Reduced expression of transforming growth factor β type I receptor contributes to the malignancy of human colon carcinoma cells

Jing Wang, Wei Han, Elizabeth Zborowska, Jiurong Liang, Xiaofan Wang, James K.V. Willson, Lu Zhe Sun, Michael G. Brattain

Research output: Contribution to journalArticlepeer-review

112 Scopus citations

Abstract

Transforming growth factor β (TGFβ) type I (RI) and type II (RII) receptors are essential for TGFβ signal transduction. A human colon carcinoma cell line, designated GEO, is marginally responsive to TGFβ and expresses a low level of RI mRNA relative to colon carcinoma cells, which are highly responsive to TGFβ. Hence, the role of RI as a limiting factor for TGFβ sensitivity and the contribution of low RI levels to the malignant phenotype of GEO cells were examined. Stable transfection of a tetracycline- regulatable rat RI cDNA increased TGFβ1 binding to RI and resulted in increased growth inhibition by exogenous TGβ1. In contrast, although stable transfection of an RII expression vector into the same GEO cells increased TGFβ1 binding to RII, growth inhibition by exogenous TGFβ1 was not altered. This indicated that the low level of RI is a limiting factor for the growth-inhibitory effects of TGFβ in GEO cells. RI-transfected cells were growth-arrested at a lower saturation density than GEO control cells. They also showed reduced growth and clonogenicity in plating efficiency and soft agarose assays, whereas RII-transfected cells did not show any differences from the NEO control cells in these assays. Tetracycline repressed RI expression in transfected cells and reversed the reduction in plating efficiency of RI-transfected clones, confirming that growth effects were due to increased RI expression in transfected cells. TGFβ1 neutralizing antibody stimulated the proliferation of RI-transfected cells but had little effect on GEO control cells, indicating that increased autocrine-negative TGFβ activity also resulted from increased RI expression. Tumorigenicity in athymic nude mice was significantly delayed in RI-transfected cells. These results indicate that low RI expression can be a limiting factor for response to exogenous TGFβ, as well as TGFβ autocrine-negative activity, and that reduction of RI expression can contribute to malignant progression.

Original languageEnglish (US)
Pages (from-to)17366-17371
Number of pages6
JournalJournal of Biological Chemistry
Volume271
Issue number29
DOIs
StatePublished - 1996

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Reduced expression of transforming growth factor β type I receptor contributes to the malignancy of human colon carcinoma cells'. Together they form a unique fingerprint.

Cite this