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:

Differential effects of transforming growth factor on cell cycle regulatory molecules in human myeloid leukemia cells

Oncogene volume 20, pages 6840–6850 (2001)Cite this article

Abstract

In this report we have studied the mechanism by which Transforming Growth Factor beta (TGFβ) inhibits growth of human myeloid leukemia cell lines. TGFβ1 arrested cells in G1 phase and significantly downregulated the expression of cyclin D2, cyclin D3, cdk4, cyclin A, and cdk2. The downregulation of the molecules resulted in approximately 50–90% decrease of the molecule-dependent kinase activity, varying with each molecule. Although treatment of cells with TGFβ1 up-regulated accumulation of p27kip1 in both nucleus and cytoplasm, the association of the p27kip1 with cdk2, cyclin A, cyclin D2, cyclin D3, and cdk4 was markedly down-regulated, suggesting that p27kip1 is not responsible for the downregulation of the kinase activity. In contrast, TGFβ1 upregulated cyclin E-associated p27kip1 with no effect on the expression of cyclin E. p27kip1-immunodepletion upregulated cyclin E-dependent kinase activity by more than 10-fold in TGFβ1-treated cells but not in proliferating cells; whereas immunodepletion of p27kip1 from cdk2-immunoprecipitates markedly downregulated cdk2 kinase activity in the lysates extracted from both proliferating and TGFβ-treated cells. Consistent with this observation, TGFβ1 and p27kip1 antisense cDNA had a synergistic or additive inhibitory effect on cdk2 but not cyclin E-dependent kinase activity. Our data suggest that (1) TGFβ1-mediated growth inhibition is accomplished through multiple pathways and (2) p27kip1 has opposing effects on cdk2 and cyclin E activity in response to TGFβ1.

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

Similar content being viewed by others

References

  • Ando K, Ajchenbaum-Cymbalista F, Griffin JD . 1993 Proc. Natl. Acad. Sci. USA 90: 9571–9575

  • Bates S, Bonetta L, MacAllan D, Parry D, Holder A, Dickson C, Peters G . 1994 Oncogene 9: 71–79

  • Cheng M, Olivier P, Diehl JA, Fero M, Roussel MF, Roberts JM, Sherr CJ . 1999 EMBO J. 18: 1571–1583

  • Drexler HG, Meyer C, Zaborski M, Uphoff CC, Quentmeier H . 1998 Leuk. Res. 22: 927–938

  • Eween ME, Sluse HK, Whitehouse LL, Livingston DM . 1993 Cell 74: 1009–1020

  • Fautsch MP, Eblen ST, Anders RA, Burnette RJ, Leof EB . 1995 J. Cell Biochem. 58: 517–526

  • Geng Y, Weinberg RA . 1993 Proc. Natl. Acad. Sci. USA 90: 10315–10319

  • Guan KL, Jenkins CW, Li Y, Nichols MA, Okeefe CL, Matera AG, Xiong Y . 1994 Genes Dev. 8: 2939–2952

  • Hannon GJ, Beach D . 1994 Nature 371: 257–261

  • Harper JW, Admi GR, Wei N, Keymarsi K, Elledge SJ . 1993 Cell 75: 805–816

  • Hengst L, Dulic V, Slingerland JM, Lees E, Reed SI . 1994 Proc. Natl. Acad. Sci. USA 91: 5291–5295

  • Hirai H, Roussel MF, Kato JY, Ashmum RA, Sherr CJ . 1995 Mol. Cell. Biol. 15: 2672–2681

  • Hu X, Cress DW, Zhong Q, Zuckerman KS . 2000 Biochem. Biophys. Res. Commun. 276: 930–939

  • Hu X, Moscinski LC, Zuckerman KS . 1999 Exp. Hematol. 27: 605–614

  • Hunter T . 1995 Cell 80: 225–236

  • Kamb A, Gruis NA, Weaver-Feldhaus J, Lui O, Harshman K, Tavigian SV, Stocker E, Day RS, Johnson BE, Skolnick MH . 1994 Science 264: 436–440

  • Kato JY, Matsuoka M, Massague PJ, Sherr CJ . 1994 Cell 79: 487–496

  • Kato JY, Sherr CJ . 1993 Proc. Natl. Acad. Sci. USA 90: 11513–11517

  • Koff A, Giordano A, Desai D, Yamashita K, Harper JW, Elledge S, Nishimoto T, Morgan DO . 1992 Science 257: 1689–1694

  • Koff A, Ohtsuki M, Polyak K, Roberts JM, Massague J . 1993 Science 260: 536–539

  • LaBaer J, Garrett MD, Stevenson LF, Slingerland JM, Sandhu C, Chou HS, Harlow FA . 1997 Genes Dev. 11: 847–862

  • Lew DJ, Dulic V, Reed SI . 1991 Cell 66: 1197–1206

  • Liu M, Lee MH, Cohen M, Bommakanti M, Freedman LP . 1996 Genes Dev. 10: 142–153

  • Matsuoka S, Edwards MC, Bai C, Parker S, Zhang P, Baldini A, Harpen JW, Elledge SJ . 1995 Genes Dev. 9: 650–662

  • Matsushime H, Quelle DE, Shurtleff SA, Shibuya M, Sherr CJ, Kato JY . 1994 Mol. Cell. Biol. 14: 2066–2076

  • Matsushime H, Ewen ME, Strom DK, Kato JY, Hanks SK, Roussel MF, Sherr CJ . 1992 Cell 71: 323–334

  • Matsushime H, Roussel MF, Ashmun RA, Sherr CJ . 1991 Cell 65: 701–713

  • Meyerson M, Harlow E . 1994 Mol. Cell. Biol. 14: 2077–2086

  • Nakayama K, Ishida N, Shirane M, Inomata A, Inoue T, Shishido N, Horii I, Loh DY, Nakayama K . 1996 Cell 85: 707–720

  • Nourse J, Firpo E, Flanagan WM, Coats S, Polyak K, Lee MH, Massague J, Crabtree GR, Roberts JM . 1994 Nature 372: 570–573

  • Orend G, Hunter T, Ruoslahti E . 1998 Oncogene 16: 2575–2583

  • Pagano M, Pepperkok R, Lukas J, Baldin V, Ansorge W, Bartek J, Draetta G . 1993 J. Cell Biol. 121: 101–111

  • Polyak K, Kato JY, Solomon MJ . 1994 Genes Dev. 8: 9–22

  • Polyak K, Lee MH, Bromage HE, Koff A, Roberts JM, Tempst P, Massague J . 1994 Cell 78: 59–66

  • Poon RYC, Toyoshima H, Hunter T . 1995 Mol. Biol. Cell 6: 1197–1213

  • Porter PL, Malone KE, Heagerty PJ, Alexander GM, Gatli LA, Firpo EJ, Daling JR, Roberts JM . 1997 Nat. Med. 3: 222–225

  • Resnitzky D, Gossen M, Bujard H, Reed SI . 1994 Mol. Cell. Biol. 14: 1669–1679

  • Reynisdottir I, Polyak K, Iavarone A, Massague J . 1995 Genes Dev. 9: 1831–1845

  • Reynisdottir I, Massague J . 1997 Genes Dev. 11: 492–503

  • Russo AA, Jeffrey PD, Patten AK, Massague J, Pavletich NP . 1996 Nature 382: 325–331

  • Sherr CJ . 1993 Cell 73: 1059–1065

  • Sherr CJ . 1994 Cell 79: 551–555

  • Sherr CJ, Roberts JM . 1995 Genes Dev. 9: 1149–1163

  • Singh SP, Lipman J, Goldman H, Ellis Jr FH, Aizenman L, Cangi MG, Signoretti S, Chiaur DS, Pagano M, Loda M . 1998 Cancer Res. 58: 1730–1735

  • Slingerland JM, Hengst L, Pan C, Alexander D, Stampfer M, Reed SI . 1994 Mol. Cell. Biol. 14: 3683–3694

  • Toyoshima H, Hunter T . 1994 Cell 78: 67–74

  • Tsai L, Lees E, Faha B, Harlow E, Riabowol K . 1993 Oncogene 8: 1593–1602

  • Wang G, Miskimins R, Miskimins WK . 1999 Oncogene 18: 5204–5210

  • Xiong Y, Connolly T, Futcher B, Beach D . 1991 Cell 65: 691–699

Download references

Author information

Authors and Affiliations

  1. Interdisciplinary Oncology Program, University of South Florida, and H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA

    Xiaotang Hu, Qing Zhong, Ariana B Fisher, Matthew Bryington & Kenneth S Zuckerman

  2. Department of Biochemistry and Molecular Biology, University of South Florida, and H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA

    Xiaohong Zhang & Kenneth S Zuckerman

Authors
  1. Xiaotang Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaohong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qing Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ariana B Fisher
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Matthew Bryington
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kenneth S Zuckerman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiaotang Hu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hu, X., Zhang, X., Zhong, Q. et al. Differential effects of transforming growth factor on cell cycle regulatory molecules in human myeloid leukemia cells. Oncogene 20, 6840–6850 (2001). https://doi.org/10.1038/sj.onc.1204790

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1204790

Keywords

This article is cited by

Search

Advanced search

Quick links