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Results demonstrate that mammalian Sir2alpha interacts with p53 inhibiting deacetylation of p53 as well as enhancing acetylation of p53 in vivo. Data also suggest that Sir2alpha represses p53-dependent apoptosis during DNA damage and oxidative stress.

Research has been conducted on Parkin-like ubiquitin ligase Parc. The authors report the identification of Parc as cytoplasmic anchor protein in p53-associated protein complexes, and inform that this protein regulates p53 subcellular localization and function.

Repression of gene transcription is mediated by histone deacetylases containing repressor–co-repressor complexes, which are recruited to promoters of target genes via interactions with sequence-specific transcription factors. The mammalian Sin3A co-repressor complex contains a core of at least seven proteins including the pRb-interacting protein RBP1 and a putative tumor suppressor p33ING1b. By biochemical purification and mass spectrometry, we have identified a novel component p40 from this complex. p40 bears homology to both yeast Sds3, a component of yeast histone deacetylase complexes, and its mammalian homologue mSds3. The p40-associated complex purified from human cells shows a strong histone deacetylase activity. When tethered to a Gal-DNA binding domain, the Gal-p40 is able to significantly repress transcription of a Gal-luciferase promoter. Interestingly, database analysis reveals that p40 is also highly homologous to BRMS1, a breast carcinoma metastasis suppressor, and overexpression of p40 in human cells can significantly inhibit cell growth. Thus, our data indicate that p40 may be critically involved in transcription repression of cell growth-associated gene expression by recruiting the HDAC1 deacetylase complex. [Copyright &y& Elsevier]

Investigates the negative control of p53 tumor suppressor genes by the nicotinamide adenine dinucleotide-dependent histone deacetylation of Sir2alpha. Association of cellular metabolism with gene silencing; Derivation of anti-proliferative effects from the p53 tumor suppressor; Mutations within the p53 gene.

Repression of gene transcription is mediated by histone deacetylases containing repressor-co-repressor complexes, which are recruited to promoters of target genes via interactions with sequence-specific transcription factors. The mammalian Sin3A co-repressor complex contains a core of at least seven proteins including the pRb-interacting protein RBP1 and a putative tumor suppressor p33(ING1b). By biochemical purification and mass spectrometry, we have identified a novel component p40 from this complex. p40 bears homology to both yeast Sds3, a component of yeast histone deacetylase complexes, and its mammalian homologue mSds3. The p40-associated complex purified from human cells shows a strong histone deacetylase activity. When tethered to a Gal-DNA binding domain, the Gal-p40 is able to significantly repress transcription of a Gal-luciferase promoter. Interestingly, database analysis reveals that p40 is also highly homologous to BRMS1, a breast carcinoma metastasis suppressor, and overexpression of p40 in human cells can significantly inhibit cell growth. Thus, our data indicate that p40 may be critically involved in transcription repression of cell growth-associated gene expression by recruiting the HDAC1 deacetylase complex.

The p53 tumour suppressor exerts anti-proliferative effects, including growth arrest, apoptosis and cell senescence, in response to various types of stress. However, p53 is a short-lived protein and its activity is maintained at low levels in normal cells. Numerous studies indicate that CBP/p300-mediated acetyl-transferase activity is critical for its role in both catalysing p53 acetylation and activating p53-mediated function during stress response. Interestingly, two additional regulators have also been identified in the p53 acetylation pathway. PID/MTA2 is a p53-interacting protein that induces p53 deacetylation by recruiting the HDAC1 complex. Subsequent work has also identified Sir2alpha, a NAD-dependent histone deacetylase that can attenuate p53 transcriptional activity through deacetylation. The prominence of deacetylase activity on p53 certainly raises the defining question of its physiological purpose. It is likely that deacetylation proxides a quick acting mechanism to stop p53 function once transcriptional activation of target genes is no longer needed. We present data indicating that both HDAC1 and Sir2alpha are critical for p53-dependent stress response. Furthermore, we also try to define the functional consequence of p53 acetylation at the molecular level. Finally, we propose a model regarding the differential roles of HDAC1 and Sir2alpha in the regulation of p53 function.