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:

p16INK4a gene promoter variation and differential binding of a repressor, the ras-responsive zinc-finger transcription factor, RREB

Oncogene volume 22, pages 2285–2295 (2003)Cite this article

Abstract

BALB/c mice are susceptible to the development of pristane-induced plasma cell tumors, and have a rare allelic variant in the coding region of the p16INK4a (p16) tumor suppressor gene that produces a protein with impaired activity. We have now found that the BALB/c p16 promoter has an allelic variant that may also compromise p16 activity. Following pristane treatment, BALB/c p16 mRNA levels in B cells were lower than that in DBA/2 or C.D2-Pctr1, a resistant BALB/c congenic strain that harbors DBA/2 chromatin surrounding the p16 locus. Four sequence variants were found between BALB/c and DBA/2 in the p16 promoter region. In reporter assays, the DBA promoter was at least four times more active in driving luciferase expression than the BALB/c promoter. Most of the difference in activity was localized to a single nucleotide deletion in BALB/c. This deletion created a consensus binding site for RREB, a ras-responsive transcriptional element with zinc-finger binding motifs. Transient transfections with RREB confirmed that the p16 promoter can be downregulated by RREB, in a Ras- or Mek-dependent manner, and that the BALB/c promoter is more sensitive than DBA/2 to regulation by RREB. BALB/c mice have both regulatory and coding region defects that may contribute to the impairment of p16 gene function.

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 8
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  • Alani RM, Young AZ and Shifflett CB . (2001). Proc. Natl. Acad. Sci. USA, 98, 7812–7816.

  • Anborgh PH, Qian X, Papageorge AG, Vass WC, DeClue JE and Lowy DR . (1999). Mol. Cell Biol., 19, 4611–4622.

  • Baylin SB and Bestor TH . (2002). Cancer Cell, 1, 299–305.

  • Bottorff D, Stang S, Agellon S and Stone JC . (1995). Mol. Cell Biol., 15, 5113–5122.

  • Brown RT, Ades IZ and Nordan RP . (1995). J. Biol. Chem., 270, 31129–31135.

  • Dilworth D, Liu L, Stewart AK, Berenson JR, Lassman N and Hogg D . (1999). Blood, 95, 1869–1871.

  • Ewen ME, Sluss HK, Sherr CJ, Matsushime H, Kato JY and Livingston DM . (1993). Cell, 73, 487–497.

  • Goodrich DW, Wang NP, Qian Y-W, Lee EY-HP and Lee W-H . (1991). Cell, 67, 293–302.

  • Herzog CR, Noh S, Lantry LE, Guan K-L and You M . (1999). Mol. Carcinogenesis., 25, 92–98.

  • Hilbert DM, Kopf M, Mock BA, Kohler G and Rudikoff S . (1995). J. Exp. Med., 182, 243–248.

  • Hussussian CJ, Struewing JP, Goldstein AM, Higgins PAT, Ally DS, Sheahan MD, Clark WH, Tucker MA and Dracopoli NC . (1994). Nat. Genet., 8, 15–21.

  • Jones PA and Baylin SB . (2002). Nat. Rev. Genet., 3, 415–428.

  • Kaneko S, Nishioka J, Tanaka M, Nakashima K and Nobori T . (1999). Biochem. Mol. Biol. Int., 47, 205–215.

  • Kato J-Y, Matsushime H, Hiebert SW, Ewen ME and Sherr CJ . (1993). Genes Dev., 7, 331–342.

  • Klangby U, Okan I, Magnusson KP, Wendland M, Lind P and Wiman KG . (1998). Blood, 91, 1680–1687.

  • Krimpenfort P, Quon KC, Mooi WJ, Loonstra A and Berns A . (2001). Nature, 413, 83–86.

  • Matsushime H, Quelle DE, Shurtleff SA, Shibuya M, Sherr CJ and Kato J-Y . (1994). Mol. Cell Biol., 14, 2066–2076.

  • Mock BA, Hartley J, Le Tissier P, Wax JS and Potter M . (1997). Blood, 90, 4092–4098.

  • Mock BA, Krall MA and Dosik JK . (1993). Proc. Natl. Acad. Sci. USA, 90, 9499–9503.

  • Morse III HC, Hartley JW and Potter M . (1980). Progress in Myeloma. Potter M. (ed), Elsevier North Holland. Inc.: Amsterdam, pp. 263–279.

    Book  Google Scholar 

  • Myohanen S and Baylin SB . (2001). J. Biol. Chem., 276, 1634–1642.

  • Nordan RP and Potter M . (1986). Science, 233, 566–569.

  • Ogata A, Chauhan D, Teoh G, Treon SP, Urashima M, Schlossman RL and Anderson KC . (1997). J. Immunol., 159, 2212–2221.

  • Ohtani N, Zebedee Z, Hunt TJ, Stinson JA, Sugimoto M, Ohashi Y, Sharrocks AD, Peters G and Hara E . (2001). Nature, 409, 1067–1070.

  • Passegue E and Wagner EF . (2000). EMBO J., 19, 2969–2979.

  • Potter M . (1984). Cancer Surveys, 3, 247–264.

  • Potter M and Boyce CR . (1962). Nature, 193, 1086–1087.

  • Potter M, Morrison S, Wiener F, Zhang XK and Miller FW . (1994a). J. Natl. Cancer Inst., 86, 1058–1065.

  • Potter M, Mushinski EB, Wax JS, Hartley J and Mock B . (1994b). Cancer Res., 54, 969–975.

  • Puthier D, Bataille R and Amiot M . (1999). Eur. J. Immunol., 29, 3945–3950.

  • Sambrook J, Fritsch EF and Maniatis T . (1989). Molecular Cloning: A Laboratory Manual, 2nd edn. Cold Spring Harbor: New York.

    Google Scholar 

  • Sharpless NE, Bardeesy N, Lee K-H, Carrasco D, Castrillon DH, Aguirre AJ, Wu EA, Horner JW and DePinho RA . (2001). Nature, 413, 86–91.

  • Soloff EV, Herzog CR and You M . (1996). Gene, 180, 213–215.

  • Taniai M, Higuchi H, Burgart LJ and Gores GJ . (2002). Gastroenterology, 123, 1090–1098.

  • Thiagalingam A, de Bustros A, Borges M, Jasti R, Compton D, Diamond L, Mabry M, Ball DW, Baylin SB and Nelkin BD . (1996). Mol. Cell. Biol., 16, 5335–5345.

  • Wang W, Wu J, Zhang Z and Tong T . (2001). J. Biol. Chem., 276, 48655–48661.

  • Zhang S and Mock BA . (1999). Curr. Topics Microbiol. Immunol., 246, 363–368.

  • Zhang S, Ramsay ES and Mock BA . (1998). Proc. Natl. Acad. Sci. USA, 95, 2429–2434.

  • Zhang SL, DuBois W, Ramsay ES, Bliskovski V, Morse III HC, Taddesse-Heath L, Vass WC, DePinho RA and Mock BA . (2001). Mol. Cell. Biol., 21, 310–318.

Download references

Acknowledgements

We thank Wendy DuBois for providing us with pristane-primed mice, Klaus Felix for sharing his time and protocols in the isolation and enrichment of splenic lymphocytes for B cells, Barry Nelkin (JHU) for providing us with an RREB cDNA, Christine Meek for her efforts in sequencing the p16 promoter and RREB constructs, Bill Vass for his assistance with the NIH 3T3 transfections, and Wei Shi for valuable discussions.

Author information

Authors and Affiliations

  1. Laboratory of Genetics, Center for Cancer Research, NCI, NIH, 37 Convent Drive, MSC 4255, Bldg. 37, Rm 2B-08, Bethesda, 20892-4255, MD, USA

    Shuling Zhang, Chanelle Redman, Valeri Bliskovski, Edward S Ramsay & Beverly A Mock

  2. Laboratory of Cellular Oncology, Center for Cancer Research, NCI, NIH, 37 Convent Drive, MSC 4263, Bldg. 37, Rm 4106, Bethesda, 20892-4263, MD, USA

    Xiaolan Qian & Douglas R Lowy

Authors
  1. Shuling Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaolan Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chanelle Redman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Valeri Bliskovski
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Edward S Ramsay
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Douglas R Lowy
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Beverly A Mock
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Beverly A Mock.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, S., Qian, X., Redman, C. et al. p16INK4a gene promoter variation and differential binding of a repressor, the ras-responsive zinc-finger transcription factor, RREB. Oncogene 22, 2285–2295 (2003). https://doi.org/10.1038/sj.onc.1206257

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1206257

Keywords

This article is cited by

Search

Advanced search

Quick links