DIFFERENTIAL-EFFECTS OF TRANSFORMING GROWTH-FACTOR-BETA-1 ON PROTEIN-LEVELS OF P21 WAF AND CDK-2 AND ON CDK-2 KINASE-ACTIVITY IN HUMAN RD AND CCL64 MINK LUNG-CELLS

Currently, the cyclin-dependent kinase inhibitor p21 WAF-1 is consider ed to be a crucial downstream effector in the p53-specific pathway of negative growth control in mammalian cells. Wild-type p53, but not mut ant forms of this protein, transactivate the WAF-1 gene. We show a cor relation between growth-inhibition and induction of WAF-1 protein expr ession following transforming growth factor-beta 1 (TGF-beta 1) treatm ent of two human tumour cell lines devoid of wild-type p53 protein and in SV40-transformed WI38 fibroblasts. Inversely, TGF-beta 1 treatment of normal WI38 fibroblasts stimulates their growth and represses WAF- 1 protein synthesis. As the mink lung epithelial CCL64 cell line is fr equently used in TGF-B studies we included it in this study: TGF-beta 1 growth-inhibition is accompanied by induction of WAF-1 synthesis con comitantly with a reduction of cdk2 synthesis and of its histone kinas e activity. However in the human tumour line RD, TGF-beta 1 did not af fect cdk-2 protein levels but did reduce its histone kinase activity.