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:

Mitogen regulated induction of FRA-1 proto-oncogene is controlled by the transcription factors binding to both serum and TPA response elements

Oncogene volume 24, pages 4193–4205 (2005)Cite this article

Abstract

FRA-1, a member of the FOS family of transcription factors, is overexpressed in a variety of human tumors, and contributes to tumor progression. In addition to mitogens, various toxicants and carcinogens persistently induce FRA-1 expression in vitro and in vivo. Although the mitogen induced expression of c-FOS is relatively well understood, it is poorly defined in the case of FRA-1. Our recent analysis of the FRA-1 promoter has shown a critical role for a TRE located at −318 in mediating the TPA-induced expression. The −379 to −283 bp promoter segment containing a critical TRE (−318), however, is insufficient for the induction of FRA-1 promoter. Here, we show that a 40-bp (−276/−237) segment, comprising a TCF binding site and the CArG box (collectively known as serum response element, SRE), and an ATF site, is also necessary for the FRA-1 induction by TPA and EGF. Interestingly, the −283 to +32 bp FRA-1 promoter fragment containing an SRE and an ATF site alone was also insufficient to confer TPA sensitivity to a reporter gene. However, in association with the −318 TRE, the SRE and ATF sites imparted a strong TPA-inducibility to the reporter. Similarly, EGF also required these motifs for the full induction of this gene. Using ChIP assays we show that, in contrast to c-Jun, SRF, Elk1, ATF1 and CREB proteins bind to SRE and ATF sites of the FRA-1 promoter, constitutively. RNAi-mediated knockdown of endogenous SRF, ELK1 and c-JUN protein expression significantly reduced TPA-stimulated FRA-1 promoter activity. Thus, a bipartite enhancer formed by an upstream TRE and the downstream SRE and ATF sites and the cognate factors is necessary and sufficient for the regulation of FRA-1 in response to mitogens.

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
Figure 8
Figure 9
Figure 10
Figure 11

Similar content being viewed by others

Abbreviations

AP-1:

activator protein-1

ATF:

activating transcription factor

ChIP:

chromatin immunoprecipitation

EBS:

Ets-binding site

EMSA:

electrophoretic mobility shift assay

FRA-1 or FOSL-1:

fos-related antigen 1

Luc:

luciferase

TCF:

ternary complex factor

TPA:

12-O-tetradecanoylphorbol-13-acetate

TRE:

TPA response element

SRF:

serum response factor

SRE:

serum response element

References

  • Adiseshaiah P, Papaiahgari SR, Vuong H, Kalvakolanu DV and Reddy SP . (2003). J. Biol. Chem., 278, 47423–47433.

  • Andersen H, Mahmood S, Tkach V, Cohn M, Kustikova O, Grigorian M, Berezin V, Bock E, Lukanidin E and Tulchinsky E . (2002). Oncogene, 21, 4843–4848.

  • Bergers G, Graninger P, Braselmann S, Wrighton C and Busslinger M . (1995). Mol. Cell. Biol., 15, 3748–3758.

  • Brusselbach S, Mohle-Steinlein U, Wang ZQ, Schreiber M, Lucibello FC, Muller R and Wagner EF . (1995). Oncogene, 10, 79–86.

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

  • Cook SJ, Aziz N and McMahon M . (1999). Mol. Cell. Biol., 19, 330–341.

  • Eferl R and Wagner EF . (2003). Nat. Rev. Cancer, 3, 859–868.

  • Gupta P and Prywes R . (2002). J. Biol. Chem., 277, 50550–50556.

  • Herrera RE, Shaw PE and Nordheim A . (1989). Nature, 340, 68–70.

  • Hu YC, Lam KY, Law S, Wong J and Srivastava G . (2001). Clin. Cancer Res., 7, 2213–2221.

  • Hurd TW, Culbert AA, Webster KJ and Tavare JM . (2002). Biochem. J., 368, 573–580.

  • Jochum W, David JP, Elliott C, Wutz A, Plenk Jr H, Matsuo K and Wagner EF . (2000). Nat. Med., 6, 980–984.

  • Konig H . (1991). Nucleic Acids Res., 19, 3607–3611.

  • Kustikova O, Kramerov D, Grigorian M, Berezin V, Bock E, Lukanidin E and Tulchinsky E . (1998). Mol. Cell Biol., 18, 7095–7105.

  • Lee TC, Shi Y and Schwartz RJ . (1992). Proc. Natl. Acad. Sci. USA, 89, 9814–9818.

  • Matsui M, Tokuhara M, Konuma Y, Nomura N and Ishizaki R . (1990). Oncogene, 5, 249–255.

  • Papaiahgari S, Kleeberger SR, Cho HY, Kalvakolanu DV and Reddy SP . (2004). J. Biol. Chem., 279, 42302–42312.

  • Parks WC and Shapiro SD . (2001). Respir. Res., 2, 10–19.

  • Patterson T, Vuong H, Liaw Y-S, Wu R, Kalvakolanu DV and Reddy SP . (2001). Oncogene, 20, 634–644.

  • Price MA, Cruzalegui FH and Treisman R . (1996). EMBO J., 15, 6552–6563.

  • Ramos-Nino ME, Timblin CR and Mossman BT . (2002). Cancer Res., 62, 6065–6069.

  • Reddy SP and Mossman BT . (2002). Am. J. Physiol. Lung Cell. Mol. Physiol., 283, L1161–L1178.

  • Reddy SP, Vuong H and Adiseshaiah P . (2002). Am. J. Respir. Crit. Care Med., 165, A828.

  • Robertson LM, Kerppola TK, Vendrell M, Luk D, Smeyne RJ, Bocchiaro C, Morgan JI and Curran T . (1995). Neuron, 14, 241–252.

  • Runkel L, Shaw PE, Herrera RE, Hipskind RA and Nordheim A . (1991). Mol. Cell. Biol., 11, 1270–1280.

  • Schreiber M, Poirier C, Franchi A, Kurzbauer R, Guenet JL, Carle GF and Wagner EF . (1997). Oncogene, 15, 1171–1178.

  • Selvaraj A and Prywes R . (2004). BMC Mol. Biol., 5, 13.

  • Soh JW, Lee EH, Prywes R and Weinstein IB . (1999). Mol. Cell. Biol., 19, 1313–1324.

  • Tornaletti S and Pfeifer GP . (1995). J. Mol. Biol., 249, 714–728.

  • Treisman R . (1995). EMBO J., 14, 4905–4913.

  • Treisman R . (1996). Curr. Opin. Cell Biol., 8, 205–215.

  • Tsuchiya H, Fujii M, Niki T, Tokuhara M, Matsui M and Seiki M . (1993). J. Virol., 67, 7001–7007.

  • Tulchinsky E . (2000). Histol. Histopathol., 15, 921–928.

  • Vallone D, Battista S, Pierantoni GM, Fedele M, Casalino L, Santoro M, Viglietto G, Fusco A and Verde P . (1997). EMBO J., 16, 5310–5321.

  • van Riggelen J, Buchwalter G, Soto U, De-Castro Arce J, Zur Hausen H, Wasylyk B and Rosl F . (2005). J. Biol. Chem., 280, 3286–3294.

  • Vial E and Marshall CJ . (2003). J. Cell. Sci., 116, 4957–4963.

  • Wang Y and Prywes R . (2000). Oncogene, 19, 1379–1385.

  • Whitmarsh AJ, Shore P, Sharrocks AD and Davis RJ . (1995). Science, 269, 403–407.

  • Wisdom R and Verma IM . (1993). Mol. Cell Biol., 13, 2635–2643.

  • Yang SH, Yates PR, Whitmarsh AJ, Davis RJ and Sharrocks AD . (1998). Mol. Cell. Biol., 18, 710–720.

  • Zajchowski DA, Bartholdi MF, Gong Y, Webster L, Liu HL, Munishkin A, Beauheim C, Harvey S, Ethier SP and Johnson PH . (2001). Cancer Res., 61, 5168–5178.

Download references

Acknowledgements

We thank Jawed Alam, Michael Birrer, Ron Prywes and Andrew Sharrocks for providing various expression vectors used in this study. This work was supported by NIH Grants ES011863, HL58122 and HL66109 (to SPR) and CA105005 and CA78282 (to DVK). We acknowledge the Johns Hopkins Urban Environmental Health Center for use of its core facilities, supported by grant ES30819.

Author information

Authors and Affiliations

  1. Department of Environmental Health Sciences, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD, 21205, USA

    Pavan Adiseshaiah, Suneetha Peddakama, Qin Zhang & Sekhar P Reddy

  2. University of Maryland Greenbaum Cancer Center, Maryland, MD 21201, USA

    Dhanunjaya V Kalvakolanu

  3. Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, MD, 21205, USA

    Sekhar P Reddy

Authors
  1. Pavan Adiseshaiah
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Suneetha Peddakama
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dhanunjaya V Kalvakolanu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sekhar P Reddy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sekhar P Reddy.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Adiseshaiah, P., Peddakama, S., Zhang, Q. et al. Mitogen regulated induction of FRA-1 proto-oncogene is controlled by the transcription factors binding to both serum and TPA response elements. Oncogene 24, 4193–4205 (2005). https://doi.org/10.1038/sj.onc.1208583

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1208583

Keywords

This article is cited by

Search

Advanced search

Quick links