Transcriptional repression by wild-type p53 utilizes histone deacetylases, mediated by interaction with mSin3a

Abstract

There is growing evidence that the p53 tumor suppressor protein not only can function to activate gene transcription but also to repress the expression of specific genes. Although recent studies have implicated the transcriptional repression function of p53 in the pathway of apoptosis, the molecular basis of this activity remains poorly understood. This study takes a first step toward elucidating this mechanism. We report that trichostatin A (TSA), an inhibitor of histone deacetylases (HDACs), abrogates the ability of p53 to repress the transcription of two genes that it negatively regulates, Map4 and stathmin. Consistent with this finding, we report that p53 physically associates in vivo with HDACs. This interaction is not direct but, rather, is mediated by the corepressor mSin3a. Both wild-type p53 and mSin3a, but not mutant p53, can be found bound to the Map4 promoter at times when this promoter preferentially associates with deacetylated histones in vivo. Significantly, inhibition of p53-mediated transcriptional repression with TSA markedly inhibits apoptosis induction by p53. These data offer the first mechanistic insights for p53-mediated transcriptional repression and underscore the importance of this activity for apoptosis induction by this protein.

Transcriptional regulation by p53: one protein, many possibilities

“…With respect to Pol II inhibition, several mechanisms have been documented (Figure 3). These include repression of transcription activators by physical interaction with and preventing them from activating the promoter [111][112][113][114][115][116] or by displacing them from the adjusting or overlapping binding sites within the promoter, [117][118][119][120] interference with the assembly of transcription machinery, 7,121 repression through the recruitment of histone deacetylase (HDAC) and, possibly, other chromatin modifying factors, [122][123][124] and finally through novel REs with the unique architecture that dictates the outcome of p53 binding. 14,125 Combination of two of the above mechanisms has been also documented.…”

“…126 It should be noted, that the p53-dependent transcriptional repression that depends on HDAC recruitment, has perhaps the most complicated scenario, and in many cases it is mediated by the presence of additional protein(s). The known mediators include mSin3a, 122,127 SnoN 128 and p52. 129 In certain cases p53-induced repression seems to depend on the activation of p53-dependent targets.…”

“…133 This domain is also important for p53-Sin3a-mediated transcription inhibition. 75,122 The Cterminal domain of p53 is required for the interaction between p53 and Ets-1 protein, which is necessary for TXSA repression. 112 It is intriguing that the presence of a functionally active DBD is required for the inhibition to occur even if binding of p53 to the RE is not necessary.…”

Association of p53 gene alterations with the expression of antiapoptotic survivin splice variants in breast cancer

“…It was found that wt-p53 can transcriptionally repress survivin expression by interfering with E2F-1 after an interaction with survivin core promoter harbouring a potential p53-binding site (Hoffman et al, 2002). It was also observed that the recruitment of Sin-3 (a corepressor factor) and histone deacetylases (HDAC) by p53 is involved in the inhibitory effect of p53 on survivin (Murphy et al, 1999;Hoffman et al, 2002). However, other studies did not find that p53 could physically associate the p53-binding site with the survivin core promoter, but reached the similar conclusion that HDAC was involved in the repressing effects of p53 on survivin expression (Mirza et al, 2002;Punga and Akusjarvi, 2003;Este`ve et al, 2005).…”

Drug resistance associated with loss of p53 involves extensive alterations in microtubule composition and dynamics

“…We recently reported that chemoresistance present in p53-deficient cells might be attributed to defective apoptotic pathways (Galmarini et al, 2001). However, p53 also associates with microtubules in vitro and in vivo (Giannakakou et al, 2000b), and has been reported to regulate negatively the putative microtubule-stabilising protein microtubule-associated protein 4 (MAP4), the microtubule-related inhibitor of apoptosis survivin (Mirza et al, 2002), and the microtubule-destabilising protein stathmin/OP18 (Johnsen et al, 2000;Murphy et al, 1999). Whether these interactions of p53 with the microtubule network directly affect microtubule composition and dynamics thus favouring drug resistance is not known.…”