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

Oncogene. 2002 Apr 25;21(18):2785-96. doi: 10.1038/sj.onc.1205375.


The inappropriate expression of TGFalpha in growth arrest contributes to malignant progression in human colon carcinoma cells. Early stage, non-progressed colon tumor cells show a down-regulation of TGFalpha in growth arrest and require both nutrients and growth factors for re-entry into the cell cycle. In contrast, highly progressed cells up-regulate TGFalpha during growth arrest and require only nutrients for re-entry. Given the importance of TGFalpha in malignant progression, this work addressed the regulation of TGFalpha expression in the early stage colon carcinoma cell line, FET. Growth-arrested FET cells down-regulated the expression of TGFalpha, 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 TGFalpha 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 TGFalpha/EGF response element within the TGFalpha 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 TGFalpha in FET cells by constitutive TGFalpha 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 TGFalpha autocrine loop resulting in TGFalpha-mediated EGFr activation which was critical for IGF-IR mediated re-entry into the cell cycle from the growth-arrested state.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cell Division
  • Colonic Neoplasms
  • DNA / biosynthesis
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Gene Expression
  • Humans
  • Insulin / pharmacology
  • Insulin-Like Growth Factor I / pharmacology
  • Receptor, IGF Type 1 / genetics
  • Receptor, IGF Type 1 / metabolism*
  • S Phase
  • Signal Transduction*
  • Transforming Growth Factor alpha / metabolism*
  • Tumor Cells, Cultured


  • Insulin
  • Transforming Growth Factor alpha
  • Insulin-Like Growth Factor I
  • DNA
  • ErbB Receptors
  • Receptor, IGF Type 1