ABERRANT REGULATION OF TRANSFORMING GROWTH-FACTOR-ALPHA DURING THE ESTABLISHMENT OF GROWTH ARREST AND QUIESCENCE OF GROWTH-FACTOR INDEPENDENT CELLS

Autocrine transforming growth factor alpha (TGF alpha) is an important positive growth effector in malignant cells and plays a significant r ole in generating the growth factor-independent phenotype associated w ith malignant progression. However, the molecular mechanisms by which TGF alpha confers a growth advantage in progression is poorly understo od. The highly tumorigenic cell line HCT116 up-regulates TGF alpha mRN A expression during growth arrest, whereas the poorly tumorigenic grow th factor-dependent FET cell line down-regulates TGF alpha mRNA expres sion as it becomes quiescent. We have identified a 25-bp sequence at - 201 to -225 within the TGF alpha promoter which mediates the different ial regulation of TGF alpha expression during quiescence establishment in these two cell lines. This same sequence confers TGF alpha promote r responsiveness to exogenous growth factor or autocrine TGF alpha. Th e abberant upregulation of TGF alpha mRNA in quiescent HCT116 cells ma y allow them to return to the dividing state under more stringent cond itions (nutrient replenishment alone) then quiescent FET cells (requir es nutrients and growth factors). Antisense TGF alpha approaches showe d that the dysregulated TGF alpha expression in quiescent HCT116 cells is a function of the strong TGF alpha autocrine loop (not inhibited b y blocking antibodies) in these cells.