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:

TAp63-dependent induction of growth differentiation factor 15 (GDF15) plays a critical role in the regulation of keratinocyte differentiation

Oncogene volume 27, pages 409–420 (2008)Cite this article

Abstract

Since p63-deficient mice display severe defects in formation of epidermis, p63 has been considered to be a multi-isoform p53 family member essential for epidermal development. However, it is still unclear how p63 could contribute to keratinocyte differentiation. In the present study, we have found that TAp63α is induced in association with the upregulation and a secretion of growth differentiation factor 15 (GDF15) during the keratinocyte differentiation of HaCaT cells bearing p53 mutation. Short interference RNA-mediated knockdown of the endogenous TAp63 resulted in a remarkable reduction of GDF15. Luciferase reporter assay and reverse transcription–PCR analysis demonstrated that enforced expression of TAp63α significantly increases the luciferase activity driven by GDF15 promoter and the expression of GDF15. Consistent with these results, the proximal p53/p63-binding site within the GDF15 promoter region was required for the TAp63α-mediated transcriptional activation of GDF15, and TAp63α was recruited onto this site. Furthermore, siRNA-mediated knockdown of the endogenous GDF15 permitted cell growth and inhibited the expression of the differentiation markers such as keratin 10 and involucrin in response to differentiation stimuli. Taken together, our present results provide a novel insight into understanding the molecular mechanisms behind TAp63α-mediated keratinocyte differentiation.

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
Figure 7

Similar content being viewed by others

References

  • Agarwal MK, Hastak K, Jackson MW, Breit SN, Stark GR, Agarwal ML . (2006). Macrophage inhibitory cytokine 1 mediates a p53-dependent protective arrest in S phase in response to starvation for DNA precursors. Proc Natl Acad Sci USA 103: 16278–16283.

    Article  CAS  Google Scholar 

  • Ago T, Sadoshima J . (2006). GDF15, a cardioprotective TGF-β superfamily protein. Circ Res 98: 294–297.

    Article  CAS  Google Scholar 

  • Baek SJ, Kim KS, Nixon JB, Wilson LC, Eling TE . (2001). Cyclooxygenase inhibitors regulate the expression of a TGF-β superfamily member that has proapoptotic and antitumorigenic activities. Mol Pharmacol 59: 901–908.

    Article  CAS  Google Scholar 

  • Baek SJ, Wilson LC, Eling TE . (2002). Resveratrol enhances the expression of non-steroidal anti-inflammatory drug-activated gene (NAG-1) by increasing the expression of p53. Carcinogenesis 23: 425–434.

    Article  CAS  Google Scholar 

  • Bauskin AR, Brown DA, Kuffner T, Johnen H, Luo XW, Hunter M et al. (2006). Role of macrophage inhibitory cytokine-1 in tumorigenesis and diagnosis of cancer. Cancer Res 66: 4983–4986.

    Article  CAS  Google Scholar 

  • Bootcov MR, Bauskin AR, Valenzuela SM, Moore AG, Bansal M, He XY et al. (1997). MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-β superfamily. Proc Natl Acad Sci USA 94: 11514–11519.

    Article  CAS  Google Scholar 

  • Bottner M, Suter-Crazzolara C, Schober A, Unsicker K . (1999). Expression of a novel member of the TGF-β superfamily, growth/differentiation factor-15/macrophage-inhibiting cytokine-1 (GDF-15/MIC-1) in adult rat tissues. Cell Tissue Res 297: 103–110.

    Article  CAS  Google Scholar 

  • Boukamp P, Petrussevska RT, Breitkreutz D, Hornung J, Markham A, Fusenig NE . (1988). Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line. J Cell Biol 106: 761–771.

    Article  CAS  Google Scholar 

  • Bourdon JC, Fernandes K, Murray-Zmijewski F, Liu G, Diot A, Xirodimas DP et al. (2005). p53 isoforms can regulate p53 transcriptional activity. Genes Dev 19: 2122–2137.

    Article  CAS  Google Scholar 

  • Candi E, Rufini A, Terrinoni A, Dinsdale D, Ranalli M, Paradisi A et al. (2006a). Differential roles of p63 isoforms in epidermal development: selective genetic complementation in p63 null mice. Cell Death Differ 13: 1037–1047.

    Article  CAS  Google Scholar 

  • Candi E, Terrinoni A, Rufini A, Chikh A, Lena AM, Suzuki Y et al. (2006b). p63 is upstream of IKK alpha in epidermal development. J Cell Sci 119: 4617–4622.

    Article  CAS  Google Scholar 

  • De Laurenzi V, Rossi A, Terrinoni A, Barcaroli D, Levrero M, Costanzo A et al. (2000). p63 and p73 transactivate differentiation gene promoters in human keratinocytes. Biochem Biophys Res Commun 273: 342–346.

    Article  CAS  Google Scholar 

  • Hromas R, Hufford M, Sutton J, Xu D, Li Y, Lu L . (1997). PLAB, a novel placental bone morphogenetic protein. Biochim Biophys Acta 1354: 40–44.

    Article  CAS  Google Scholar 

  • Ikawa S, Nakagawara A, Ikawa Y . (1999). p53 family genes: structural comparison, expression and mutation. Cell Death Differ 6: 1154–1161.

    Article  CAS  Google Scholar 

  • Kaghad M, Bonnet H, Yang A, Creancier L, Biscan JC, Valent A et al. (1997). Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell 90: 809–819.

    Article  CAS  Google Scholar 

  • King KE, Ponnamperuma RM, Gerdes MJ, Tokino T, Yamashita T, Baker CC et al. (2006). Unique domain functions of p63 isotypes that differentially regulate distinct aspects of epidermal homeostasis. Carcinogenesis 27: 53–63.

    Article  CAS  Google Scholar 

  • Koster MI, Dai D, Roop DR . (2007). Conflicting roles for p63 in skin development and carcinogenesis. Cell Cycle 6: 269–273.

    Article  CAS  Google Scholar 

  • Koster MI, Kim S, Huang J, Williams T, Roop DR . (2006). TAp63α induces AP-2γ as an early event in epidermal morphogenesis. Dev Biol 289: 253–261.

    Article  CAS  Google Scholar 

  • Koster MI, Kim S, Mills AA, DeMayo FJ, Roop DR . (2004). p63 is the molecular switch for initiation of an epithelial stratification program. Genes Dev 18: 126–131.

    Article  CAS  Google Scholar 

  • Lambert JR, Kelly JA, Shim M, Huffer WE, Nordeen SK, Baek SJ et al. (2006). Prostate derived factor in human prostate cancer cells: gene induction by vitamin D via a p53-dependent mechanism and inhibition of prostate cancer cell growth. J Cell Physiol 208: 566–574.

    Article  CAS  Google Scholar 

  • Lapi E, Iovino A, Fontemaggi G, Soliera AR, Iacovelli S, Sacchi A et al. (2006). S100A2 gene is a direct transcriptional target of p53 homologues during keratinocyte differentiation. Oncogene 25: 3628–3637.

    Article  CAS  Google Scholar 

  • Lehman TA, Modali R, Boukamp P, Stanek J, Bennett WP, Welsh JA et al. (1993). p53 mutations in human immortalized epithelial cell lines. Carcinogenesis 14: 833–839.

    Article  CAS  Google Scholar 

  • Li PX, Wong J, Ayed A, Ngo D, Brade AM, Arrowsmith C et al. (2000). Placental transforming growth factor-beta is a downstream mediator of the growth arrest and apoptotic response of tumor cells to DNA damage and p53 overexpression. J Biol Chem 275: 20127–20135.

    Article  CAS  Google Scholar 

  • Mills AA, Zheng B, Wang XJ, Vogel H, Roop DR, Bradley A . (1999). p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature 398: 708–713.

    Article  CAS  Google Scholar 

  • Nazarova N, Qiao S, Golovko O, Lou YR, Tuohimaa P . (2004). Calcitriol-induced prostate-derived factor: autocrine control of prostate cancer cell growth. Int J Cancer 112: 951–958.

    Article  CAS  Google Scholar 

  • Osada M, Park HL, Nagakawa Y, Yamashita K, Fomenkov A, Kim MS et al. (2005). Differential recognition of response elements determines target gene specificity for p53 and p63. Mol Cell Biol 25: 6077–6089.

    Article  CAS  Google Scholar 

  • Osada M, Park HL, Park MJ, Liu JW, Wu G, Trink B et al. (2007). A p53-type response element in the GDF15 promoter confers high specificity for p53 activation. Biochem Biophys Res Commun 354: 913–918.

    Article  CAS  Google Scholar 

  • Paralkar VM, Vail AL, Grasser WA, Brown TA, Xu H, Vukicevic S et al. (1998). Cloning and characterization of a novel member of the transforming growth factor-β/bone morphogenetic protein family. J Biol Chem 273: 13760–13767.

    Article  CAS  Google Scholar 

  • Roninson IB . (2003). Tumor cell senescence in cancer treatment. Cancer Res 63: 2705–2715.

    CAS  Google Scholar 

  • Tan M, Wang Y, Guan K, Sun Y . (2000). PTGF-β, a type β transforming growth factor (TGF-β) superfamily member, is a p53 target gene that inhibits tumor cell growth via TGF-β signaling pathway. Proc Natl Acad Sci USA 97: 109–114.

    Article  CAS  Google Scholar 

  • Uchida K, Chaudhary LR, Sugimura Y, Adkisson HD, Hruska KA . (2003). Proprotein convertases regulate activity of prostate epithelial cell differentiation markers and are modulated in human prostate cancer cells. J Cell Biochem 88: 394–399.

    Article  CAS  Google Scholar 

  • Yang A, Kaghad M, Wang Y, Gillett E, Fleming MD, Dotsch V et al. (1998). p63, a p53 homolog at 3q27–29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol Cell 2: 305–316.

    Article  CAS  Google Scholar 

  • Yang A, McKeon F . (2000). p63 and p73: p53 mimics, menaces and more. Nat Rev Mol Cell Biol 1: 199–207.

    Article  CAS  Google Scholar 

  • Yang A, Schweitzer R, Sun D, Kaghad M, Walker N, Bronson RT et al. (1999). p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 398: 714–718.

    Article  CAS  Google Scholar 

  • Yang A, Walker N, Bronson R, Kaghad M, Oosterwegel M, Bonnin J et al. (2000). p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours. Nature 404: 99–103.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to Dr G Melino for providing TAp63α and ΔNp63α expression plasmids. We also thank Ms Y Nakamura for technical assistance. This work was supported in part by a grant-in-aid from the Ministry of Health, Labour and Welfare for Third Term Comprehensive Control Research for Cancer, a grant-in-aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology, Japan, a grant-in-aid for Scientific Research from Japan Society for the Promotion of Science, Uehara Memorial Foundation and Hisamitsu Pharmaceutical Co.

Author information

Authors and Affiliations

  1. Division of Biochemistry, Chiba Cancer Center Research Institute, Chiba, Japan

    T Ichikawa, Y Suenaga, T Ozaki & A Nakagawara

  2. Research Center for Functional Genomics, Hisamitsu Pharmaceutical Co., Inc., Chiba, Japan

    T Ichikawa & T Koda

  3. Department of Molecular Biology and Oncology, Chiba University Graduate School of Medicine, Chiba, Japan

    Y Suenaga, T Ozaki & A Nakagawara

Authors
  1. T Ichikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y Suenaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T Koda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T Ozaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A Nakagawara
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A Nakagawara.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ichikawa, T., Suenaga, Y., Koda, T. et al. TAp63-dependent induction of growth differentiation factor 15 (GDF15) plays a critical role in the regulation of keratinocyte differentiation. Oncogene 27, 409–420 (2008). https://doi.org/10.1038/sj.onc.1210658

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210658

Keywords

This article is cited by

Search

Advanced search

Quick links