摘要：

human HDAC2 was identified based on a yeast two-hybrid screening using YY1 transcription factor as bait (22). YY1 negatively regulates transcription by tethering HDAC2 to DNA as a corepressor. Both HDAC1 and HDAC2 associate stably with mSin3A in mediating transcriptional repression. This HDAC-mSin3 complex can be recruited to specific promoters via interactions with a growing number of sequence-specific transcription factors (19 -20). These include unliganded nu- clear hormone receptors (e.g. RAR and TR), Mad/Max and Mxi/Max heterodimer (23), MeCP2 (24), and p53 (25). As well as being associated with mSin3A, HDAC1/2 are components of the NuRD (nucleosome-remodeling histone deacetylase) com- plex which has been implicated a role in transcriptional repres- sion by DNA methylation (26 -27). Mammalian HDAC3 was cloned by the searches of EST data bases (28 -29) and found to repress YY1-mediated transcriptional repression via direct in- teractions with YY1 (28). Searches of EST data bases led to the discovery of three more histone deacetylases HDAC4, HDAC5, and HDAC6 (30 -33). Sequence alignment analysis reveals that the mammalian HDACs identified so far fall into two groups, the yeast RPD3 protein-like (HDAC1, -2, and -3) and the yeast HDA1 protein-like (HDAC4, -5, and -6) (21, 30, 33). It is be- coming evident that each group of HDACs is utilized by distinct sets of transcriptional repressors (20).Whether HDACs play a role in regulating p53 function re- mains unaddressed. In the discovery of HIV Tat acetylation (16), treatment of cells with histone deacetylase inhibitor TSA (34) was found to synergistically work with Tat in activating HIV-1 promoter, presumably through inhibiting the deacetyla- tion of Tat. Furthermore, it was found that the retinoblastoma (Rb)-associated histone deacetylase could deacetylate E2F1 (18). These studies raise the possibility that, similar to Tat and E2F1, modification of p53 by HDACs might play a direct role in regulating p53 function. In support of this hypothesis, in the course of studying the transcriptional repression function of p53 in apoptosis, Murphy et al. (25) found p53 recruited HDACs, via interactions with mSin3A, to repress two genes, Map4 and stathmin. The underlying mechanism at least in- volves core histone deacetylation. However, the possibility of p53 deacetylation has not been examined. In the present study, we report that mammalian HDAC1, -2, and -3 specifically down-regulate the transactivation activity of p53. The inhibi- tion is HDAC dosage-dependent and requires the deacetylase activity of HDACs. Most importantly, the down-regulation of p53 function by HDACs relies largely on the C-terminal 30 residues of p53, the region containing the basic lysines (Lys- 373 and Lys-382) that have been shown to be acetylated by p300/CBP in vivo (4, 8, 9). These results of functional assays are further supported by the fact that HDACs form a complex with p53 and significantly deacetylate p53 both in vitro and in vivo. Finally, we show that HDACs inhibit the activity of BAX promoter, a nature system responsive to p53, in a p53-depend- ent manner. Our findings strongly suggest that HDAC1, -2, and -3 participate in p53-mediated gene regulation, at least in part by directly deacetylating p53.

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