Inability of transforming growth factor-β to cause SnoN degradation leads to resistance to transforming growth factor-β-induced growth arrest in esophageal cancer cells

Jeffery S. Edmiston, William Andrew Yeudall, Theodore D. Chung, Deborah A. Lebman

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

It is well established that loss of a growth inhibitory response to transforming growth factor-β (TGF-β) is a common feature of epithelial cancers including esophageal cancer. However, the molecular basis for the abrogation of this key homeostatic mechanism is poorly understood. In esophageal cancer cell lines that are resistant to TGF-β-induced growth inhibition, TGF-β also fails to decrease transcription of c-myc despite the presence of functional signaling components. Consequently, to gain a better understanding of the mechanisms leading to resistance to TGF-β-induced growth arrest, the basis for the inability to decrease c-myc transcription was investigated. Regardless of sensitivity to TGF-β-induced growth arrest, TGF-β enhanced the ability of Smad3-protein complexes to bind c-myc regulatory elements. However, in a growth inhibition-resistant esophageal cancer cell line, the Smad3-protein complexes contained the SnoN oncoprotein. Furthermore, in esophageal cancer cell lines that are resistant to TGF-β-induced growth arrest, TGF-β does not cause degradation of SnoN. Analyses of the effect of modulating SnoN expression in both growth inhibition-sensitive and growth inhibition-resistant cell lines showed that degradation of SnoN is a prerequisite for both TGF-β-induced repression of c-myc transcription and growth arrest. The data indicate that SnoN-Smad3 complexes do not cause repression of c-myc transcription but rather prevent functionality of active repressor complexes. Thus, these studies reveal a novel mechanism for resistance to TGF-β-induced growth inhibition in esophageal cancer, namely the failure to degrade SnoN. In addition, they show that SnoN can block TGF-β repression of gene transcription.

Original languageEnglish (US)
Pages (from-to)4782-4788
Number of pages7
JournalCancer Research
Volume65
Issue number11
DOIs
StatePublished - Jun 1 2005
Externally publishedYes

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Transforming Growth Factors
Esophageal Neoplasms
Growth
Smad3 Protein
Cell Line
Oncogene Proteins

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Inability of transforming growth factor-β to cause SnoN degradation leads to resistance to transforming growth factor-β-induced growth arrest in esophageal cancer cells. / Edmiston, Jeffery S.; Yeudall, William Andrew; Chung, Theodore D.; Lebman, Deborah A.

In: Cancer Research, Vol. 65, No. 11, 01.06.2005, p. 4782-4788.

Research output: Contribution to journalArticle

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