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Demonstration that mutation of the type II transforming growth factor beta receptor inactivates its tumor suppressor activity in replication error-positive colon carcinoma cells.

Publication ,  Journal Article
Wang, J; Sun, L; Myeroff, L; Wang, X; Gentry, LE; Yang, J; Liang, J; Zborowska, E; Markowitz, S; Willson, JK
Published in: J Biol Chem
September 15, 1995

Escape from negative growth regulation by transforming growth factor beta (TGF-beta) as a result of the loss of TGF-beta type II receptor (RII) expression has been found to be associated with the replication error (RER) colorectal cancer genotype, which is characteristic of hereditary nonpolyposis colorectal cancers. The RER-positive HCT 116 colon carcinoma cell line was examined for RII mutations. A 1-base deletion was found within a sequence of 10 repeating adenines (nucleotides 709-718), which resulted in a frameshift mutation. Although it is reasonable to predict that the loss of RII function would be an important determinant of malignancy, the large number of potential mutations in cells of this phenotype raises the possibility that an RII mutation may not be a key event in the tumorigenic phenotype of these cells. One way to test directly the importance of RII mutations in determining the malignant phenotype would be to restore its expression. If restoration of expression leads to diminished tumorigenicity, it would indicate that RII mutation is an important determinant of malignancy in the RER phenotype. To determine whether restoration of RII would lead to reversal of malignancy in RER colon cancers, an RII expression vector was transfected into the HCT 116 cell line. RII stable clones showed mRNA and protein expression of transfected RII. The fibronectin mRNA level was increased by exogenous TGF-beta 1 treatment in a dose-dependent manner in RII-positive clones, whereas the control cells remained insensitive. The RII transfectants showed reduced clonogenicity in both monolayer culture and soft agarose. They were growth arrested at a lower saturation density than control cells. TGF-beta 1-neutralizing antibody stimulated the proliferation of RII-transfected but not control cells, indicating that the alterations in the growth parameters of the transfected cells were due to the acquisition of autocrine-negative activity. Tumorigenicity in athymic mice was reduced and delayed in RII transfectants. These results indicate that reconstitution of TGF-beta autocrine activity by reexpression of RII can reverse malignancy in RER colon cancers, thus verifying that the malignancy of hereditary nonpolyposis colorectal cancer can be directly associated with the loss of RII expression.

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Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

September 15, 1995

Volume

270

Issue

37

Start / End Page

22044 / 22049

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Transplantation, Heterologous
  • Transforming Growth Factor beta
  • Transfection
  • Recombinant Proteins
  • Receptors, Transforming Growth Factor beta
  • Receptor, Transforming Growth Factor-beta Type II
  • RNA, Messenger
  • Protein Serine-Threonine Kinases
  • Polymerase Chain Reaction
 

Citation

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Wang, J., Sun, L., Myeroff, L., Wang, X., Gentry, L. E., Yang, J., … Willson, J. K. (1995). Demonstration that mutation of the type II transforming growth factor beta receptor inactivates its tumor suppressor activity in replication error-positive colon carcinoma cells. J Biol Chem, 270(37), 22044–22049. https://doi.org/10.1074/jbc.270.37.22044
Wang, J., L. Sun, L. Myeroff, X. Wang, L. E. Gentry, J. Yang, J. Liang, E. Zborowska, S. Markowitz, and J. K. Willson. “Demonstration that mutation of the type II transforming growth factor beta receptor inactivates its tumor suppressor activity in replication error-positive colon carcinoma cells.J Biol Chem 270, no. 37 (September 15, 1995): 22044–49. https://doi.org/10.1074/jbc.270.37.22044.
Wang, J., et al. “Demonstration that mutation of the type II transforming growth factor beta receptor inactivates its tumor suppressor activity in replication error-positive colon carcinoma cells.J Biol Chem, vol. 270, no. 37, Sept. 1995, pp. 22044–49. Pubmed, doi:10.1074/jbc.270.37.22044.
Wang J, Sun L, Myeroff L, Wang X, Gentry LE, Yang J, Liang J, Zborowska E, Markowitz S, Willson JK. Demonstration that mutation of the type II transforming growth factor beta receptor inactivates its tumor suppressor activity in replication error-positive colon carcinoma cells. J Biol Chem. 1995 Sep 15;270(37):22044–22049.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

September 15, 1995

Volume

270

Issue

37

Start / End Page

22044 / 22049

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Transplantation, Heterologous
  • Transforming Growth Factor beta
  • Transfection
  • Recombinant Proteins
  • Receptors, Transforming Growth Factor beta
  • Receptor, Transforming Growth Factor-beta Type II
  • RNA, Messenger
  • Protein Serine-Threonine Kinases
  • Polymerase Chain Reaction