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.

  • Original Paper
  • Published:

p53 in human embryonal carcinoma: identification of a transferable, transcriptional repression domain in the N-terminal region of p53

Oncogene volume 24, pages 1481–1490 (2005)Cite this article

Abstract

Testicular germ cell tumors (TGCTs) arise despite possessing high levels of wild-type p53, suggesting p53 latency. We have previously shown that p53 repression in TGCT-derived human embryonal carcinoma (EC) is relieved upon treatment with all-trans retinoic acid (RA), resulting in enhanced p53 transactivation activity. To further investigate p53 repression in EC, a series of gal4-p53 truncation constructs were generated. Deletion of the core DNA-binding region, residues 117–274, had no effect on basal or RA-induced p53 activity. Progressively, larger truncations were made in the C- or N-terminal direction. Deletion of residues toward the C-terminus of p53 as far as residue 354 did not affect either the basal or RA-inducible activity of gal4-p53. When a small region in the N-terminus was deleted (residues 105–116), relief of the basal repression of p53 activity characteristic of EC was observed. Fusion of this region to the VP16 activation domain (VPAD) resulted in a 10–20-fold repression of VPAD activity in NT2/D1 human EC cells, indicating that this region acts as a heterologous repressor. Owing to its location in the N-terminal half of p53, we have named this region the p53 N-terminal Repression Domain (p53-NRD). The p53-NRD mediated repression in a variety of cell lines, with the most prominent repression observed in human EC cells. While RA alone had no effect on p53-NRD activity, cotreatment with RA and the histone deacetylase inhibitor trichostatin-A (TSA) completely relieved p53-NRD-mediated repression. In contrast, NRD-mediated repression was not sensitive to RA and TSA in a derived RA-resistant cell line with a retinoic acid receptor gamma (RARγ) defect, but sensitivity could be restored with transfection of RARγ. These data indicate that a unique repressor domain resides in p53 at residues 90–116 whose activity can be modulated in the presence of ‘differentiation therapy’ and ‘transcription therapy’ agents.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  • Andrews PW . (1984). Dev. Biol., 103, 285–293.

  • Andrews PW . (2002). Philos. Trans. R. Soc. London. B. Biol. Sci., 357, 405–417.

  • Bargonetti J, Manfredi JJ, Chen X, Marshak DR and Prives C . (1993). Genes Dev., 7, 2565–2574.

  • Benard J, Douc-Rasy S and Ahomadegbe J . (2003). Hum. Mutat., 21, 182–191.

  • Brooks CL and Gu W . (2003). Curr. Opin. Cell Biol., 15, 164–171.

  • Burger H, Nooter K, Boersma AW, Kortland CJ and Stoter G . (1998). Br. J. Cancer, 77, 1562–1567.

  • Burger H, Nooter K, Boersma AW, van Wingerden KE, Looijenga LH, Jochemsen AG and Stoter G . (1999). Int. J. Cancer, 81, 620–628.

  • Chaganti RS and Houldsworth J . (2000). Cancer Res., 60, 1475–1482.

  • Cho Y, Gorina S, Jeffrey PD and Pavletich NP . (1994). Science, 265, 346–355.

  • Chresta CM, Masters JR and Hickman JA . (1996). Cancer Res., 56, 1834–1841.

  • Curtin JC, Dragnev KH, Sekula D, Christie AJ, Dmitrovsky E and Spinella MJ . (2001). Oncogene, 20, 2559–2569.

  • Einhorn LH . (2002). Chest Surg. Clin. N. Am., 12, 695–706.

  • Ferrara FF, Fazi F, Bianchini A, Padula F, Gelmetti V, Minucci S, Mancini M, Pelicci PG, Lo Coco F and Nervi C . (2001). Cancer Res., 61, 2–7.

  • Freemantle SJ, Kerley JC, Olsen SL, Gross RH and Spinella MJ . (2002). Oncogene, 21, 2880–2889.

  • Freemantle SJ, Spinella MJ and Dmitrovsky E . (2003). Oncogene, 22, 7305–7315.

  • Glass CK and Rosenfeld MG . (2000). Genes Dev., 14, 121–141.

  • Gu J, Rubin RM and Yuan ZM . (2001). Oncogene, 20, 3519–3527.

  • Heimdal K, Lothe RA, Lystad S, Holm R, Fossa SD and Borresen AL . (1993). Genes Chromosomes Cancer, 6, 92–97.

  • Ho J and Benchimol S . (2003). Cell Death and Differ., 10, 404–408.

  • Hoffman WH, Biade S, Zilfou JT, Chen J and Murphy M . (2002). J. Biol. Chem., 277, 3247–3257.

  • Hong WK and Sporn MB . (1997). Science, 278, 1073–1077.

  • Houldsworth J, Xiao H, Murty VV, Chen W, Ray B, Reuter VE, Bosl GJ and Chaganti RS . (1998). Oncogene, 16, 2345–2349.

  • Huyghe E, Matsuda T and Thonneau P . (2003). J. Urol., 170, 5–11.

  • Johnson RA, Ince TA and Scotto KW . (2001). J. Biol. Chem., 276, 27716–27720.

  • Johnstone RW . (2002). Nat. Rev. Drug Discov., 1, 287–299.

  • Jones RH and Vasey PA . (2003). Eur. J. Cancer, 39, 147–156.

  • Juan LJ, Shia WJ, Chen MH, Yang WM, Seto E, Lin YS and Wu CW . (2000). J. Biol. Chem., 275, 20436–20443.

  • Kersemaekers AM, Mayer F, Molier M, van Weeren PC, Oosterhuis JW, Bokemeyer C and Looijenga LH . (2002). J. Clin. Oncol., 20, 1551–1561.

  • Kouraklis G and Theocharis S . (2002). Curr. Med. Chem. Anti-Canc. Agents, 2, 477–484.

  • Langenfeld J, Kiyokawa H, Sekula D, Boyle JO and Dmitrovsky E . (1997). Proc. Natl. Acad. Sci. USA, 94, 12070–12074.

  • Lin RJ, Nagy L, Inoue S, Shao W, Miller WH and Evans RM . (1998). Nature, 391, 811–814.

  • Lippman SM, Lee JJ, Karp DD, Vokes EE, Benner SE, Goodman GE, Khuri FR, Marks R, Winn RJ, Fry W, Graziano SL, Gandara DR, Okawara G, Woodhouse CL, Williams B, Perez C, Kim HW, Lotan R, Roth JA and Hong WK . (2001). J. Natl. Cancer Inst., 93, 605–618.

  • Luo J, Nikolaev AY, Imai S, Chen D, Su F, Shiloh A, Guarente L and Gu W . (2001). Cell, 107, 137–148.

  • Luo J, Su F, Chen D, Shiloh A and Gu W . (2000). Nature, 408, 377–381.

  • Lutzker SG and Levine AJ . (1996). Nat. Med., 2, 804–810.

  • Lutzker SG, Mathew R and Taller DR . (2001). Oncogene, 20, 2982–2986.

  • Mangelsdorf DJ, Umesono K and Evans RM . (1994). The Retinoids: Biology, Chemistry and Medicine Sporn MB, Roberts AB, Goodman DS. (eds). Raven Press, Ltd: New York, pp. 319–349.

    Google Scholar 

  • Moasser MM, Khoo KS, Maerz WJ, Zelenetz A and Dmitrovsky E . (1996). Differentiation, 60, 251–257.

  • Moasser MM, Reuter VE and Dmitrovsky E . (1995). Oncogene, 10, 1537–1543.

  • Nason-Burchenal K and Dmitrovsky E . (1999). Retinoids: Handbook of Experimental Pharmacology. Nau H and Blaner WS. (eds) Springer-Verlag: Berlin, pp. 301–322.

    Book  Google Scholar 

  • Oren M . (2003). Cell Death. Differ., 10, 431–442.

  • Pandolfi PP . (2001). Oncogene, 20, 3116–3127.

  • Pavletich NP, Chambers KA and Pabo CO . (1993). Genes Dev., 7, 2556–2564.

  • Peng HQ, Hogg D, Malkin D, Bailey D, Gallie BL, Bulbul M, Jewett M, Buchanan J and Goss PE . (1993). Cancer Res., 53, 3574–3578.

  • Petti MC, Fazi F, Gentile M, Diverio D, De Fabritiis P, De Propris MS, Fiorini R, Spiriti MA, Padula F, Pelicci PG, Nervi C and Lo Coco F . (2002). Blood, 100, 1065–1067.

  • Ronca F, Yee KS and Yu VC . (1999). J. Biol. Chem., 274, 18128–18134.

  • Shin DM, Mao L, Papadimitrakopoulou VM, Clayman G, El-Naggar A, Shin HJ, Lee JJ, Lee JS, Gillenwater A, Myers J, Lippman SM, Hittelman WN and Hong WK . (2000). J. Natl. Cancer. Inst., 92, 69–73.

  • Shin DM, Xu XC, Lippman SM, Lee JJ, Lee JS, Batsakis JG, Ro JY, Martin JW, Hittelman WN, Lotan R and Hong WK . (1997). Clin. Cancer Res., 3, 875–880.

  • Spinella MJ, Freemantle SJ, Sekula D, Chang JH, Christie AJ and Dmitrovsky E . (1999). J. Biol. Chem., 274, 22013–22018.

  • Spinella MJ, Kerley JS, White K and Curtin JC . (2003). J. Nutr., 133, 273S–276S.

  • Spinella MJ, Kitareewan S, Mellado B, Sekula D, Khoo KS and Dmitrovsky E . (1998). Oncogene, 16, 3471–3480.

  • Sun SY and Lotan R . (2002). Crit. Rev. Oncol. Hematol., 41, 41–55.

  • Varley J . (2003). Methods Mol. Biol., 222, 117–129.

  • Vaziri H, Dessain SK, Ng Eaton E, Imai SI, Frye RA, Pandita TK, Guarente L and Weinberg RA . (2001). Cell, 107, 149–159.

  • Wadgaonkar R and Collins T . (1999). J. Biol. Chem., 274, 13760–13767.

  • Zamble DB, Jacks T and Lippard SJ . (1998). Proc. Natl. Acad. Sci. USA, 95, 6163–6168.

  • Zeng X, Keller D, Wu L and Lu H . (2000). Cancer Res., 60, 6184–6188.

  • Zhou DC, Kim SH, Ding W, Schultz C, Warrell RP and Gallagher RE . (2002). Blood, 99, 1356–1363.

  • Zilfou JT, Hoffman WH, Sank M, George DL and Murphy MT . (2001). Mol. Cell Biol., 21, 3974–3985.

Download references

Acknowledgements

This work was supported by the National Institute of Health Grant K01-CA75154 and the American Cancer Society Grant RSG-01-144-01. We thank Ethan Dmitrovsky for helpful discussion and Aimee Pike and Sarah Freemantle for assistance with Western analysis.

Author information

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH, 03755, USA

    Joshua C Curtin & Michael J Spinella

  2. Norris Cotton Cancer Center, Dartmouth Hitchcock Medical Center, Hanover, NH, 03755, USA

    Michael J Spinella

Authors
  1. Joshua C Curtin
    View author publications

    Search author on:PubMed Google Scholar

  2. Michael J Spinella
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Michael J Spinella.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Curtin, J., Spinella, M. p53 in human embryonal carcinoma: identification of a transferable, transcriptional repression domain in the N-terminal region of p53. Oncogene 24, 1481–1490 (2005). https://doi.org/10.1038/sj.onc.1208130

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/sj.onc.1208130

Keywords

This article is cited by

Search

Advanced search

Quick links