Activation and repression of p21(WAF1/CIP1) transcription by RB binding proteins

The Cdk inhibitor p21(WAF1/CIP1) is a negative regulator of the cell cycle, although its expression is induced by a number of mitogens that promote ce ll proliferation. We have found that E2F1 and E2F3, transcription factors t hat activate genes required for cell cycle progression, are strong activato rs of the p21 promoter. In contrast, HBP1 (HMG-box protein-1), a novel reti noblastoma protein-binding protein, can repress the p21 promoter and inhibi t induction of p21 expression by E2F, Both E2Fs and HBP1 regulate p21 trans cription through cis-acting elements located between nucleotides -119 to 16 of the p21 promoter and the DNA binding domains of each of these protein s are required for activity. Sequences between -119 and -60 basepairs conta ining four Spl consensus elements and two noncanonical E2F binding sites ar e of major importance for E2F activation, although E2F1 and E2F3 differ in the extent of their ability to activate expression when this segment is del eted. The opposing effects of E2Fs and HBP1 on p21 promoter activity sugges t that interplay between these factors may determine the level of p21 trans cription in vivo.