A NOVEL CYTOPLASMIC SUBSTRATE FOR CDK4 AND CDK6 IN NORMAL AND MALIGNANT EPITHELIAL DERIVED CELLS

Cyclins and cyclin-dependent kinases (cdk) have been identified as imp ortant regulators of cell replication. Molecular alteration in the cdk pathways appear to be important in cancer with some cyclins (eg cycli n D and E) proposed to be oncogenes and some inhibitors of cdk (eg p16 ) proposed to be tumor suppressor genes, In human breast carcinoma cel l line MDA361 both cyclin D and E are overexpressed and cdk 4 and 6 ar e the predominate kinases which phosphorylate retinoblastoma protein a nd to a greater extent a novel 88 kDa protein. This 88 kDa protein was detected as a significant substrate in five of seven breast carcinoma cell lines, three lung carcinoma cell lines as well as in primary bre ast and lung epithelium. Normal human and murine T lymphocytes and est ablished lymphoid cell lines are devoid of this protein and minimal am ounts were detected in normal human fibroblast. In contrast to retinob lastoma protein, the 88 kDa protein appears to be more prevalent in th e cytosolic than the nuclear subfraction. The phosphorylation of this 88 kDa protein by the G(1) associated cdks suggest that this protein m ay represent another targeted substrate regulating the G(1) phase of t he cell cycle.