Aberrant regulation of transforming growth factor-α during the establishment of growth arrest and quiescence of growth factor independent cells

Gillian M. Howell, Lisa E. Humphrey, Rana A. Awwad, Degeng Wang, Alan Koterba, Basker Periyasamy, Junhua Yang, Wenhui Li, James K.V. Willson, Barry L. Ziober, Kevin Coleman, Joan Carboni, Mark Lynch, Michael G. Brattain

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18 Scopus citations

Abstract

Autocrine transforming growth factor α (TGFα) is an important positive growth effector in maligant cells and plays a significant role in generating the growth factor-independent phenotype associated with malignant progression. However, the molecular mechanisms by which TGFα confers a growth advantage in progression is poorly understood. The highly tumorigenic cell line HCT116 up-regulates TGFα mRNA expression during growth arrest, whereas the poorly tumorigenic growth factor-dependent FET cell line down- regulates TGFα mRNA expression as it becomes quiescent. We have identified a 25-bp sequence at -201 to -225 within the TGFα promoter which mediates the differential regulation of TGFα expression during quiescence establishment in these two cell lines. This same sequence confers TGFα promoter responsiveness to exogenous growth factor or autocrine TGFα. The abberant upregulation of TGFα mRNA in quiescent HCT116 cells may allow them to return to the dividing state under more stringent conditions (nutrient replenishment alone) then quiescent FET cells (requires nutrients and growth factors). Antisense TGFα approaches showed that the dysregulated TGFα expression in quiescent HCT116 cells is a function of the strong TGFα autocrine loop (not inhibited by blocking antibodies) in these cells.

Original languageEnglish (US)
Pages (from-to)9214-9223
Number of pages10
JournalJournal of Biological Chemistry
Volume273
Issue number15
DOIs
StatePublished - Apr 10 1998

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Howell, G. M., Humphrey, L. E., Awwad, R. A., Wang, D., Koterba, A., Periyasamy, B., Yang, J., Li, W., Willson, J. K. V., Ziober, B. L., Coleman, K., Carboni, J., Lynch, M., & Brattain, M. G. (1998). Aberrant regulation of transforming growth factor-α during the establishment of growth arrest and quiescence of growth factor independent cells. Journal of Biological Chemistry, 273(15), 9214-9223. https://doi.org/10.1074/jbc.273.15.9214