Abstract
NF-Y transcription factor binds to CCAAT boxes on promoters of cell cycle regulatory genes such as cdc2, cyclin B, cdc25C, and cyclin A. We previously reported that the DNA binding activity of NF-Y is regulated by p53-p21-cdk2 pathway. CBF/HSP70 was originally identified as a transcription factor binding to the CCAAT box on the hsp70 promoter and mediates transcription repression of hsp70 pro- moter by p53. Recently it was demonstrated that CBF/HSP70 interacts and cooperates with NF-Y. In this study, we found that p53 represses the trans-cription of CBF/HSP70. Since transactivation ability of NF-Y is regulated in a cell cycle-dependent manner, we examined the transcription of CBF/HSP70 during the cell cycle. After synchronization of a human bladder carcinoma cell lacking functional p53 at early S phase, we infect the cells with adenovirus encoding p53. Cells infected with control virus progressed to S and G2 after release from the arrest. In contrast, cells expressing p53 enter S and G2 phases, but arrest at G2/M. The expression of CBF/HSP70 was induced at S/G2 phase in cells infected with a control virus, but kept to be repressed in cells expressing p53. Thus, these results suggest that p53 suppresses the expression of cell cycle regulatory genes though inhibiting both CCAAT binding factors, CBF/HSP70 and NF-Y.
Highlights
Inactivation of p53 tumor suppressor gene occurs in over half of all human tumors, implying that loss of this gene represents a fundamentally important step in genomic instability and susceptibility to malignant transformation (Hollstein et al, 1991; Kastan et al, 1995; Seo and Jung, 2004)
To examine whether p53 regulate the expression of CCAAT-binding factor (CBF).heat shock protein 70 (HSP70), we infected EJ cells with recombinant adenovirus encoding p53 (Ad-p53) or its control virus (Ad- E1) and examined mRNA levels of CBF/HSP70
We infected the cells with the control virus and found that mRNA levels of CBF/HSP70 was not changed (Figure 1A)
Summary
Inactivation of p53 tumor suppressor gene occurs in over half of all human tumors, implying that loss of this gene represents a fundamentally important step in genomic instability and susceptibility to malignant transformation (Hollstein et al, 1991; Kastan et al, 1995; Seo and Jung, 2004). These results suggest that p53 suppresses the expression of cell cycle regulatory genes though inhibiting both CCAAT binding factors, CBF/HSP70 and NF-Y. In addition to playing a role as a DNA-binding dependent transcription activator, p53 has been reported to negatively regulate the transcription of a number of genes. We previously reported that p53 inhibits cell cycle dependent transcription of cell cycle regulatory genes such as cdc2 and cyclin B genes, which, in turn, results in inactivation of cdc2 kinase and cell cycle arrest at G2 checkpoint (Park et al, 2000).
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