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:

Loss of tumor progression locus 2 (tpl2) enhances tumorigenesis and inflammation in two-stage skin carcinogenesis

Oncogene volume 30, pages 389–397 (2011)Cite this article

Subjects

Abstract

Tumor progression locus 2 (Tpl2) is a serine/threonine kinase in the mitogen-activated protein kinase signal transduction cascade known to regulate inflammatory pathways. Previously identified as an oncogene, its mutation or overexpression is reported in a variety of human cancers. To address its role in skin carcinogenesis, Tpl2−/− or wild-type (WT) C57BL/6 mice were subjected to a two-stage dimethylbenzanthracene/12-O-tetradecanoylphorbol-13-acetate (TPA) mouse skin carcinogenesis model. Tpl2−/− mice developed a significantly higher incidence of tumors (80%) than WT mice (17%), as well as a reduced tumor latency and a significantly higher number of total tumors (113 vs 6). Moreover, Tpl2−/− mice treated with TPA experienced significantly higher nuclear factor kappaB (NF-κB) activation, edema, infiltrating neutrophils and production of proinflammatory cytokines than did WT mice. We investigated the role of the p38, JNK, MEK and NF-κB signaling pathways both in vitro and in vivo in WT and Tpl2−/− mice by using inhibitors for each of these pathways. We confirmed that the proinflammatory effect in Tpl2−/− mice was due to heightened activity of the NF-κB pathway. These studies indicate that Tpl2 may serve more as a tumor suppressor than as an oncogene in chemically induced skin carcinogenesis, with its absence contributing to both tumorigenesis and inflammation.

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

References

  • Aoki M, Akiyama T, Miyoshi J, Toyoshima K . (1991). Identification and characterization of protein products of the cot oncogene with serine kinase activity. Oncogene 6: 1515–1519.

    CAS  PubMed  Google Scholar 

  • Beinke S, Deka J, Lang V, Belich MP, Walker PA, Howell S et al. (2003). NF-kappaB1 p105 negatively regulates TPL-2 MEK kinase activity. Mol Cell Biol 23: 4739–4752.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Beinke S, Robinson MJ, Hugunin M, Ley SC . (2004). Lipopolysaccharide activation of the TPL-2/MEK/extracellular signal-regulated kinase mitogen-activated protein kinase cascade is regulated by IkappaB kinase-induced proteolysis of NF-kappaB1 p105. Mol Cell Biol 24: 9658–9667.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Belich MP, Salmerón A, Johnston LH, Ley SC . (1999). TPL-2 kinase regulates the proteolysis of the NF-kappaB-inhibitory protein NF-kappaB1 p105. Nature 397: 363–368.

    Article  CAS  PubMed  Google Scholar 

  • Brunda MJ, Luistro L, Warrier RR, Wright RB, Hubbard BR, Murphy M et al. (1993). Antitumor and antimetastatic activity of interleukin 12 against murine tumors. J Exp Med 178: 1223–1230.

    Article  CAS  PubMed  Google Scholar 

  • Cataisson C, Pearson AJ, Torgerson S, Nedospasov SA, Yuspa SH . (2005). Protein kinase C alpha-mediated chemotaxis of neutrophils requires NF-kappa B activity but is independent of TNF alpha signaling in mouse skin in vivo. J Immunol 174: 1686–1692.

    Article  CAS  PubMed  Google Scholar 

  • Ceci JD, Patriotis CP, Tsatsanis C, Makris AM, Kovatch R, Swing DA et al. (1997). Tpl-2 is an oncogenic kinase that is activated by carboxy-terminal truncation. Genes Dev 11: 688–700.

    Article  CAS  PubMed  Google Scholar 

  • Clark AM, Reynolds SH, Anderson M, Wiest JS . (2004). Mutational activation of the MAP3K8 protooncogene in lung cancer. Genes Chromosomes Cancer 41: 99–108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chiariello M, Marinissen MJ, Gutkind JS . (2000). Multiple mitogen-activated protein kinase signaling pathways connect the Cot oncoprotein to the c-jun promoter and to cellular transformation. Mol Cell Biol 20: 1747–1758.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Colombo MP, Vagliani M, Spreafico F, Parenza M, Chiodoni C, Melani C et al. (1996). Amount of interleukin 12 available at the tumor site is critical for tumor regression. Cancer Res. 56: 2531–2534.

    CAS  PubMed  Google Scholar 

  • Coussens LM, Werb Z . (2002). Inflammation and cancer. Nature 420: 860–867.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • de Visser KE, Eichten A, Coussens LM . (2006). Paradoxical roles of the immune system during cancer development. Nat Rev Cancer 6: 24–37.

    Article  CAS  PubMed  Google Scholar 

  • DiGiovanni J, Prichett WP, Decina PC, Diamond L . (1984). DBA/2 mice are as sensitive as SENCAR mice to skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate. Carcinogenesis 5: 1493–1498.

    Article  CAS  PubMed  Google Scholar 

  • Dumitru CD, Ceci JD, Tsatsanis C, Kontoyiannis D, Stamatakis K, Lin JH et al. (2000). TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway. Cell 103: 1071–1083.

    Article  CAS  PubMed  Google Scholar 

  • Glick A, Ryscavage A, Perez-Lorenzo R, Hennings H, Yuspa S, Darwiche N . (2007). The high-risk benign tumor: evidence from the two-stage skin cancer model and relevance for human cancer. Mol Carcinog 46: 605–610.

    Article  CAS  PubMed  Google Scholar 

  • Griner EM, Kazanietz MG . (2007). Protein kinase C and other diacylglycerol effectors in cancer. Nat Rev Cancer 7: 281–294.

    Article  CAS  PubMed  Google Scholar 

  • Hu Y, Green N, Gavrin LK, Janz K, Kaila N, Li HQ et al. (2006). Inhibition of Tpl2 kinase and TNFalpha production with quinoline-3-carbonitriles for the treatment of rheumatoid arthritis. Bioorg Med Chem Lett 16: 6067–6072.

    Article  CAS  PubMed  Google Scholar 

  • Jansen AP, Verwiebe EG, Dreckschmidt NE, Wheeler DL, Oberley TD, Verma AK . (2001). Protein kinase C-epsilon transgenic mice: a unique model for metastatic squamous cell carcinoma. Cancer Res 61: 808–812.

    CAS  PubMed  Google Scholar 

  • Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ . (2009). Cancer Statistics 2008. CA Cancer J Clin 59: 225–249.

    Article  PubMed  Google Scholar 

  • Kane LP, Mollenauer MN, Xu Z, Turck CW, Weiss A . (2002). Akt-dependent phosphorylation specifically regulates Cot induction of NF-kappa B-dependent transcription. Mol Cell Biol 22: 5962–5974.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Karin M . (2006). Nuclear factor-kappaB in cancer development and progression. Nature 441: 431–436.

    Article  CAS  PubMed  Google Scholar 

  • Kimura YN, Watari K, Fotovati A, Hosoi F, Yasumoto K, Izumi H et al. (2007). Inflammatory stimuli from macrophages and cancer cells synergistically promote tumor growth and angiogenesis. Canc Sci 98: 2009–2018.

    Article  CAS  Google Scholar 

  • Lichti U, Anders J, Yuspa SH . (2008). Isolation and short-term culture of primary keratinocytes, hair follicle populations and dermal cells from newborn mice and keratinocytes from adult mice for in vitro analysis and for grafting to immunodeficient mice. Nat Protoc 3: 799–810.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moore RJ, Owens DM, Stamp G, Arnott C, Burke F, East N et al. (1999). Mice deficient in tumor necrosis factor-alpha are resistant to skin carcinogenesis. Nat Med 5: 828–831.

    Article  CAS  PubMed  Google Scholar 

  • Mueller MM . (2006). Inflammation in epithelial skin tumours: old stories and new ideas. Eur J Cancer 42: 735–744.

    Article  CAS  PubMed  Google Scholar 

  • Patriotis C, Makris A, Bear SE, Tsichlis PN . (1993). Tumor progression locus 2 (Tpl-2) encodes a protein kinase involved in the progression of rodent T-cell lymphomas and in T-cell activation. Proc Natl Acad Sci USA 90: 2251–2255.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Patriotis C, Makris A, Chernoff J, Tsichlis PN . (1994). Tpl-2 acts in concert with Ras and Raf-1 to activate mitogen-activated protein kinase. Proc Natl Acad Sci USA 91: 9755–9759.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Quintanilla M, Brown K, Ramsden M, Balmain A . (1986). Carcinogen-specific mutation and amplification of Ha-ras during mouse skin carcinogenesis. Nature 322: 78–80.

    Article  CAS  PubMed  Google Scholar 

  • Reddig PJ, Dreckschmidt NE, Ahrens H, Simsiman R, Tseng CP, Zou J et al. (1999). Transgenic mice overexpressing protein kinase C delta in the epidermis are resistant to skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate. Cancer Res 59: 5710–5718.

    CAS  PubMed  Google Scholar 

  • Rijzewijk JJ, van Erp PE, Bauer FW . (1989). Two binding sites for Ki67 related to quiescent and cycling cells in human epidermis. Acta Derm Venereol 69: 512–515.

    CAS  PubMed  Google Scholar 

  • Salmeron A, Ahmad TB, Carlile GW, Pappin D, Narsimhan RP, Ley SC . (1996). Activation of MEK-1 and SEK-1 by Tpl-2 proto-oncoprotein, a novel MAP kinase kinase kinase. EMBO J 15: 817–826.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sharma SD, Meeran SM, Katiyar N, Tisdale GB, Yusuf N, Xu H et al. (2009). IL-12 deficiency suppresses 12-O-tetradecanoylphorbol-13-acetate-induced skin tumor development in 7,12-dimethylbenz(a)anthracene-initiated mouse skin through inhibition of inflammation. Carcinogenesis 30: 1970–1977.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sourvinos G, Tsatsanis C, Spandidos DA . (1999). Overexpression of the Tpl-2/Cot oncogene in human breast cancer. Oncogene 18: 4968–4973.

    Article  CAS  PubMed  Google Scholar 

  • Sugimoto K, Ohata M, Miyoshi J, Ishizaki H, Tsuboi N, Masuda A et al. (2004). A serine/threonine kinase, Cot/Tpl2, modulates bacterial DNA-induced IL-12 production and Th cell differentiation. J Clin Invest 114: 857–866.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sur I, Ulvmar M, Toftgård R . (2008). The two-faced NF-kappaB in the skin. Int Rev Immunol 27: 205–223.

    Article  CAS  PubMed  Google Scholar 

  • Tahara H, Zeh III HJ, Storkus WJ, Pappo I, Watkins SC, Gubler U et al. (1994). Fibroblasts genetically engineered to secrete interleukin 12 can suppress tumor growth and induce antitumor immunity to a murine melanoma in vivo. Cancer Res 54: 182–189.

    CAS  PubMed  Google Scholar 

  • Tomczak MF, Gadjeva M, Wang YY, Brown K, Maroulakou I, Tsichlis PN et al. (2006). Defective activation of ERK in macrophages lacking the p50/p105 subunit of NF-kappaB is responsible for elevated expression of IL-12 p40 observed after challenge with Helicobacter hepaticus. J Immunol 176: 1244–1251.

    Article  CAS  PubMed  Google Scholar 

  • Tsatsanis C, Patriotis C, Tsichlis PN . (1998). Tpl-2 induces IL-2 expression in T-cell lines by triggering multiple signaling pathways that activate NFAT and NF-kappaB. Oncogene 17: 2609–2618.

    Article  CAS  PubMed  Google Scholar 

  • Tsatsanis C, Spandidos DA . (2000). The role of oncogenic kinases in human cancer. Int J Mol Med 5: 583–590.

    CAS  PubMed  Google Scholar 

  • Tsatsanis C, Vaporidi K, Zacharioudaki V, Androulidaki A, Sykulev Y, Margioris AN et al. (2008). Tpl2 and ERK transduce antiproliferative T cell receptor signals and inhibit transformation of chronically stimulated T cells. Proc Natl Acad Sci USA 105: 2987–2992.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Van Acker GJ, Perides G, Weiss ER, Das S, Tsichlis PN, Steer ML . (2007). Tumor progression locus-2 is a critical regulator of pancreatic and lung inflammation during acute pancreatitis. J Biol Chem 282: 22140–22149.

    Article  CAS  PubMed  Google Scholar 

  • Velasco-Sampayo A, Alemany S . (2001). p27kip protein levels and E2F activity are targets of Cot kinase during G1 phase progression in T cells. J Immunol 166: 6084–6090.

    Article  CAS  PubMed  Google Scholar 

  • Watford WT, Hissong BD, Durant LR, Yamane H, Muul LM, Kanno Y et al. (2008). Tpl2 kinase regulates T cell interferon-gamma production and host resistance to Toxoplasma gondii. J Exp Med 205: 2803–2812.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yuspa SH . (1998). The pathogenesis of squamous cell cancer: lessons learned from studies of skin carcinogenesis. J Dermatol Sci 17: 1–7.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr Jyotsna Pandey for her assistance with confocal microscopy. This work was supported by the NCI/NIH Intramural Research Program.

Author information

Author notes

  1. K L DeCicco-Skinner and E L Trovato: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biology, American University, Washington, DC, USA

    K L DeCicco-Skinner & E L Trovato

  2. Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    E L Trovato, J K Simmons, P K Lepage & J S Wiest

Authors
  1. K L DeCicco-Skinner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E L Trovato
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J K Simmons
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P K Lepage
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J S Wiest
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J S Wiest.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

DeCicco-Skinner, K., Trovato, E., Simmons, J. et al. Loss of tumor progression locus 2 (tpl2) enhances tumorigenesis and inflammation in two-stage skin carcinogenesis. Oncogene 30, 389–397 (2011). https://doi.org/10.1038/onc.2010.447

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2010.447

Keywords

This article is cited by

Search

Advanced search

Quick links