Wild-type and mutant forms of p53 activate human topoisomerase I: A possible mechanism for gain of function in mutants

• Published in: Cancer research (Chicago, Ill.) Vol. 58; no. 10; pp. 2091 - 2094
• Main Authors: ALBOR, A, KAKU, S, KULESZ-MARTIN, M
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-05-1998
• Subjects: Animals; Binding Sites; Biological and medical sciences; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cells, Cultured; DNA Topoisomerases, Type I - metabolism; Enzyme Activation; Fundamental and applied biological sciences. Psychology; Humans; Mice; Molecular and cellular biology; Tumor Cells, Cultured; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - physiology; Enzyme; Transferases; Interaction; DNA topoisomerase; In vitro; Terminal; Biological fixation; Isomerases; TP53 Gene; Glutathione transferase; Point mutation; Carboxyl group; Mechanism of action; Tumor suppressor gene
• ISSN: 0008-5472; 1538-7445

p53-interacting proteins from mouse epidermal cells and human myelogenous leukemia cells were isolated by affinity chromatography using glutathione S-transferase (GST)-p53 fusion proteins. One of these proteins was topoisomerase I, whose interaction with p53 was recently reported. A carboxyl-terminal fragment containing the last 92 amino acids of p53 (GST-299-390) was sufficient for binding to topoisomerase I. Nanomolar concentrations of either GST-p53 or GST-299-390 enhanced the catalytic activity of purified human topoisomerase I. Purified wild-type human p53 and point mutants Ser-239, Ser-245, and His-273 were equivalent in their enhancement of human topoisomerase I activity. Because topoisomerase I is thought to promote genetic recombination, competence to enhance topoisomerase I catalytic activity coupled with a deficiency in transcriptional activity may be a mechanism for gain of function in mutant p53 proteins.