TUMOR SUPPRESSION AND INHIBITION OF ANEUPLOID CELL ACCUMULATION IN HUMAN BRAIN-TUMOR CELLS BY ECTOPIC OVEREXPRESSION OF THE CYCLIN-DEPENDENT KINASE INHIBITOR P27(KIP1)

To investigate how overexpression of p27(KIP1), a downstream effector of TGF-beta and a universal cyclin-dependent kinase (CDK) inhibitor co uld influence the malignant phenotype of malignant human brain tumor c ells, an adenovirus vector system was used to transfer the human p27(K IP1) gene (Adp27(KIP1)) into the human astrocytoma cell line, U-373MG. Inhibition of CDK activity in Adp27(KIP1)-infected cells was indicate d by inhibition of [H-3]thymidine incorporation, an increase in cell d oubling time and by cell cycle arrest in G(1). Notably, ectopic overex pression of p27(KIP1) was associated with a marked decrease in the acc umulation of aneuploid cells. Diminished malignant potential of Adp27( KIP1)-infected cells was manifested by the loss of anchorage-independe nt growth in soft agar and by the inability to induce tumorgenesis in a xenograft model. These studies suggest that p27(KIP1) is a tumor sup pressor gene and supports the use of Adp27(KIP1) for gene therapy of h uman brain tumors.