Effect of Tumor Suppressors on Cell Cycle-Regulatory Genes: RB Suppresses p34 cdc2 Expression and Normal p53 Suppresses Cyclin A Expression

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We show that expression of the p34 cdc2 and cyclin A genes is induced by interleukin-2 in normal human T cells and present evidence to support the idea that these genes are deregulated in leukemic T cells. Our DNA sequencing data indicate that the promoter region of the p34 cdc2 gene contains putative E2F-like binding sites which are recognized by Rb and binding sites for c- myb, Sp1, and ATF, and that the promoter region of the cyclin A gene contains binding sites for p53, Sp1, and ATF. In this study we focus on the effect of p53 and Rb on these cell cycle-regulatory genes. Cotransfection of Y79 human retinoblastoma cells with a p34 cdc2 promoter-luciferase expression vector and a plasmid expressing the retinoblastoma gene (RB) indicated that RB suppresses p34 cdc2 expression. Cotransfection of B104 rat neuroblastoma cells with a cyclin A promoter-luciferase expression vector and a plasmid expressing the normal or mutant p53 indicated that only the normal p53 suppresses cyclin A expression. In normal T cells, PHA stimulation reduces the amount of complexes in the p34 cdc2 promoter between the E2F-like binding site and the RB gene product. These complexes were not detected in leukemic T cells. Our data support the idea that tumor suppressors modulate the expression of cell cycle-regulatory genes: RB regulates p34 cdc2 expression and p53 regulates cyclin A expression.