Effects of ectopic overexpression of p21(WAF1/CIP1) on aneuploidy and the malignant phenotype of human brain tumor cells.

Abstract	p21WAF1/CIP1 is a downstream effector of the p53 tumor suppressor gene and a universal cyclin-dependent kinase (CDK) inhibitor. To determine the ability of p21WAF1/CIP1 to function as a tumor suppressor, we constructed a replication-defective adenovirus vector containing p21WAF1/CIP1 (Adp21WAF1/CIP1) to effect ectopic overexpression in a p53-defective human astrocytoma cell line, U-373MG. We observed a marked decrease in CDC2 and CDK2 kinase activity associated with a corresponding decrease in the amount of CDC2 but not CDK2 protein; a decreased growth potential of Adp21WAF1/CIP1-infected cells demonstrated by diminished [3H]thymidine incorporation, increased cell doubling time and G1-arrested cell cycle; an association between Adp21WAF1/CIP1-infected cells and inhibition of aneuploid cell accumulation; and an alteration of the malignant phenotype of cells was evidenced by the loss of anchorage-independent growth in soft agar and the failure to induce tumorigenesis in both peripheral and intracerebral xenograft models, including the prevention of tumor formation Adp21WAF1/CIP1 infection 2 days post tumor cell implantation. Adp21WAF1/CIP1. Adp21WAF1/CIP1 appears to be a strong candidate for gene therapy studies based on these studies indicating that Adp21WAF1/CIP1 inhibits proliferation, tumorigenicity and aneuploidy in human brain tumor cells.
Authors	J Chen, T Willingham, M Shuford, D Bruce, E Rushing, Y Smith, P D Nisen
Journal	Oncogene (Oncogene) Vol. 13 Issue 7 Pg. 1395-403 (Oct 03 1996) ISSN: 0950-9232 [Print] England
PMID	8875977 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References	CDKN1A protein, human Cdkn1a protein, mouse Cell Cycle Proteins Cyclin-Dependent Kinase Inhibitor p21 Cyclins Cyclin-Dependent Kinases
Topics	Aneuploidy Animals Apoptosis Astrocytoma (genetics, metabolism, therapy) Brain Neoplasms (genetics, metabolism, therapy) Cell Cycle Proteins (metabolism) Cell Division (genetics) Cyclin-Dependent Kinase Inhibitor p21 Cyclin-Dependent Kinases (metabolism) Cyclins (metabolism, physiology) Defective Viruses G1 Phase (physiology) Genes, p53 (physiology) Genetic Therapy Genetic Vectors Humans Mice Mice, Nude Phenotype Transplantation, Heterologous Tumor Cells, Cultured

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