Loss of the G1-S control of cyclin A expression during tumoral progression of Chinese hamster lung fibroblasts.

The expression of cyclin A, one of the key regulators of cell cycle progression in association with cdc2/cdk2 protein kinases and which undergoes cyclic accumulation during the cell cycle, has been investigated in CCL39 Chinese hamster lung fibroblasts and in two transformed variants, A71 and 39Py. Whereas A71 (selected after tumor induction in nude mice) is subject to growth arrest (less than 5% of labeled nuclei after 24 h of serum starvation), 39Py (obtained after transformation by polyoma virus) is not (more than 50% of labeled nuclei). In both cells, cyclin A expression was correlated with establishment of S phase, with a progressive deregulation of its G1 controls. This deregulation was not detected with the two early response genes c-fos and c-myc. The kinetics of accumulation of cyclin A lagged behind that of [3H]thymidine incorporation, thereby questioning a direct role for cyclin A in S phase triggering. Moreover, transforming growth factor beta 1, which is known to inhibit alpha-thrombin or fibroblast growth factor-induced mitogenicity in G0-arrested CCL39 cells, is shown here to down-regulate cyclin A expression in both CCL39 and A71 cells but has no effect on 39Py cells. These data establish cyclin A as a sensitive marker for the loss of growth factor requirement.