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:

Upregulation of p21WAF1/CIP1 leads to morphologic changes and esterase activity in TPA-mediated differentiation of human prostate cancer cell line TSU-Pr1

Oncogene volume 20, pages 1220–1228 (2001)Cite this article

Abstract

We reported previously that human prostate cancer cell line TSU-Pr1 can differentiate into microglia-like cells by 12-O-tetra-decanoylphorbol-13-acetate (TPA) treatment. In this study, we identified a signal transduction pathway involved in TPA-induced TSU-Pr1 cell differentiation and investigated the mechanism of growth arrest that accompanies this differentiation. TPA-induced differentiation and growth arrest of TSU-Pr1 cells were inhibited by treatment with Protein kinase C (PKC) inhibitor GF109203X and mitogen-activated protein (MAP) kinase inhibitor PD98059. Treatment of TSU-Pr1 cells with TPA for 15 min or longer resulted in translocation of PKCα, PKCγ, and PKCε from cytosolic to membrane fraction. Our results suggest that TPA-induced TSU-Pr1 cell differentiation is associated with activation of MAP kinase and PKCα, PKCγ, and PKCε. The mechanism of growth arrest in TSU-Pr1 cells that underwent TPA-induced differentiation were examined for factors in the signaling pathway downstream of MAP kinase that control the cell cycle. Upregulation of p21WAF1/CIP1 cyclin-dependent kinase inhibitor protein was observed in a manner dependent on PKC or MAP kinase. Moreover, adenovirus-mediated overexpression of recombinant p21WAF1/CIP1 in TSU-Pr1 cells result in growth arrest, morphological change to microglia-like cells, and increased α-naphthyl acetate esterase activity, all of which are associated with cellular differentiation. Thus, our results indicate that p21WAF1/CIP1 mediates TPA-induced growth arrest and differentiation of TSU-Pr1 cells.

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

Similar content being viewed by others

Abbreviations

TPA:

12-O-tetra-decanoylphorbol-13-acetate

PKC:

protein kinase C

PKA:

protein kinase A

MAP kinase:

mitogen-activated protein kinase

ERK:

extracellular signal-regulated protein kinase

FBS:

fetal bovine serum

JNK:

c-Jun NH2-terminal protein kinase

CDK:

cyclin dependent kinase

AP2:

activator protein 2

pRB:

retinoblastoma protein

References

  • Akashi M, Osawa Y, Koeffler HP and Hachiya M. . 1999 Biochem. J. 337: 607–616.

  • Asada M, Yamada T, Fukumuro K and Mizutani S. . 1998 Leukemia 12: 1944–1950.

  • Barboule N, Lafon C, Chadebech P, Vidal S and Valette A. . 1999 FEBS Lett. 444: 32–37.

  • Barendsen N, Mueller M and Chen B. . 1990 Leuk. Res. 14: 467–474.

  • Beier F, Taylor AC and LuValle P. . 1999 J. Biol. Chem. 274: 30273–30279.

  • Bouche M, Zappelli F, Polimeni M, Adamo S, Wetsel WC, Senni MI and Molinaro M. . 1995 Cell Growth Differ. 6: 845–852.

  • Chang BD, Watanabe K, Broude EV, Fang J, Poole JC, Kalinichenko TV and Roninson IB. . 2000 Proc. Natl. Acad. Sci. USA 97: 4291–4296.

  • Chen J, Willingham T, Shuford M, Bruce D, Rushing E, Smith Y and Nisen PD. . 1996 Oncogene 13: 1395–1403.

  • Cobb MH and Goldsmith EJ. . 1995 J. Biol. Chem. 270: 14843–14846.

  • Das D, Pintucci G and Stern A. . 2000 FEBS Lett. 472: 50–52.

  • Dekker LV and Parker PJ. . 1994 Trends Biochem. Sci. 19: 73–77.

  • 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.

  • Erhardt JA and Pittman RN. . 1998 J. Biol. Chem. 273: 23517–23523.

  • Fowles LF, Martin ML, Nelsen L, Stacey KJ, Redd D, Clark YM, Nagamine Y, McMahon M, Hume DA and Ostrowski MC. . 1998 Mol. Cell Biol. 18: 5148–5156.

  • Frey MR, Saxon ML, Zhao X, Rollins A, Evans SS and Black JD. . 1997 J. Biol. Chem. 272: 9424–9435.

  • Gartel AL, Serfas MS, Gartel M, Goufman E, Wu GS, El-Deiry WS and Tyner AL. . 1996 Exp. Cell Res. 227: 171–181.

  • Halevy O, Novitch BG, Spicer DB, Skapek SX, Rhee J, Hannon GJ, Beach D and Lassar AB. . 1995 Science 267: 1018–1021.

  • Hall MC, Li Y, Pong RC, Ely B, Sagalowsky AI and Hsieh JT. . 2000 J. Urol. 163: 1033–1038.

  • Heikkila J, Jalava A and Eriksson K. . 1993 Biochem. Biophys. Res. Commun. 197: 1185–1193.

  • Heikkila JE, Akerlind G and Akerman KE. . 1989 J. Cell Physiol. 140: 593–600.

  • Hoshi M, Nishida E and Sakai H. . 1988 J. Biol. Chem. 263: 5396–5401.

  • Huppi K, Siwarski D, Dosik J, Michieli P, Chedid M, Reed S, Mock B, Givol D and Mushinski JF. . 1994 Oncogene 9: 3017–3020.

  • Iizumi T, Yazaki T, Kanoh S, Kondo I and Koiso K. . 1987 J. Urol. 137: 1304–1306.

  • Itayasu T, Shimizu T, Iizumi T, Oshio S, Umeda T and Takeda K. . 1998 Anticancer Res. 18: 113–118.

  • Jaken S and Kiley SC. . 1994 Trends Cell Biol. 4: 223–227.

  • Jiang H, Lin J, Su Z, Collart FR, Huberman E and Fisher PB. . 1994 Oncogene 9: 3397–3406.

  • Joshi US, Chen YQ, Kalemkerian GP, Adil MR, Kraut M and Sarkar FH. . 1998a Cancer Gene Ther. 5: 183–191.

  • Joshi US, Dergham ST, Chen YQ, Dugan MC, Crissman JD, Vaitkevicius VK and Sarkar FH. . 1998b Pancreas 16: 107–113.

  • Kagawa S, Fujiwara T, Kadowaki Y, Fukazawa T, Sok-Joo R, Roth JA and Tanaka N. . 1999 Cell Death Differ. 6: 765–772.

  • Kolch W, Heidecker G, Kochs G, Hummel R, Vahidi H, Mischak H, Finkenzeller G, Marme D and Rapp UR. . 1993 Nature 364: 249–252.

  • L'Allemain G, Lavoie JN, Rivard N, Baldin V and Pouyssegur J. . 1997 Oncogene 14: 1981–1990.

  • Liu J, Shen X, Nguyen VA, Kunos G and Gao B. . 2000 J. Biol. Chem. 275: 11846–11851.

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

  • Macleod K, Sherry N, Hannon G, Beach D, Tokino T, Kinzler K, Vogelstein B and Jacks T. . 1995 Genes Dev. 9: 935–944.

  • Marshall CJ. . 1994 Curr. Opin. Genet. Dev. 4: 82–89.

  • Milanini J, Vinals F, Pouyssegur J and Pages G. . 1998 J. Biol. Chem. 273: 18165–18172.

  • Missero C, Calautti E, Eckner R, Chin J, Tsai L, Livingston D and Dotto GP. . 1995 Proc. Natl. Acad. Sci. USA 92: 5451–5455.

  • Mitsui K, Matsumoto A, Ohtsuka S, Ohtsubo M and Yoshimura A. . 1999 Biochem. Biophys. Res. Commun. 264: 457–464.

  • Miyake S, Makimura M, Kanegae Y, Harada S, Sato Y, Takamori K, Tokuda C and Saito I. . 1996 Proc. Natl. Acad. Sci. USA 93: 1320–1324.

  • McShea A, Samuel T, Eppel JT, Galloway DA and Funk JO. . 2000 J. Biol. Chem. 275: 23181–23186.

  • Newton AC. . 1997 Curr. Opin. Cell Biol. 9: 161–167.

  • Nishikawa M, Uemura Y, Hidaka H and Shirakawa S. . 1986 Life Sci. 39: 1101–1107.

  • Nishizuka Y. . 1995 FASEB J. 9: 484–496.

  • Powell CT, Brittis NJ, Stec D, Hug H, Heston WDW and Fair WR. . 1996 Cell Growth Differ. 7: 419–428.

  • Rapp UR. . 1991 Oncogene 6: 495–500.

  • Ray LB and Sturgill TW. . 1987 Proc. Natl. Acad. Sci. USA 84: 1502–1506.

  • Rossomando AJ, Payne DM, Weber MJ and Sturgill TW. . 1989 Proc. Natl. Acad. Sci. USA 86: 6940–6943.

  • Rovera G, Ferraro D, Pagliardi GL, Vartikar J, Pessano S, Bottera L, Abraham S and Lebman D. . 1982 Ann. NY Acad. Sci. 397: 211–220.

  • Rovera G, O'Brien TG and Diamond L. . 1979 Science 204: 868–870.

  • Steinman RA, Hoffman B, Iro A, Guillouf C, Liebermann DA and El-Houseini ME. . 1994 Oncogene 9: 3389–3396.

  • Takahashi N, Shinizu T and Takeda K. . 2000 Prostate 44: 328–333.

  • Ueda Y, Hirai S, Osada S, Suzuki A, Mizuno K and Ohno S. . 1996 J. Biol. Chem. 271: 23512–23519.

  • Wang Z, Su ZZ, Fisher PB, Wang S, VanTuyle G and Grant S. . 1998 Exp. Cell Res. 244: 105–116.

  • Yam LT, Li CY and Crosby WH. . 1971 Am. J. Clin. Pathol. 55: 283–290.

  • Yamauchi Y, Nagasawa K, Mayumi T, Horiuchi T and Niho Y. . 1989 Br. J. Cancer 60: 15–19.

  • Yang Z, Perkins ND, Ohno T, Nabel EG and Nabel GJ. . 1995 Nat. Med. 1: 1052–1056.

  • Zeng Y and El-Deiry WS. . 1996 Oncogene. 12: 1557–1564.

  • Zeng Y, Somasundaram K and El-Deiry WS. . 1997 Nat. Genet. 15: 78–82.

  • Zezula J, Sexl V, Hutter C, Karel A and Schütz W. . 1997 J. Biol. Chem. 272: 29967–29974.

Download references

Acknowledgements

We are grateful to Dr FM Musa for this continuous support, and Mr M Koga for his excellent technical assistance. This work was supported in part by a Grant-in Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan.

Author information

Authors and Affiliations

  1. Department of Hygiene Chemistry, Faculty of Pharmaceutical Sciences, Science University of Tokyo, 12 Ichigaya-Funagawara-machi, Shinjuku-ku, Tokyo, 162-0826, Japan

    Ryo Sugibayashi, Takahisa Shimizu, Toshihiro Suzuki, Naoki Yamamoto & Ken Takeda

  2. Sapporo Medical University Department of Molecular Medicine, South-1 West-17, Chuo-ku, Sapporo, 060-8556, Japan

    Hirofumi Hamada

Authors
  1. Ryo Sugibayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takahisa Shimizu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Toshihiro Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Naoki Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hirofumi Hamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ken Takeda
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sugibayashi, R., Shimizu, T., Suzuki, T. et al. Upregulation of p21WAF1/CIP1 leads to morphologic changes and esterase activity in TPA-mediated differentiation of human prostate cancer cell line TSU-Pr1. Oncogene 20, 1220–1228 (2001). https://doi.org/10.1038/sj.onc.1204206

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1204206

Keywords

This article is cited by

Search

Advanced search

Quick links