Activation of the TGFα autocrine loop is downstream of IGF-I receptor activation during mitogenesis in growth factor dependent human colon carcinoma cells

Degeng Wang, Sandip Patil, Wenhui Li, Lisa E. Humphrey, Michael G. Brattain, Gillian M. Howell

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

The inappropriate expression of TGFα in growth arrest contributes to malignant progression in human colon carcinoma cells. Early stage, non-progressed colon tumor cells show a down-regulation of TGFα in growth arrest and require both nutrients and growth factors for re-entry into the cell cycle. In contrast, highly progressed cells up-regulate TGFα during growth arrest and require only nutrients for re-entry. Given the importance of TGFα in malignant progression, this work addressed the regulation of TGFα expression in the early stage colon carcinoma cell line, FET. Growth-arrested FET cells down-regulated the expression of TGFα, EGFr and, in turn, EGFr activation. These quiescent cells continued to express high levels of IGF-IR protein, but IGF-IR activation was undetectable. Cell cycle re-entry required exogenous growth factor activation of the IGF-IR by insulin or IGF-I. This IGF-IR activation resulted in S phase re-entry and was accompanied by an approximate threefold induction of TGFα expression along with EGFr activation at 1 h following release from growth arrest. Activation of IGF-IR occurred within 5 min of cell-cycle re-entry. Previously identified DNA binding proteins which bind to a unique TGFα/EGF response element within the TGFα promoter were similarly induced following IGF-IR activation. The addition of EGFr neutralizing antibodies abolished the activated IGF-IR stimulated S phase re-entry. Moreover, disruption of the growth arrest associated down-regulation of TGFα in FET cells by constitutive TGFα expression abrogated the requirement for IGF-IR activation for cell cycle re-entry. Consequently, this study indicates, for the first time, that IGF-IR activation up-regulates components of the TGFα autocrine loop resulting in TGFα-mediated EGFr activation which was critical for IGF-IR mediated re-entry into the cell cycle from the growth-arrested state.

Original languageEnglish
Pages (from-to)2785-2796
Number of pages12
JournalOncogene
Volume21
Issue number18
DOIs
StatePublished - 2002

Keywords

  • Autocrine transforming growth factor α
  • Colon carcinoma
  • Growth factor dependence
  • IGF-1R competence factor
  • Insulin growth factor-1 receptor

Fingerprint Dive into the research topics of 'Activation of the TGFα autocrine loop is downstream of IGF-I receptor activation during mitogenesis in growth factor dependent human colon carcinoma cells'. Together they form a unique fingerprint.

  • Cite this