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:

ΔNp63α functions as both a positive and a negative transcriptional regulator and blocks in vitro differentiation of murine keratinocytes

Oncogene volume 22, pages 3635–3644 (2003)Cite this article

Abstract

ΔNp63 is overexpressed in squamous carcinomas where it is associated with proliferation and is believed to enhance cell growth by blocking p53-mediated transactivation. In normal epithelium, ΔNp63α protein expression is abundant in basal cells and decreases with differentiation. To explore the biological consequences of ΔNp63α overexpression in relation to squamous carcinogenesis, we evaluated its effect on normal squamous differentiation and p53 transactivation function in keratinocytes. Forced overexpression of ΔNp63α in primary murine keratinocytes in vitro inhibits morphological differentiation induced by elevated extracellular [Ca2+], abrogates Ca2+-induced growth arrest, and blocks expression of maturation-specific proteins keratin 10 and filaggrin. This suggests that ΔNp63 overexpression in squamous carcinomas may serve to maintain the basal cell phenotype and promote cell survival. ΔNp63α blocks transactivation of p53 responsive reporter constructs mediated by endogenous or exogenous p53 at 17 h postinfection, as expected. However, at 41 h, when p53-mediated transactivation is diminished, ΔNp63α enhances transactivation of these reporter constructs by 2.2–12-fold over control. Maximal ΔNp63α-induced transactivation requires intact p53 responsive elements, but is independent of cellular p53 status. This positive transcriptional function of ΔNp63α appears to be cell-type specific, as it is not observed in primary dermal fibroblasts or Saos-2 cells. These findings support ΔNp63α as a master regulator of keratinocyte differentiation, and suggest a novel function of this protein in the maintenance of epithelial homeostasis.

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
Figure 4
Figure 5

Similar content being viewed by others

Abbreviations

β-gal:

β-galactosidase

DMEM:

Dulbecco's modified Eagle's medium

MOI:

multiplicity of infection

Ad-ΔNp63α:

overexpression of ΔNp63α mediated by adenovirus

References

  • Bamberger C and Schmale H . (2001). FEBS Lett., 501, 121–126.

  • Becker TC, Noel RJ, Coats WS, Gomez-Foix AM, Alam T, Gerard RD and Newgard CB . (1994). Methods Cell Biol., 43(Part A), 161–189.

  • Crook T, Nicholls JM, Brooks L, O'Nions J and Allday MJ . (2000). Oncogene, 19, 3439–3444.

  • Davison TS, Vagner C, Kaghad M, Ayed A, Caput D and Arrowsmith CH . (1999). J. Biol. Chem., 274, 18709–18714.

  • De Laurenzi V, Rossi A, Terrinoni A, Barcaroli D, Levrero M, Costanzo A, Knight RA, Guerrieri P and Melino G . (2000). Biochem. Biophys. Res. Commun., 273, 342–346.

  • Dellavalle RP, Egbert TB, Marchbank A, Su LJ, Lee LA and Walsh P . (2001). J. Dermatol. Sci., 27, 82–87.

  • Di Como CJ, Urist MJ, Babayan I, Drobnjak M, Hedvat CV, Teruya-Feldstein J, Pohar K, Hoos A and Cordon-Cardo C . (2002). Clin. Cancer Res., 8, 494–501.

  • Dohn M, Zhang S and Chen X . (2001). Oncogene, 20, 3193–3205.

  • Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery Jr CA, Butel JS and Bradley A . (1992). Nature, 356, 215–221.

  • Duijf PH, Vanmolkot KR, Propping P, Friedl W, Krieger E, McKeon F, Dotsch V, Brunner HG and van Bokhoven H . (2002). Hum. Mol. Genet., 11, 799–804.

  • Gaiddon C, Lokshin M, Ahn J, Zhang T and Prives C . (2001). Mol. Cell. Biol., 21, 1874–1887.

  • Glickman JN, Yang A, Shahsafaei A, McKeon F and Odze R . (2001). Hum. Pathol., 32, 1157–1165.

  • Hermeking H, Lengauer C, Polyak K, He TC, Zhang L, Thiagalingam S, Kinzler KW and Vogelstein B . (1997). Mol. Cell, 1, 3–11.

  • Hibi K, Trink B, Patturajan M, Westra WH, Caballero OL, Hill DE, Ratovitski EA, Jen J and Sidransky D . (2000). Proc. Natl. Acad. Sci. USA, 97, 5462–5467.

  • Hu H, Xia S-H, Li A-D, Xu X, Cai Y, Han Y-L, Wei F, Chen B-S, Huang X-P, Han Y-S, Zhang J-W, Zhang X, Wu M and Wang M-R . (2002). Int. J. Cancer, 102, 580–583.

  • Irwin MS and Kaelin WG . (2001). Cell Growth Differ., 12, 337–349.

  • Ishida S, Yamashita T, Nakaya U and Tokino T . (2000). Jpn. J. Cancer Res., 91, 174–180.

  • Kaghad M, Bonnet H, Yang A, Creancier L, Biscan J, Valent A, Minty A, Chalon P, Lelias J, Dumont X, Ferrara P, McKeon R and Caput D . (1997). Cell, 90, 809–819.

  • Kemp CJ, Donehower LA, Bradley A and Balmain A . (1993). Cell, 74, 813–822.

  • Kern SE, Kinzler KW, Bruskin A, Jarosz D, Friedman P, Prives C and Vogelstein B . (1991). Science, 252, 1708–1711.

  • Klein C, Georges G, Kunkele KP, Huber R, Engh RA and Hansen S . (2001). J. Biol. Chem., 276, 37390–37401.

  • Lee LA, Walsh P, Prater CA, Su LJ, Marchbank A, Egbert TB, Dellavalle RP, Targoff IN, Kaufman KM, Chorzelski TP and Jablonska S . (1999). J. Invest. Dermatol., 113, 146–151.

  • Liefer KM, Koster MI, Wang XJ, Yang A, McKeon F and Roop DR . (2000). Cancer Res., 60, 4016–4020.

  • Mills AA, Zheng B, Wang XJ, Vogel H, Roop DR and Bradley A . (1999). Nature, 398, 708–713.

  • Missero C, Calautti E, Eckner R, Chin J, Tsai LH, Livingston DM and Dotto GP . (1995). Proc. Natl. Acad. Sci. USA, 92, 5451–5455.

  • Moll UM, Erster S and Zaika A . (2001). Biochim. Biophys. Acta, 1552, 47–59.

  • Osada M, Ohba M, Kawahara C, Ishioka C, Kanamaru R, Katoh I, Ikawa Y, Nimura Y, Nakagawara A, Obinata M and Ikawa S . (1998). Nat. Med., 4, 839–843.

  • Parsa R, Yang A, McKeon F and Green H . (1999). J. Invest. Dermatol., 113, 1099–1105.

  • Patturajan M, Nomoto S, Sommer M, Fomenkov A, Hibi K, Zangen R, Poliak N, Califano J, Trink B, Ratovitski E and Sidransky D . (2002). Cancer Cell, 1, 369–379.

  • Pelosi G, Pasini F, Stenholm CO, Pastorino U, Maisonneuve P, Sonzogni A, Maffini F, Pruneri G, Fraggetta F, Cavallon A, Roz E, Iannucci A, Bresaola E, and Viale G . (2002). J. Pathol., 198, 100–109.

  • Ratovitski EA, Patturajan M, Hibi K, Trink B, Yamaguchi K and Sidransky D . (2001). Proc. Natl. Acad. Sci. USA, 98, 1817–1822.

  • Reis-Filho JS, Torio B, Albergaria A and Schmitt FC . (2002). J. Cutan. Pathol., 29, 517–523.

  • Senoo M, Matsumura Y and Habu S . (2002). Oncogene, 21, 2455–2465.

  • Senoo M, Seki N, Ohira M, Sugano S, Watanabe M, Inuzuka S, Okamoto T, Tachibana M, Tanaka T, Shinkai Y and Kato H . (1998). Biochem. Biophys. Res. Commun., 248, 603–607.

  • Senoo M, Tsuchiya I, Matsumura Y, Mori T, Saito Y, Kato H, Okamoto T and Habu S . (2001). Br. J. Cancer, 84, 1235–1241.

  • Serber Z, Lai HC, Yang A, Ou HD, Sigal MS, Kelly AE, Darimont BD, Duijf PHG, van Bokhoven H, McKeon F and Dotsch V . (2002). Mol. Cell. Biol., 22, 8601–8611.

  • Shimada A, Kato S, Enjo K, Osada M, Ikawa Y, Kohno K, Obinata M, Kanamaru R, Ikawa S and Ishioka C . (1999). Cancer Res., 59, 2781–2786.

  • Trink B, Okami K, Wu L, Sriuranpong V, Jen J and Sidransky D . (1998). Nat. Med., 4, 747–748.

  • Veri MC, DeBell KE, Seminario MC, DiBaldassarre A, Reischl I, Rawat R, Graham L, Noviello C, Rellahan BL, Miscia S, Wange RL and Bonvini E . (2001). Mol. Cell. Biol., 21, 6939–6950.

  • Weinberg WC, Azzoli CG, Chapman K, Levine AJ and Yuspa SH . (1995). Oncogene, 10, 2271–2279.

  • Weinberg WC, Azzoli CG, Kadiwar N and Yuspa SH . (1994). Cancer Res., 54, 5584–5592.

  • Yamaguchi K, Wu L, Cabellero OL, Hibi K, Trink B, Resto V, Cairns P, Okami K, Koch WM, Sidransky D and Jen J . (2000). Int. J. Cancer, 86, 684–689.

  • Yang A, Kaghad M, Caput D and McKeon F . (2002). Trends Genet., 18, 90–95.

  • Yang A, Kaghad M, Wang Y, Gillett E, Fleming MD, Dotsch V, Andrews NC, Caput D and McKeon F . (1998). Mol. Cell, 2, 305–316.

  • Yang A and McKeon F . (2000). Nat. Rev. Mol. Cell Biol., 1, 199–207.

  • Yang A, Schweitzer R, Sun D, Kaghad M, Walker N, Bronson RT, Tabin C, Sharpe A, Caput D, Crum C and McKeon F . (1999). Nature, 398, 714–718.

  • Yang A, Walker N, Bronson R, Kaghad M, Oosterwegel M, Bonnin J, Vagner C, Bonnet H, Dikkes P, Sharpe A, McKeon F and Caput D . (2000). Nature, 404, 99–103.

  • Yuspa SH, Kilkenny AE, Steinert PM and Roop DR . (1989). J. Cell. Biol., 109, 1207–1217.

  • Ziegler A, Jonason AS, Leffell DJ, Simon JA, Sharma HW, Kimmelman J, Remington L, Jacks T and Brash DE . (1994). Nature, 372, 773–776.

Download references

Acknowledgements

We are grateful to Dr Bert Vogelstein for providing the p53-responsive reporter plasmids, and to Dr David Sidransky for the adenovirus encoding p40 and matched vector control. We thank Laurie Graham for assistance with the FACSCalibur. This project was supported in part by an appointment to the Research Participation Program at CBER/FDA administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the US Food and Drug Administration.

Author information

Authors and Affiliations

  1. Center for Biologics Evaluation and Research, FDA, Bethesda, 20892, MD, USA

    Kathryn E King, Roshini M Ponnamperuma & Wendy C Weinberg

  2. Sapporo Medical University School of Medicine, Sapporo, 060-8556, Japan

    Toshiharu Yamashita & Takashi Tokino

  3. University of Colorado School of Medicine and Denver Health Medical Center, Denver, 80262, CO, USA

    Lela A Lee

  4. National Institute of Dental and Craniofacial Research, NIH, Bethesda, 20892, MD, USA

    Marian F Young

Authors
  1. Kathryn E King
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Roshini M Ponnamperuma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Toshiharu Yamashita
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Takashi Tokino
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lela A Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marian F Young
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wendy C Weinberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wendy C Weinberg.

Rights and permissions

Reprints and permissions

About this article

Cite this article

King, K., Ponnamperuma, R., Yamashita, T. et al. ΔNp63α functions as both a positive and a negative transcriptional regulator and blocks in vitro differentiation of murine keratinocytes. Oncogene 22, 3635–3644 (2003). https://doi.org/10.1038/sj.onc.1206536

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1206536

Keywords

This article is cited by

Search

Advanced search

Quick links