MECHANISMS OF TRANSFORMING GROWTH FACTOR-BETA1-INDUCED CELL-CYCLE ARREST

Mitogenic stimulation of normal cells initiates a sequence of events leading to activation of cyclin-dependent kinases, phosphorylation of Rb, and subsequent entry of the cell into the S phase. Evidence is accumulating that transforming growth factor-beta 1 (TGF beta 1) inhibits cell cycle progression by blocking a number of steps involved in cdk activation, thus preventing the massive phosphorylation of Rb in late G1. Many types of cancer have lost sensitivity to the growth-inhibitory actions of TGF beta 1, which is thought to be an important step in the process of oncogenic transformation. Recent findings suggest that in many cancers TGF beta 1 insensitivity may result from disregulated expression of cyclin, cdk, and cdk inhibitor genes. These alterations allow inappropriate cdk activation and Rb phosphorylation, resulting in inactivation of the growth suppressive functions of Rb and uninhibited S phase entry. Further work will be needed to clarify the mechanisms of cdk inhibition by TGF beta 1 and how these events are linked to TGF beta 1 receptor-ligand binding and signaling.