Mitogenic stimulation of normal cells initiates a sequence of events l
eading to activation of cyclin-dependent kinases, phosphorylation of R
b, and subsequent entry of the cell into the S phase. Evidence is accu
mulating that transforming growth factor-beta 1 (TGF beta 1) inhibits
cell cycle progression by blocking a number of steps involved in cdk a
ctivation, thus preventing the massive phosphorylation of Rb in late G
1. 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 th
e process of oncogenic transformation. Recent findings suggest that in
many cancers TGF beta 1 insensitivity may result from disregulated ex
pression of cyclin, cdk, and cdk inhibitor genes. These alterations al
low 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.