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 Article
  • Published:

Activation of p38- and CRM1-dependent nuclear export promotes E2F1 degradation during keratinocyte differentiation

Oncogene volume 26, pages 1147–1154 (2007)Cite this article

Abstract

E2F factors modulate a plethora of cell functions, including proliferation, differentiation, DNA repair and apoptosis. We have shown that differentiation in primary epidermal keratinocytes leads to E2F1 downregulation via activation of protein kinase C and p38 mitogen-activated protein kinase. We now demonstrate that E2F1 downregulation in differentiating keratinocytes involves its ubiquitination, as well as proteasomal degradation subsequent to CRM1-dependent nuclear export. E2F1 nuclear export specifically in response to differentiation requires regions adjacent to the cyclin A-binding domain in the N-terminus of this protein. Significantly, inhibition of p38 interferes with nuclear export and degradation of E2F1 during differentiation, but has no effect on E2F1 in undifferentiated cells. Thus, induction of differentiation in epidermal keratinocytes activates a specific program for post-transcriptional downregulation of E2F1, which involves signaling through p38 and activation of nuclear export pathways.

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
Figure 6

Similar content being viewed by others

References

  • Apostolova MD, Ivanova IA, Dagnino C, D'Souza SJA, Dagnino L . (2002). Active import and export mechanisms regulate E2F-5 subcellular localization. J Biol Chem 277: 34471–34479.

    Article  CAS  Google Scholar 

  • Asher G, Shaul Y . (2005). p53 Proteasomal degradation. Cell Cycle 4: 1015–1018.

    Article  CAS  Google Scholar 

  • Byrne C, Hardman MJ, Nield K . (2003). Covering the limb – formation of the integument. J Anat 202: 113–124.

    Article  Google Scholar 

  • Campanero MR, Flemington EK . (1997). Regulation of E2F through ubiquitin–proteasome-dependent degradation: stabilization by the pRB tumor suppressor protein. Proc Natl Acad Sci USA 94: 2221–2226.

    Article  CAS  Google Scholar 

  • Chang WY, Bryce DM, D'Souza SJA, Dagnino L . (2004). The DP-1 transcription factor is required for keratinocyte growth and epidermal stratification. J Biol Chem 279: 51343–51353.

    Article  CAS  Google Scholar 

  • D'Souza SJA, Pajak A, Balazsi K, Dagnino L . (2001). Ca+2 and BMP-6 signalling regulate E2F during epidermal keratinocyte differentiation. J Biol Chem 276: 23531–23538.

    Article  CAS  Google Scholar 

  • D'Souza SJA, Vespa A, Murkherjee S, Maher A, Pajak S, Dagnino L . (2002). E2F-1 is essential for normal epidermal wound repair. J Biol Chem 277: 10626–10632.

    Article  CAS  Google Scholar 

  • Dagnino L, Fry CJ, Bartley SM, Farnham P, Gallie BL, Phillips RA . (1997a). Expression patterns of the E2F family of transcription factors during mouse nervous system development. Mech Dev 66: 13–25.

    Article  CAS  Google Scholar 

  • Dagnino L, Fry CJ, Bartley SM, Farnham P, Gallie BL, Phillips RA . (1997b). Expression patterns of the E2F family of transcription factors during murine epithelial development. Cell Growth Differ 8: 553–563.

    CAS  PubMed  Google Scholar 

  • Dicker AJ, Popa C, Dahler AL, Serewko MM, Hilditch-Maguire PA, Frazer IH et al. (2000). E2F-1 induces proliferation-specific genes and suppresses squamous differentiation-specific genes in human epidermal keratinocytes. Oncogene 19: 2887–2894.

    Article  CAS  Google Scholar 

  • Dlugosz AA, Glick AB, Tennenbaum T, Weinberg WC, Yuspa SH . (1995). Isolation and utilization of epidermal keratinocytes for oncogene research. Methods Enzymol 254: 3–20.

    Article  CAS  Google Scholar 

  • Efimova T, La Cell P, Welter JF, Eckert RL . (1998). Regulation of human involucrin promoter activity by a protein kinase C, Ras. MEKK1, MEK3 p38/RK, AP1 signal transduction pathway. J Biol Chem 38: 24387–24395.

    Article  Google Scholar 

  • Fajas L, Landsberg RL, Huss-Garcia Y, Sardet C, Lees JA, Auwerx J . (2002). E2Fs regulate adipocyte differentiation. Dev Cell 3: 39–49.

    Article  CAS  Google Scholar 

  • Freedman DA, Levine JA . (1998). Nuclear export is required for degradation of endogenous p53 by MDM2 and human papilloma virus E6. Mol Cell Biol 18: 7288–7293.

    Article  CAS  Google Scholar 

  • Gaubatz S, Lees JA, Lindeman GJ, Livingston DM . (2001). E2F4 is exported from the nucleus in a CRM1-dependent manner. Mol Cell Biol 21: 1384–1392.

    Article  CAS  Google Scholar 

  • Gill RM, Hamel PA . (2000). Subcellular compartmentalization of E2F family members is required for maintenance of the postmitotic state in terminally differentiated muscle. J Cell Biol 148: 1187–1201.

    Article  CAS  Google Scholar 

  • Gomez DA, Martinez-Martinez S, Maldonado JL, Ortega-Perez I, Redondo JM . (2000). A role for the p38 MAP kinase pathway in the nuclear shuttling of NFATp. J Biol Chem 275: 13872–13878.

    Article  Google Scholar 

  • Ito M, Liu Y, Yang Z, Nguyen J, Liang F, Morris RJ et al. (2005). Stem cells in the hair follicle bulge contribute to wound repair, but not to homeostasis of the epidermis. Nat Med 11: 1351–1354.

    Article  CAS  Google Scholar 

  • Ivanova IA, D'Souza SJA, Dagnino L . (2006). E2F stability is regulated by a novel-PKC/p38 MAP kinase signalling pathway during keratinocyte differentiation. Oncogene 25: 430–437.

    Article  CAS  Google Scholar 

  • Jones SJ, Dicker AJ, Dahler AL, Saunders NA . (1997). E2F as a regulator of keratinocyte proliferation: implications for skin tumor development. J Invest Dermatol 109: 187–193.

    Article  CAS  Google Scholar 

  • Marti A, Wirbelauer C, Scheffner M, Krek W . (1999). Interaction between ubiquitin–protein ligase SCFSKP2 and E2F-1 underlies the regulation of E2F-1 degradation. Nat Cell Biol 1: 14–19.

    Article  CAS  Google Scholar 

  • Muller H, Moroni MC, Vigo E, Petersen BO, Bartek J, Helin K . (1997). Induction of S-phase entry by E2F transcription factors depends on their nuclear localization. Mol Cell Biol 17: 5508–5520.

    Article  CAS  Google Scholar 

  • Ruiz S, Santos M, Paramio JM . (2006). Is the loss of pRb essential for the mouse skin carcinogenesis? Cell Cycle 5: 625–629.

    Article  CAS  Google Scholar 

  • Ruiz S, Santos M, Segrelles C, Leis H, Jorcano JL, Berns A et al. (2004). Unique and overlapping functions of pRb and p107 in the control of proliferation and differentiation in epidermis. Development 131: 2737–2748.

    Article  CAS  Google Scholar 

  • Vespa A, D'Souza SJA, Dagnino L . (2005). A novel role for integrin-linked kinase in epithelial sheet morphogenesis. Mol Biol Cell 16: 4084–4095.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Drs M Tini and S D'Souza for helpful comments on the manuscript. This work was supported by grants to LD from the Natural Science and Engineering Research Council of Canada, and the National Cancer Institute of Canada (NCIC) with funds from the Canadian Cancer Society and the Terry Fox Foundation, raised through the Terry Fox Run. IAI holds research studentships from the Terry Fox Foundation, through an award from NCIC, and from the Canadian Institutes of Health Research Training Program in Cancer Research and Technology Transfer.

Author information

Authors and Affiliations

  1. Department of Physiology and Pharmacology and Regulatory Biology, University of Western Ontario, London, Ontario, Canada

    I A Ivanova & L Dagnino

  2. Department of Paediatrics, Child Health Research Institute and Lawson Health Research Institute, University of Western Ontario, London, Ontario, Canada

    L Dagnino

Authors
  1. I A Ivanova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L Dagnino
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L Dagnino.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ivanova, I., Dagnino, L. Activation of p38- and CRM1-dependent nuclear export promotes E2F1 degradation during keratinocyte differentiation. Oncogene 26, 1147–1154 (2007). https://doi.org/10.1038/sj.onc.1209894

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1209894

Keywords

This article is cited by

Search

Advanced search

Quick links