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:

Dominant-negative c-Jun (TAM67) target genes: HMGA1 is required for tumor promoter-induced transformation

Oncogene volume 23, pages 4466–4476 (2004)Cite this article

Abstract

Activation of the transcription factor AP-1 (activator protein-1) is required for tumor promotion and maintenance of malignant phenotype. A number of AP-1-regulated genes that play a role in tumor progression have been identified. However, AP-1-regulated genes driving tumor induction are yet to be defined. Previous studies have established that expression of a dominant-negative c-Jun (TAM67) inhibits phorbol 12-tetradecanoyl-13-acetate (TPA)-induced AP-1 transactivation as well as transformation in mouse epidermal JB6/P+ cells and tumor promotion in mouse skin carcinogenesis. In this study, we utilized the tumor promotion-sensitive JB6/P+ cells to identify AP-1-regulated TAM67 target genes and to establish causal significance in transformation for one target gene. A 2700 cDNA microarray was queried with RNA from TPA-treated P+ cells with or without TAM67 expression. Under conditions in which TAM expression inhibited TPA-induced transformation, microarray analysis identified a subset of six genes induced by TPA and suppressed by TAM67. One of the identified genes, the high-mobility group protein A1 (Hmga1) is induced by TPA in P+, but not in transformation-resistant P cells. We show that TPA induction of the architectural transcription factor HMGA1 is inhibited by TAM67, is extracellular–signal-regulated kinase (ERK)-activation dependent, and is mediated by AP-1. HMGA1 antisense construct transfected into P+ cells blocked HMGA1 protein expression and inhibited TPA-induced transformation indicating that HMGA1 is required for transformation. HMGA1 is not however sufficient as HMGA1a or HMGA1b overexpression did not confer transformation sensitivity on P− cells. Although HMGA1 expression is ERK dependent, it is not the only ERK-dependent event required for transformation because it does not suffice to rescue ERK-deficient P− cells. Our study shows (a) TAM 67 when it inhibits AP-1 and transformation, targets a relatively small number of genes; (b) HMGA1, a TAM67 target gene, is causally related to transformation and therefore a potentially important target for cancer prevention.

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 7
Figure 5
Figure 6
Figure 8

Similar content being viewed by others

References

  • Abe N, Watanabe T, Sugiyama M, Uchimura H, Chiappetta G, Fusco A and Atomi Y . (1999). Cancer Res., 59, 1169–1174.

  • Angel P and Karin M . (1991). Biochim. Biophys. Acta, 1072, 129–157.

  • Angel P, Szabowski A and Schorpp-Kistner M . (2001). Oncogene, 20, 2413–2423.

  • Balmain A . (2001). Nat. Rev. Cancer, 1, 77–82.

  • Berlingieri MT, Pierantoni GM, Giancotti V, Santoro M and Fusco A . (2002). Oncogene, 21, 2971–2980.

  • Bernstein LR, Bravo R and Colburn NH . (1992). Mol. Carcinog., 6, 221–229.

  • Bernstein LR and Colburn NH . (1989). Science, 244, 566–569.

  • Bernstein LR, Ferris DK, Colburn NH and Sobel ME . (1994). J. Biol. Chem., 269, 9401–9404.

  • Bouallaga I, Teissier S, Yaniv M and Thierry F . (2003). Mol. Cell. Biol., 23, 2329–2340.

  • Brown PH, Alani R, Pries LH, Szabo E and Birrer MJ . (1993). Oncogene, 8, 877–886.

  • Budunova IV, Perez P, Vaden VR, Spiegelman VS, Slaga TJ and Jorcano JL . (1999). Oncogene, 18, 7423–7431.

  • Bustin M and Reeves R . (1996). Prog. Nucleic Acid. Res. Mol. Biol., 54, 35–100.

  • Chang PL, Cao M and Hicks P . (2003). Carcinogenesis, 24, 1749–1758.

  • Chiappetta G, Bandiera A, Berlingieri MT, Visconti R, Manfioletti G, Battista S, Martinez-Tello FJ, Santoro M, Giancotti V and Fusco A . (1995). Oncogene, 10, 1307–1314.

  • Chin MT, Pellacani A, Wang H, Lin SS, Jain MK, Perrella MA and Lee ME . (1998). J. Biol. Chem., 273, 9755–9760.

  • Chinenov Y and Kerppola TK . (2001). Oncogene, 20, 2438–2452.

  • Cmarik JL, Li Y, Ogram SA, Min H, Reeves R and Colburn NH . (1998). Oncogene, 16, 3387–3396.

  • Cmarik JL, Min H, Hegamyer G, Zhan S, Kulesz-Martin M, Yoshinaga H, Matsuhashi S and Colburn NH . (1999). Proc. Natl. Acad. Sci. USA, 96, 14037–14042.

  • Colburn NH, Former BF, Nelson KA and Yuspa SH . (1979). Nature, 281, 589–591.

  • Colburn NH, Gindhart TD, Hegamyer GA, Blumberg PM, Delclos KB, Magun BE and Lockyer J . (1982). Cancer Res., 42, 3093–3097.

  • Colburn NH, Wendel EJ and Abruzzo G . (1981). Proc. Natl. Acad. Sci. USA, 78, 6912–6916.

  • Cooper S, Young MR, Colburn N and Bowden GT . (2003). Mol. Cancer Res., 1, 848–854.

  • Craig AM, Smith JH and Denhardt DT . (1989). J. Biol. Chem., 264, 9682–9689.

  • Dhar A, Young MR and Colburn NH . (2002). Mol. Cell. Biochem., 234-235, 185–193.

  • Dong Z, Birrer MJ, Watts RG, Matrisian LM and Colburn NH . (1994). Proc. Natl. Acad. Sci. USA, 91, 609–613.

  • Dong Z, Lavrovsky V and Colburn NH . (1995). Carcinogenesis, 16, 749–756.

  • Du W, Thanos D and Maniatis T . (1993). Cell, 74, 887–898.

  • Eto I . (1998). Cell Prolif., 31, 71–92.

  • Friedmann M, Holth LT, Zoghbi HY and Reeves R . (1993). Nucleic Acids Res., 21, 4259–4267.

  • Frost JA, Geppert TD, Cobb MH and Feramisco JR . (1994). Proc. Natl. Acad. Sci. USA, 91, 3844–3848.

  • Hanahan D and Weinberg RA . (2000). Cell, 100, 57–70.

  • Himes SR, Coles LS, Reeves R and Shannon MF . (1996). Immunity, 5, 479–489.

  • Himes SR, Reeves R, Attema J, Nissen M, Li Y and Shannon MF . (2000). J. Immunol., 164, 3157–3168.

  • Hsu T-C, Nair R, Tulsian P, Hegamyer G, Young MR and Colburn NH . (2001). Cancer Res., 61, 4160–4168.

  • Huang C, Ma WY and Dong Z . (1999). Oncogene, 18, 2828–2835.

  • Huang C, Ma WY, Young MR, Colburn N and Dong Z . (1998). Proc. Natl. Acad. Sci. USA, 95, 156–161.

  • Jochum W, Passegue E and Wagner EF . (2001). Oncogene, 20, 2401–2412.

  • Johnston IM, Spence HJ, Winnie JN, McGarry L, Vass JK, Meagher L, Stapleton G and Ozanne BW . (2000). Oncogene, 19, 5348–5358.

  • Karin M, Liu Z and Zandi E . (1997). Curr. Opin. Cell. Biol., 9, 240–246.

  • Kovacic P and Jacintho JD . (2001). Curr. Med. Chem., 8, 773–796.

  • Lewis H, Kaszubska W, DeLamarter JF and Whelan J . (1994). Mol. Cell. Biol., 14, 5701–5709.

  • Li J-J, Cao Y, Young MR and Colburn NH . (2000). Mol. Carcinogen., 29, 159–169.

  • Li JJ, Westergaard C, Ghosh P and Colburn NH . (1997). Cancer Res., 57, 3569–3576.

  • Ogram SA and Reeves R . (1995). J. Biol. Chem., 270, 14235–14242.

  • Ozanne BW, McGarry L, Spence HJ, Johnston I, Winnie J, Meagher L and Stapleton G . (2000). Eur. J. Cancer, 36, 1640–1648.

  • Pedulla ML, Treff NR, Resar LM and Reeves R . (2001). Gene, 271, 51–58.

  • Ram TG, Reeves R and Hosick HL . (1993). Cancer Res., 53, 2655–2660.

  • Reeves R, Edberg DD and Li Y . (2001). Mol. Cell. Biol., 21, 575–594.

  • Reeves R and Nissen MS . (1999). Methods Enzymol., 304, 155–188.

  • Robles AI and Conti CJ . (1995). Carcinogen., 16, 781–786.

  • Shaulian E and Karin M . (2001). Oncogene, 20, 2390–2400.

  • Sovak MA, Bellas RE, Kim DW, Zanieski GJ, Rogers AE, Traish AM and Sonenshein GE . (1997). J. Clin. Invest., 100, 2952–2960.

  • Suzukawa K, Weber TJ and Colburn NH . (2002). Environ. Health Perspect., 110, 865–870.

  • Tamimi Y, van der Poel HG, Denyn MM, Umbas R, Karthaus HF, Debruyne FM and Schalken JA . (1993). Cancer Res., 53, 5512–5516.

  • Thanos D and Maniatis T . (1995). Cell, 83, 1091–1100.

  • van Dam H and Castellazzi M . (2001). Oncogene, 20, 2453–2464.

  • Watts RG, Ben-Ari ET, Bernstein LR, Birrer MJ, Winterstein D, Wendel E and Colburn NH . (1995). Mol. Carcinogen., 13, 27–36.

  • Watts RG, Huang C, Young MR, Li JJ, Dong Z, Pennie WD and Colburn NH . (1998). Oncogene, 17, 3493–3498.

  • Whiteside ST and Israel A . (1997). Semin. Cancer Biol., 8, 75–82.

  • Wood LJ, Maher JF, Bunton TE and Resar LM . (2000a). Cancer Res., 60, 4256–4261.

  • Wood LJ, Mukherjee M, Dolde CE, Xu Y, Maher JF, Bunton TE, Williams JB and Resar LM . (2000b). Mol. Cell. Biol., 20, 5490–5502.

  • Yang CS, Maliakal P and Meng X . (2002). Annu. Rev. Pharmacol. Toxicol., 42, 25–54.

  • Yang HS, Jansen AP, Komar AA, Zheng X, Merrick WC, Costes S, Lockett SJ, Sonenberg N and Colburn NH . (2003). Mol. Cell. Biol., 23, 26–37.

  • Yang H-S, Jansen AP, Nair R, Shibara K, Verma AK, Cmarik JL and Colburn NH . (2001). Oncogene, 20, 669–676.

  • Young MR, Farrell L, Lambert PF, Awasthi P and Colburn NH . (2002a). Mol. Carcinogen., 34, 72–77.

  • Young MR, Li JJ, Rincon M, Flavell RA, Sathyanarayana BK, Hunziker R and Colburn N . (1999). Proc. Natl. Acad. Sci. USA, 96, 9827–9832.

  • Young MR, Nair R, Bucheimer N, Tulsian P, Brown N, Chapp C, Hsu TC and Colburn NH . (2002b). Mol. Cell. Biol., 22, 587–598.

  • Young MR, Yang HS and Colburn NH . (2003). Trends Mol. Med., 9, 36–41.

Download references

Acknowledgements

We thank Ms. Jen Adair (Department of Biochemistry, School of Molecular Biosciences, Washington State University) for providing the figure showing specificity of the MR-19 antibody to HMGA1 and not HMGA2. We thank Mrs Annie Rogers (Basic Research Laboratory, National Cancer Institute, Frederick, MD, USA) for help with editing.

Author information

Authors and Affiliations

  1. Gene Regulation Section, Laboratory of Cancer Prevention, NCI at Frederick, Frederick, 21702-1201, MD, USA

    Arindam Dhar, Jing Hu & Nancy H Colburn

  2. Department of Biochemistry, School of Molecular Bioscience, Washington State University, Pullman, 99164-4660, WA, USA

    Raymond Reeves

  3. Division of Pediatric Hematology, School of Medicine, Johns Hopkins University, Baltimore, 21205, MD, USA

    Linda MS Resar

Authors
  1. Arindam Dhar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jing Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Raymond Reeves
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Linda MS Resar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nancy H Colburn
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Arindam Dhar.

Additional information

Supplementary information accompanies the paper on Oncogene website (http://www.nature.com/onc).

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dhar, A., Hu, J., Reeves, R. et al. Dominant-negative c-Jun (TAM67) target genes: HMGA1 is required for tumor promoter-induced transformation. Oncogene 23, 4466–4476 (2004). https://doi.org/10.1038/sj.onc.1207581

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207581

Keywords

This article is cited by

Search

Advanced search

Quick links