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J Biol Chem, Vol. 273, Issue 15, 9214-9223, April 10, 1998

Aberrant Regulation of Transforming Growth Factor- 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, and Michael G. Brattain

From the  Department of Biochemistry and Molecular Biology, Medical College of Ohio, Toledo, Ohio 43699-0008, the Department of Molecular Genetics, Oncology Drug Discovery, Bristol Myers Squibb, Princeton, New Jersey 08543-4000, the  Department of Medicine, Case Western Reserve University/Ireland Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106, and the ^§§ Department of Stomatology, University of California, San Francisco, California 94143

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

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