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:

KLF2 inhibits Jurkat T leukemia cell growth via upregulation of cyclin-dependent kinase inhibitor p21WAF1/CIP1

Oncogene volume 23, pages 8088–8096 (2004)Cite this article

Abstract

Krüppel-like factor 2 (KLF2) is a member of the KLF family of zinc-finger transcription factors and is involved in maintaining T-cell quiescence, regulating preadipocyte differentiation, endothelial cell function and lung development. We used a tetracycline-inducible system in Jurkat T leukemia cells to study the biological role of KLF2 in cellular growth and differentiation. Our results show that expression of KLF2 inhibits cell growth in autonomously proliferating Jurkat cells. Further, 3H-thymidine uptake assays indicate that KLF2 inhibits DNA synthesis in these cells. Moreover, both activation and inhibitory domains are required for KLF2 to suppress Jurkat cell proliferation. In addition, KLF2 upregulates p21WAF1/CIP1 expression. Additionally, we found that KLF2 upregulates p21WAF1/CIP1 promoter activity in Jurkat, HepG2 and SW480 cells. Our analysis shows that the potential KLF2 responsive elements are located between −124 and −60 of the p21WAF1/CIP1 promoter. The sole CACCC site, a sequence recognized by KLF2, in this region is not the element responsive to KLF2. Finally, we determined that the Sp1-3-binding site is the functional responsive element of KLF2 in the p21WAF1/CIP1 promoter, and we conclude that KLF2 directly regulates p21WAF1/CIP1 expression.

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

Similar content being viewed by others

Abbreviations

LKLF:

lung Krüppel-like factor

KLF2:

Krüppel-like factor 2

HA:

hemagglutin

Tet:

Tetracycline

Dox:

Doxycycline

Multiple RT–PCR:

multiple reverse transcription polymerase chain reaction

luc:

Luciferase

β-gal:

β-galactosidase

References

  • Anderson KP, Kern CB, Crable SC and Lingrel JB . (1995). Mol. Cell. Biol., 15, 5957–5965.

  • Banerjee SS, Feinberg MW, Watanabe M, Gray S, Haspel RL, Denkinger DJ, Kawahara R, Hauner H and Jain MK . (2003). J. Biol. Chem., 278, 2581–2584.

  • Black AR, Black JD and Azizkhan-Clifford J . (2001). J. Cell. Physiol., 188, 143–160.

  • Buckley AF, Kuo CT and Leiden JM . (2001). Nat. Immunol., 2, 698–704.

  • Chen J, Jackson PK, Kirschner MW and Dutta A . (1995). Nature, 374, 386–388.

  • Conkright MD, Wani MA and Lingrel JB . (2001). J. Biol. Chem., 276, 29299–29306.

  • Datto MB, Yu Y and Wang XF . (1995). J. Biol. Chem., 270, 28623–28628.

  • Denkinger DJ, Cushman-Vokoun AM and Kawahara RS . (2001). Gene, 281, 133–142.

  • Dynlacht B . (1997). Nature, 389, 149–152.

  • el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW and Vogelstein B . (1993). Cell, 75, 817–825.

  • Gartel AL and Tyner AL . (1999). Exp Cell. Res., 246, 280–289.

  • Geiman DE, Ton-That H, Johnson JM and Yang VW . (2000). Nucleic Acids Res., 28, 1106–1113.

  • Gossen M, Freundlieb S, Bender G, Muller G, Hillen W and Bujard H . (1995). Science, 268, 1766–1769.

  • Harper JW, Adami GR, Wei N, Keyomarsi K and Elledge SJ . (1993). Cell, 75, 805–816.

  • Harper JW and Elledge SJ . (1996). Curr. Opin. Genet. Dev., 6, 56–64.

  • Koritschoner NP, Bocco JL, Panzetta-Dutari GM, Dumur CI, Flury A and Patrito LC . (1997). J. Biol. Chem., 272, 9573–9580.

  • Kuo CT, Veselits ML, Barton KP, Lu MM, Clendenin C and Leiden JM . (1997a). Genes Dev., 11, 2996–3006.

  • Kuo CT, Veselits ML and Leiden JM . (1997b). Science, 277, 1986–1990.

  • Kuo CT, Veselits ML and Leiden JM . (1997c). Science, 278, 788–789.

  • Lagger G, Doetzlhofer A, Schuettengruber B, Haidweger E, Simboeck E, Tischler J, Chiocca S, Suske G, Rotheneder H, Wintersberger E and Seiser C . (2003). Mol. Cell. Biol., 23, 2669–2679.

  • Lu S, Jenster G and Epner DE . (2000). Mol. Endocrinol., 14, 753–760.

  • Nakano K, Mizuno T, Sowa Y, Orita T, Yoshino T, Okuyama Y, Fujita T, Ohtani-Fujita N, Matsukawa Y, Tokino T, Yamagishi H, Oka T, Nomura H and Sakai T . (1997). J. Biol. Chem., 272, 22199–22206.

  • Narla G, Heath KE, Reeves HL, Li D, Giono LE, Kimmelman AC, Glucksman MJ, Narla J, Eng FJ, Chan AM, Ferrari AC, Martignetti JA and Friedman SL . (2001). Science, 294, 2563–2566.

  • Omotehara F, Kawamata H, Uchida D, Hino S, Nakashiro K and Fujimori T . (2002). Br. J. Cancer, 87, 1042–1046.

  • Ratziu V, Lalazar A, Wong L, Dang Q, Collins C, Shaulian E, Jensen S and Friedman SL . (1998). Proc. Natl. Acad. Sci. USA, 95, 9500–9505.

  • Seoane J, Le HV and Massague J . (2002). Nature, 419, 729–734.

  • Sherr CJ . (1994). Cell, 79, 551–555.

  • Sherr CJ and Roberts JM . (1995). Genes Dev., 9, 1149–1163.

  • Shie JL, Chen ZY, O'Brien MJ, Pestell RG, Lee ME and Tseng CC . (2000). Am. J. Physiol. Gastrointest. Liver Physiol., 279, G806–G814.

  • Shields JM, Christy RJ and Yang VW . (1996). J. Biol. Chem., 271, 20009–20017.

  • Somasundaram K, Zhang H, Zeng YX, Houvras Y, Peng Y, Zhang H, Wu GS, Licht JD, Weber BL and El-Deiry WS . (1997). Nature, 389, 187–190.

  • Wang CH, Tsao YP, Chen HJ, Chen HL, Wang HW and Chen SL . (2000). Biochem. Biophys. Res. Commun., 270, 303–310.

  • Wani MA, Conkright MD, Jeffries S, Hughes MJ and Lingrel JB . (1999a). Genomics, 60, 78–86.

  • Wani MA, Means Jr RT and Lingrel JB . (1998). Transgenic Res., 7, 229–238.

  • Wani MA, Wert SE and Lingrel JB . (1999b). J. Biol. Chem., 274, 21180–21185.

  • Yang ZY, Perkins ND, Ohno T, Nabel EG and Nabel GJ . (1995). Nat. Med., 1, 1052–1056.

  • Zeng YX, Somasundaram K and el-Deiry WS . (1997). Nat. Genet., 15, 78–82.

  • Zhang H, Xiong Y and Beach D . (1993). Mol. Biol. Cell., 4, 897–906.

  • Zhang W, Geiman DE, Shields JM, Dang DT, Mahatan CS, Kaestner KH, Biggs JR, Kraft AS and Yang VW . (2000). J. Biol. Chem., 275, 18391–18398.

Download references

Acknowledgements

We. thank Drs Abdel-Malek Z and Manga P (University of Cincinnati) for kindly providing human normal fibroblasts and melanoma cell line (Mel-188), respectively. We also acknowledge Dr B Vogelstein (John Hopkins University), Dr H Kawamata and Dr T Fujimori (Dokkyo University School of Medicine, Japan), and Dr T Sakai (Kyoto Prefecture University of Medicine, Japan) for kindly providing WWP Luc, pGL3-WWP and pGL3-WWP-0.2, pWP124 and pWPdel-SmaI, respectively. This work was supported by National Institutes of Health grant RO1 HL 57281 (to JBL).

Author information

Authors and Affiliations

  1. Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, College of Medicine, 231 Albert Sabin Way, Cincinnati, 45267, OH, USA

    Jinghai Wu & Jerry B Lingrel

Authors
  1. Jinghai Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jerry B Lingrel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jerry B Lingrel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wu, J., Lingrel, J. KLF2 inhibits Jurkat T leukemia cell growth via upregulation of cyclin-dependent kinase inhibitor p21WAF1/CIP1. Oncogene 23, 8088–8096 (2004). https://doi.org/10.1038/sj.onc.1207996

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207996

Keywords

This article is cited by

Search

Advanced search

Quick links