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Transforming growth factor-beta-mediated p15(INK4B) induction and growth inhibition in astrocytes is SMAD3-dependent and a pathway prominently altered in human glioma cell lines.

Publication ,  Journal Article
Rich, JN; Zhang, M; Datto, MB; Bigner, DD; Wang, XF
Published in: J Biol Chem
December 3, 1999

We sought to characterize the pathway by which the multifunctional cytokine transforming growth factor-beta (TGF-beta) inhibits the proliferation of normal astrocytes, and we analyzed the alterations in the TGF-beta pathway in human glioma cell lines. Upon TGF-beta treatment, primary rat astrocytes showed a significant decrease in DNA synthesis upon thymidine incorporation with a cell cycle arrest in the G(1) phase. Western analysis of the astrocytes revealed that the expression of the cyclin-dependent kinase inhibitor (CdkI) p15(INK4B) was significantly up-regulated upon TGF-beta treatment without a change in other CdkI levels. The retinoblastoma protein (Rb) became hypophosphorylated, and Cdk2 activity decreased. Analysis of Smad3 null mouse astrocytes showed a significant loss of both TGF-beta-mediated growth inhibition and p15(INK4B) induction compared with wild-type mouse astrocytes. Infection of rat astrocytes by SMAD3 and SMAD4 adenoviruses failed to induce increased expression of p15(INK4B), implying indirect transcriptional regulation of p15(INK4B) by SMAD3. High-grade human gliomas secrete TGF-beta, yet are resistant to its growth inhibitory effects. Analysis of the effects of TGF-beta on 12 human glioma cell lines showed that TGF-beta mildly inhibited the growth of six lines, had no effect on four lines, and stimulated the growth of two lines. The majority of glioma lines had homozygous deletions of the p15(INK4B) gene, except for two lines that expressed p15(INK4B) protein, which was induced further upon TGF-beta treatment. Three lines mildly induced CdkI p21(WAF1) expression in response to TGF-beta. Most tumor lines retained other TGF-beta-mediated responses, including extracellular matrix protein and angiogenic factor secretion, which may contribute to increased malignant behavior. This suggests that the loss of p15(INK4B) may explain, in part, the selective loss of growth inhibition by TGF-beta in gliomas to form a more aggressive tumor phenotype.

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Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

December 3, 1999

Volume

274

Issue

49

Start / End Page

35053 / 35058

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Tumor Cells, Cultured
  • Transforming Growth Factor beta
  • Trans-Activators
  • Smad3 Protein
  • Signal Transduction
  • Rats
  • Protein Serine-Threonine Kinases
  • Protein Kinases
  • Mice
 

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Rich, J. N., Zhang, M., Datto, M. B., Bigner, D. D., & Wang, X. F. (1999). Transforming growth factor-beta-mediated p15(INK4B) induction and growth inhibition in astrocytes is SMAD3-dependent and a pathway prominently altered in human glioma cell lines. J Biol Chem, 274(49), 35053–35058. https://doi.org/10.1074/jbc.274.49.35053
Rich, J. N., M. Zhang, M. B. Datto, D. D. Bigner, and X. F. Wang. “Transforming growth factor-beta-mediated p15(INK4B) induction and growth inhibition in astrocytes is SMAD3-dependent and a pathway prominently altered in human glioma cell lines.J Biol Chem 274, no. 49 (December 3, 1999): 35053–58. https://doi.org/10.1074/jbc.274.49.35053.
Rich, J. N., et al. “Transforming growth factor-beta-mediated p15(INK4B) induction and growth inhibition in astrocytes is SMAD3-dependent and a pathway prominently altered in human glioma cell lines.J Biol Chem, vol. 274, no. 49, Dec. 1999, pp. 35053–58. Pubmed, doi:10.1074/jbc.274.49.35053.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

December 3, 1999

Volume

274

Issue

49

Start / End Page

35053 / 35058

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Tumor Cells, Cultured
  • Transforming Growth Factor beta
  • Trans-Activators
  • Smad3 Protein
  • Signal Transduction
  • Rats
  • Protein Serine-Threonine Kinases
  • Protein Kinases
  • Mice