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Loss of phosphatase and tensin homologue increases transforming growth factor beta-mediated invasion with enhanced SMAD3 transcriptional activity.

Publication ,  Journal Article
Hjelmeland, AB; Hjelmeland, MD; Shi, Q; Hart, JL; Bigner, DD; Wang, X-F; Kontos, CD; Rich, JN
Published in: Cancer Res
December 15, 2005

In normal epithelial tissues, the multifunctional cytokine transforming growth factor-beta (TGF-beta) acts as a tumor suppressor through growth inhibition and induction of differentiation whereas in advanced cancers, TGF-beta promotes tumor progression through induction of tumor invasion, neoangiogenesis, and immunosuppression. The molecular mechanisms through which TGF-beta shifts from a tumor suppressor to a tumor enhancer are poorly understood. We now show a role for the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) in repressing the protumorigenic effects of TGF-beta. The TGF-beta effector SMAD3 inducibly interacts with PTEN on TGF-beta treatment under endogenous conditions. RNA interference (RNAi) suppression of PTEN expression enhances SMAD3 transcriptional activity and TGF-beta-mediated induction of SMAD3 target genes whereas reconstitution of PTEN in a null cancer cell line represses the expression of TGF-beta-regulated target genes. Targeting PTEN expression through RNAi in a PTEN wild-type cell line increases TGF-beta-mediated invasion but does not affect TGF-beta-mediated growth inhibition. Reconstitution of PTEN expression in a PTEN-null cell line blocks TGF-beta-induced invasion but does not modulate TGF-beta-mediated growth regulation. These effects are distinct from Akt and Forkhead family members that also interact with SMAD3 to regulate apoptosis or proliferation, respectively. Pharmacologic inhibitors targeting TGF-beta receptors and phosphatidylinositol 3-kinase signaling downstream from PTEN cooperate to block TGF-beta-mediated invasion. Thus, the loss of PTEN expression in human cancers may contribute to a role for TGF-beta as a tumor enhancer with specific effects on cellular motility and invasion.

Duke Scholars

Published In

Cancer Res

DOI

ISSN

0008-5472

Publication Date

December 15, 2005

Volume

65

Issue

24

Start / End Page

11276 / 11281

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Transforming Growth Factor beta
  • Transcription, Genetic
  • Tensins
  • Smad3 Protein
  • Smad2 Protein
  • Signal Transduction
  • RNA, Small Interfering
  • Proto-Oncogene Proteins c-akt
  • Promoter Regions, Genetic
 

Citation

APA
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ICMJE
MLA
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Hjelmeland, A. B., Hjelmeland, M. D., Shi, Q., Hart, J. L., Bigner, D. D., Wang, X.-F., … Rich, J. N. (2005). Loss of phosphatase and tensin homologue increases transforming growth factor beta-mediated invasion with enhanced SMAD3 transcriptional activity. Cancer Res, 65(24), 11276–11281. https://doi.org/10.1158/0008-5472.CAN-05-3016
Hjelmeland, Anita B., Mark D. Hjelmeland, Qing Shi, Janet L. Hart, Darell D. Bigner, Xiao-Fan Wang, Christopher D. Kontos, and Jeremy N. Rich. “Loss of phosphatase and tensin homologue increases transforming growth factor beta-mediated invasion with enhanced SMAD3 transcriptional activity.Cancer Res 65, no. 24 (December 15, 2005): 11276–81. https://doi.org/10.1158/0008-5472.CAN-05-3016.
Hjelmeland AB, Hjelmeland MD, Shi Q, Hart JL, Bigner DD, Wang X-F, et al. Loss of phosphatase and tensin homologue increases transforming growth factor beta-mediated invasion with enhanced SMAD3 transcriptional activity. Cancer Res. 2005 Dec 15;65(24):11276–81.
Hjelmeland, Anita B., et al. “Loss of phosphatase and tensin homologue increases transforming growth factor beta-mediated invasion with enhanced SMAD3 transcriptional activity.Cancer Res, vol. 65, no. 24, Dec. 2005, pp. 11276–81. Pubmed, doi:10.1158/0008-5472.CAN-05-3016.
Hjelmeland AB, Hjelmeland MD, Shi Q, Hart JL, Bigner DD, Wang X-F, Kontos CD, Rich JN. Loss of phosphatase and tensin homologue increases transforming growth factor beta-mediated invasion with enhanced SMAD3 transcriptional activity. Cancer Res. 2005 Dec 15;65(24):11276–11281.

Published In

Cancer Res

DOI

ISSN

0008-5472

Publication Date

December 15, 2005

Volume

65

Issue

24

Start / End Page

11276 / 11281

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Transforming Growth Factor beta
  • Transcription, Genetic
  • Tensins
  • Smad3 Protein
  • Smad2 Protein
  • Signal Transduction
  • RNA, Small Interfering
  • Proto-Oncogene Proteins c-akt
  • Promoter Regions, Genetic