Search tips
Search criteria 


Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
J Clin Invest. 1996 April 15; 97(8): 1983–1988.
PMCID: PMC507269

Tumor suppression and inhibition of aneuploid cell accumulation in human brain tumor cells by ectopic overexpression of the cyclin-dependent kinase inhibitor p27KIP1.


To investigate how overexpression of p27KIP1, a downstream effector of TGF-beta and a universal cyclin-dependent kinase (CDK) inhibitor could influence the malignant phenotype of malignant human brain tumor cells, an adenovirus vector system was used to transfer the human p27KIP1 gene (Adp27KIP1) into the human astrocytoma cell line, U-373MG. Inhibition of CDK activity in Adp27KIP1-infected cells was indicated by inhibition of [3H]thymidine incorporation, an increase in cell doubling time and by cell cycle arrest in G1. Notably, ectopic overexpression of p27KIP1 was associated with a marked decrease in the accumulation of aneuploid cells. Diminished malignant potential of Adp27KIP1-infected cells was manifested by the loss of anchorage-independent growth in soft agar and by the inability to induce tumorgenesis in a xenograft model. These studies suggest that p27KIP1 is a tumor suppressor gene and supports the use of Adp27KIP1 for gene therapy of human brain tumors.

Full Text

The Full Text of this article is available as a PDF (198K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Polyak K, Kato JY, Solomon MJ, Sherr CJ, Massague J, Roberts JM, Koff A. p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. Genes Dev. 1994 Jan;8(1):9–22. [PubMed]
  • Polyak K, Lee MH, Erdjument-Bromage H, Koff A, Roberts JM, Tempst P, Massagué J. Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell. 1994 Jul 15;78(1):59–66. [PubMed]
  • Toyoshima H, Hunter T. p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell. 1994 Jul 15;78(1):67–74. [PubMed]
  • Ponce-Castañeda MV, Lee MH, Latres E, Polyak K, Lacombe L, Montgomery K, Mathew S, Krauter K, Sheinfeld J, Massague J, et al. p27Kip1: chromosomal mapping to 12p12-12p13.1 and absence of mutations in human tumors. Cancer Res. 1995 Mar 15;55(6):1211–1214. [PubMed]
  • Firpo EJ, Koff A, Solomon MJ, Roberts JM. Inactivation of a Cdk2 inhibitor during interleukin 2-induced proliferation of human T lymphocytes. Mol Cell Biol. 1994 Jul;14(7):4889–4901. [PMC free article] [PubMed]
  • Kato JY, Matsuoka M, Polyak K, Massagué J, Sherr CJ. Cyclic AMP-induced G1 phase arrest mediated by an inhibitor (p27Kip1) of cyclin-dependent kinase 4 activation. Cell. 1994 Nov 4;79(3):487–496. [PubMed]
  • Pietenpol JA, Bohlander SK, Sato Y, Papadopoulos N, Liu B, Friedman C, Trask BJ, Roberts JM, Kinzler KW, Rowley JD, et al. Assignment of the human p27Kip1 gene to 12p13 and its analysis in leukemias. Cancer Res. 1995 Mar 15;55(6):1206–1210. [PubMed]
  • Hartwell LH, Kastan MB. Cell cycle control and cancer. Science. 1994 Dec 16;266(5192):1821–1828. [PubMed]
  • Gómez-Foix AM, Coats WS, Baqué S, Alam T, Gerard RD, Newgard CB. Adenovirus-mediated transfer of the muscle glycogen phosphorylase gene into hepatocytes confers altered regulation of glycogen metabolism. J Biol Chem. 1992 Dec 15;267(35):25129–25134. [PubMed]
  • Chen J, Willingham T, Margraf LR, Schreiber-Agus N, DePinho RA, Nisen PD. Effects of the MYC oncogene antagonist, MAD, on proliferation, cell cycling and the malignant phenotype of human brain tumour cells. Nat Med. 1995 Jul;1(7):638–643. [PubMed]
  • Russell SJ, Ye YW, Waber PG, Shuford M, Schold SC, Jr, Nisen PD. p53 mutations, O6-alkylguanine DNA alkyltransferase activity, and sensitivity to procarbazine in human brain tumors. Cancer. 1995 Mar 15;75(6):1339–1342. [PubMed]
  • Andrew ME, Braciale TJ. Antigen-dependent proliferation of cloned continuous lines of H-2-restricted influenza virus-specific cytotoxic T lymphocytes. J Immunol. 1981 Sep;127(3):1201–1204. [PubMed]
  • Philipp A, Schneider A, Väsrik I, Finke K, Xiong Y, Beach D, Alitalo K, Eilers M. Repression of cyclin D1: a novel function of MYC. Mol Cell Biol. 1994 Jun;14(6):4032–4043. [PMC free article] [PubMed]
  • Cross SM, Sanchez CA, Morgan CA, Schimke MK, Ramel S, Idzerda RL, Raskind WH, Reid BJ. A p53-dependent mouse spindle checkpoint. Science. 1995 Mar 3;267(5202):1353–1356. [PubMed]
  • Kohl NE, Mosser SD, deSolms SJ, Giuliani EA, Pompliano DL, Graham SL, Smith RL, Scolnick EM, Oliff A, Gibbs JB. Selective inhibition of ras-dependent transformation by a farnesyltransferase inhibitor. Science. 1993 Jun 25;260(5116):1934–1937. [PubMed]
  • Xiong Y, Zhang H, Beach D. Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation. Genes Dev. 1993 Aug;7(8):1572–1583. [PubMed]
  • Hartwell L. Defects in a cell cycle checkpoint may be responsible for the genomic instability of cancer cells. Cell. 1992 Nov 13;71(4):543–546. [PubMed]
  • Livingstone LR, White A, Sprouse J, Livanos E, Jacks T, Tlsty TD. Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53. Cell. 1992 Sep 18;70(6):923–935. [PubMed]
  • Carder P, Wyllie AH, Purdie CA, Morris RG, White S, Piris J, Bird CC. Stabilised p53 facilitates aneuploid clonal divergence in colorectal cancer. Oncogene. 1993 May;8(5):1397–1401. [PubMed]
  • el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B. WAF1, a potential mediator of p53 tumor suppression. Cell. 1993 Nov 19;75(4):817–825. [PubMed]
  • Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D. p21 is a universal inhibitor of cyclin kinases. Nature. 1993 Dec 16;366(6456):701–704. [PubMed]

Articles from The Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation