Tumor suppression and inhibition of aneuploid cell accumulation in human brain tumor cells by ectopic overexpression of the cyclin-dependent kinase inhibitor p27KIP1.
To investigate how overexpression of p27KIP1, a downstream effector of TGF-beta and a universal cyclin-dependent kinase (CDK) inhibitor could influence the malignant phenotype of malignant human brain tumor cells, an adenovirus vector system was used to transfer the human p27KIP1 gene (Adp27KIP1) into the human astrocytoma cell line, U-373MG. Inhibition of CDK activity in Adp27KIP1-infected cells was indicated by inhibition of [3H]thymidine incorporation, an increase in cell doubling time and by cell cycle arrest in G1. Notably, ectopic overexpression of p27KIP1 was associated with a marked decrease in the accumulation of aneuploid cells. Diminished malignant potential of Adp27KIP1-infected cells was manifested by the loss of anchorage-independent growth in soft agar and by the inability to induce tumorgenesis in a xenograft model. These studies suggest that p27KIP1 is a tumor suppressor gene and supports the use of Adp27KIP1 for gene therapy of human brain tumors.
Chen
J
J
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, 75235, USA.
Willingham
T
T
Shuford
M
M
Nisen
P D
PD
D000782:Aneuploidy; D000818:Animals; D001254:Astrocytoma / Q000235:genetics / Q000473:pathology*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology*; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002455:Cell Division; D002460:Cell Line; D002470:Cell Survival; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004791:Enzyme Inhibitors; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000032:analysis / Q000096:biosynthesis*; D006656:Protamine Kinase / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis; D013936:Thymidine / Q000378:metabolism; D014162:Transfection; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D008869:Microtubule-Associated Proteins; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D006656:Protamine Kinase; D018844:Cyclin-Dependent Kinases; D013936:Thymidine