present in the amino terminal region of p53 are phosphorylated by the DNA-dependent protein kinase (DNA-PK) in response to DNA damage. In order to verify if specific p53 mutations occur in the multi-drug resistance phenotype, we analysed the p53 gene in two T-lymphoblastoid cell lines, CCRF-CEM and its multi-drug-resistant clone CCRF-CEM VLB100, selected for resistance to vinblastine sulfate and cross-resistant to other cytotoxic drugs. Both cell lines showed two heterozygous mutations in the DNA binding domain at codons 175 and 248. The multi-drug resistant cell line, CCRF-CEM VLB100, showed an additional mutation that involves the serine 37 whose phosphorylation is important to modulate the protein activity in response to DNA damage. The effects of these mutations on p53 transactivation capacity were evaluated. The activity of p53 on pro-apoptotic genes expression in response to DNA damage induced by (-irradiation, was affected in the vinblastine (VLB) resistant cell line but not in CCRF-CEM sensitive cell line resulting in a much reduced apoptotic cell death of the multi-drug resistant cells.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  • Adler V, Pincus MR, Minamoto T, Fuchs SY, Bluth M, Brandt-Rauf PW, Friedman FK, Robinson RC, Chen JM, Wang XW, Harris CC and Ronai Z. . 1997 Proc. Natl. Acad. Sci. USA 94: 1686–1691.

  • Blandino G, Levine AJ and Oren M. . 1999 Oncogene 18: 477–485.

  • Cheng J and Haas M. . 1990 Mol. Cell. Biol. 10: 5502–5509.

  • Cianfriglia M, Yassen A, Tombesi M, Samoggia P, Barca S and Caserta M. . 1991 Int. J. Cancer 49: 394–397.

  • Claudio PP, Howard CM, Baldi A, De Luca A, Condorelli G, Sun Y, Colburn N, Calabretta B and Giordano A. . 1994 Cancer Res. 54: 5556–5560.

  • Cohen JJ, Duke RC, Fadok VA and Sellins KS. . 1992 Annu. Rev. Immunol. 10: 267–293.

  • Delia D, Mizutani S, Lamorte G, Goi K, Iwata S and Pierotti MA. . 1996 Nat. Med. 2: 724–725.

  • Diller L, Kassel J, Nelson CE, Gryka MA, Litwak G, Gebhardt M, Bressac B, Ozturk M, Baker SJ, Volgestein B and Friend SH. . 1990 Mol.Cell. Biol. 10: 5772–5781.

  • Fields S and Jang SK. . 1990 Science 249: 1046–1049.

  • Finnie NJ, Gottlieb TM, Blunt T, Jeggo PA and Jackson SP. . 1995 Proc. Natl. Acad. Sci. USA 92: 320–324.

  • Fiscella M, Ullrich SJ, Zambrano N, Shield MT, Lin D, Lees-Miller SP, Anderson CW, Mercer WE and Appella E. . 1993 Oncogene 8: 1519–1528.

  • Friedlander P, Haupt Y, Prives C and Oren M. . 1996 Mol. Cell. Biol. 16: 4961–4971.

  • Fritsher M, Haessler C and Brandner G. . 1993 Oncogene 8: 307–318.

  • Harris CC and Hollstein M. . 1993 N. Engl. J. Med. 329: 1318–1327.

  • Hecker D, Page G, Lohrum M, Weiland S and Scheidtmann KH. . 1996 Oncogene 12: 953–961.

  • Hollstein M, Sidransky D, Volgestein B and Harris CC. . 1991 Science 253: 49–52.

  • Hooper ML. . 1994 J. Cell. Sci. Supp. 18: 13–17.

  • Houldsworth J, Xiao H, Murty VVVS, Chen W, Ray B, Reuter VE, Bosl GJ and Chaganti RSK. . 1998 Oncogene 16: 2345–2349.

  • Igata E, Inoue T, Ohtani-Fujita N, Sowa Y, Tsujimoto Y and Sakai T. . 1999 Gene. 238: 407–415.

  • Karin M and Hunter T. . 1995 Curr. Biol. 5: 747–757.

  • Kastan MB, Zhan Q, El-deiry WS, Carrier F, Jacks T, Walsh WV, Plunkett BS, Volgelstein B and Fornace JR. AJ. . 1992 Cell 71: 589–597.

  • Kerbel RS. . 1997 Nature 390: 335–336.

  • Ko LJ and Prives C. . 1996 Genes Dev. 10: 1054–1078.

  • Lees-Miller SP, Godbout R, Chan DW, Weinfeld M, Day III RS, Barron GM and Allalunis-Turner J. . 1995 Science 267: 1183–1185.

  • Lees-Miller SP, Sakaguchi K, Ullrich SJ, Appella E, Anderson CW. . 1992 Mol. Cell. Biol. 12: 5041–5049.

  • Levine A. . 1993 Annu. Rev. Biochem. 62: 623–651.

  • Levine AJ. . 1997 Cell 88: 323–331.

  • Levine AJ, Momand J and Finday CA. . 1991 Nature 351: 453–456.

  • Lowe SW, Ruley HE, Jack T and Housman DE. . 1993 Cell 74: 957–967.

  • Lu X and Lane DP. . 1993 Cell 75: 765–778.

  • Mayr GA, Reed M, Wang P, Wang Y, Schwedes JF and Tegtmeyer P. . 1995 Cancer. Res. 55: 2410–2417.

  • McCurrach ME, Connor TM, Knudson CM, Korsmeyer SJ and Lowe SW. . 1997 Proc. Natl. Acad. Sci. USA 94: 2345–2349.

  • Meek DW. . 1997 Semin. Cancer Biol. 5: 203–210.

  • Milczarek GJ, Martinez J and Bowden GT. . 1997 Life Sci. 60: 1–11.

  • Miyashite T and Reed JC. . 1995 Cell 80: 293–299.

  • Moyret C, Theillet C, Puig PL, Molés JP, Thomas G and Hamelin R. . 1994 Oncogene 9: 1739–1743.

  • Nelson WG and Kastan MB. . 1994 Mol. Cell. Biol. 14: 1815–1823.

  • Oltvai ZN, Milliman CL and Korsmeyer SJ. . 1993 Cell 74: 609–619.

  • Osifchin NE, Jiang D, Ohtani-Fujita N, Fujita T, Carroza M, Kim SJ, Sakai T and Robbins PD. . 1994 J. Biol. Chem. 269: 6383–6389.

  • Park D, Nakamura H, Chumakov AM, Said JW, Miller CW, Chen DL and Koeffler HP. . 1994 Oncogene 9: 1899–1906.

  • Polyak K, Waldman T, He TC, Kinzler KW and Volgelstein B. . 1996 Genes Dev. 10: 1945–1952.

  • Righetti SC, Della Torre G, Pilotti S, Ménard S, Ottone F, Colnaghi MI, Pierotti MA, Lavarino C, Cornarotti M, Oriana S, Bohm S, Bresciani GL, Spatti G and Zunino F. . 1996 Cancer Res. 56: 689–693.

  • Sang N, Baldi A and Giordano A. . 1995 Mol. Cell. Dif. 3: 1–29.

  • Shelling AM. . 1997 Lancet 349: 744–745.

  • Shieh SY, Ikeda M, Taya Y and Prives C. . 1997 Cell 91: 325–334.

  • Shiio Y, Yamamoto T and Yamaguchi N. . 1992 Proc. Natl. Acad. Sci. USA 89: 5206–5210.

  • Tishler RB, Lamppu DM, Park S and Price BD. . 1995 Cancer Res. 55: 6021–6025.

  • Ullrich SJ, Anderson CW, Mercer WE and Appella E. . 1992 J. Biol. Chem. 267: 15259–15262.

  • Ullrich SJ, Sakaguchi K, Lees-Miller S, Fiscella M, Mercer WE, Anderson CW and Appella E. . 1993 Proc. Natl. Acad. Sci. USA 90: 5954–5958.

  • Unger T, Nau MN, Segal S and Minna JD. . 1992 EMBO J. 11: 1383–1392.

  • White B. . 1996 Genes Dev. 10: 1–15.

  • Williams GT and Smith CA. . 1993 Cell 74: 777–779.

Download references

Acknowledgements

The authors thank Dr WS El-Deiry of Howard Hughes Medical Institute, Philadelphia, USA, for providing the luciferase p21/WAF1 promoter (P21Luc) and luciferase p53 promoter (PG13PYLuc); Prof T Sakai of Kyoto Prefectural University of Medicine, Kyoto, Japan for providing the luciferase human Bax promoter (PhBaxPF). We also thank Dr M Cianfriglia for the CCRF-CEM VLB100 line and Dr N Zini for providing the electron microscopy images. This work was supported by 40–60% MURST, by ‘Piani potenziamento della rete scientifica e tecnologica’ MURST, by ‘Funds for Selected Research Topics’ from University of Bologna by ‘IOR Ricerca Corrente’ and CNR grants to C Cinti; by NIH RO1 CA 60999-01A1 and P01 NS 36466 grants to A Giordano; by AIRC and Ministero Sanità grants to MG Paggi; by F.I.R.C. grant to A De Luca; by C.N.R. ‘Target Project on Biotechnology’ grant to M D'Esposito. PP Claudio is the recipient of a fellowship from the ‘Associazione Leonardo di Capua’, Naples, Italy.

Author information

Authors and Affiliations

  1. Institute of Normal and Pathologic Cytomorphology, CNR, c/o IOR, Bologna, 40136, Italy

    Caterina Cinti & Nadir Mario Maraldi

  2. Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, 19107, Pennsylvania, PA, USA

    Caterina Cinti, Pier Paolo Claudio, Candace M Howard & Antonio Giordano

  3. >Department of ‘Scienze Odontostomatologiche e Maxillo-Facciali', University of Naples ‘Federico II', Napoli, 80131, Italy

    Pier Paolo Claudio

  4. Laboratory for Cell Metabolism and Pharmacokinetics, Center for Experimental Research, Regina Elena Institute, 00158, Roma, Italy

    Antonio De Luca & Marco G Paggi

  5. Genome Research and Sequencing Laboratory, International Institute of Genetics and Biophysics, CNR, 80125, Napoli, Italy

    Monica Cuccurese & Maurizio D'Esposito

  6. Departement of Molecular Oncology, The Wistar Institute, Philadelphia, 19104-4268, Pennsylvania, PA, USA

    Thanos D Halazonetis

  7. Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, 19107, Pennsylvania, PA, USA

    Livio Azzoni

  8. Laboratory of Cell Biology and Electron Microscopy, IOR, Bologna, 40136, Italy

    Dario La Sala & Nadir Mario Maraldi

Authors
  1. Caterina Cinti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pier Paolo Claudio
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Antonio De Luca
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Monica Cuccurese
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Candace M Howard
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Maurizio D'Esposito
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Marco G Paggi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dario La Sala
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Livio Azzoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Thanos D Halazonetis
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Antonio Giordano
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Nadir Mario Maraldi
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cinti, C., Claudio, P., De Luca, A. et al. A serine 37 mutation associated with two missense mutations at highly conserved regions of p53 affect pro-apoptotic genes expression in a T-lymphoblastoid drug resistant cell line. Oncogene 19, 5098–5105 (2000). https://doi.org/10.1038/sj.onc.1203848

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1203848

Keywords

This article is cited by

Search

Advanced search

Quick links