Role of Akt/protein kinase B in the activity of transcriptional coactivator p300

Abstract

Akt/protein kinase B is a downstream target of PI3K pathway and plays a critical role in promotion of cell survival. The function of transcriptional coactivator p300 is required by many transcription factors to either activate or repress gene expression.Here, we show that induction of PI3K enhances the metabolic stability of endogenous p300 protein. On the other hand, repression of PI3K by LY294002 induces p300 degradation through the 26S proteasome pathway and impedes the transcriptional activity of the coactivator. In addition, Akt interacts with the coactivator and the activity of Akt is required for maintaining the steady-state level of p300. Our study provides a new insight into the molecular mechanisms by which the critical concentration of p300 protein is regulated and suggests a role for Akt in control of various cellular activities through the transcriptional coactivator p300.

Ubiquitin-Dependent Distribution of the Transcriptional Coactivator p300 in Cytoplasmic Inclusion Bodies

“…47,48 In addition, PI3K inhibitor-enhanced p300 degradation does not induce the cytoplasmic distribution of p300. 23 Here, we show that cytoplasm appears to be also a site of p300 degradation, or the fate of cytoplasmic p300 is indeed for a selective turnover. First, cytoplasmic localization of p300 is observed prior to the reduction of the coactivator induced by valproic acid (Figs.…”

“…In contrast, LY294002, a PI3K inhibitor, 38 does not induce cytoplasmic distribution of p300, although it is able to enhance p300 degradation through the 26S proteasome. 23 Taken together, these data indicate that intracellular trafficking of p300 may be involved in the control of p300 activity by HDAC inhibitors such as valproic acid and butyrate.…”

“…1), which is in accordance with other reports that p300 is mainly a nuclear protein. 23,36 However, upon 8 hours of valproic acid treatment, the p300 staining became fairly diffused throughout the nucleoplasm and 80.3% ± 6.5% of cells showed certain degree of cytoplasmic p300 staining (Fig. 1).…”

“…Many studies have established transcriptional coactivator p300 as a nuclear protein fitting to its function. 23,36 Multiple nuclear localization signal (NLS) reside in p300 to safeguard its nuclear localization. Our study suggests that nuclear export may also be involved in the control of cellular localization and nuclear activity of p300, which may be mediated by the CRM1 pathway.…”

“…21,22 We previously reported that PI3K inhibitors enhance p300 degradation through the 26S proteasome, which seems to be mediated by the nuclear proteasome system. 23 We have also established that histone deacetylase (HDAC) inhibitors are able to induce p300 degradation through the 26S proteasome pathway as well. 24,25 However, whether the selective p300 turnover is mediated exclusively by the nuclear proteasome system is still unclear.…”