The p38-interacting Protein (p38IP) Regulates G(2)/M Progression by Promoting alpha-Tubulin Acetylation via Inhibiting Ubiquitination-induced Degradation of the Acetyltransferase GCN5
- 海洋环境－已发表论文 
Background: The role of p38IP in cell cycle regulation remains unclear. Results: p38IP inhibits ubiquitination-induced GCN5 degradation and therefore promotes -tubulin acetylation, facilitating spindle formation and G(2)/M progression. Conclusion: p38IP is required for G(2)/M progression. Significance: This study reveals the necessity of p38IP for GCN5 stability and for G(2)/M progression. p38-interacting protein (p38IP) is a component of the GCN5 histone acetyltransferase-containing coactivator complex (GCN5-SAGA complex). It remains unclear whether p38IP or GCN5-SAGA is involved in cell cycle regulation. Using RNA interference to knock down p38IP, we observed that cells were arrested at the G(2)/M phase, exhibiting accumulation of cyclins, shrunken spindles, and hypoacetylation of -tubulin. Further analysis revealed that knockdown of p38IP led to proteasome-dependent degradation of GCN5. GCN5 associated with and acetylated -tubulin, and recovering GCN5 protein levels in p38IP knockdown cells by ectopic expression of GCN5 efficiently reversed -tubulin hypoacetylation and G(2)/M arrest. During the G(2)/M transition, the association of -tubulin with GCN5 increased, and the acetylation of -tubulin reached a peak. Biochemical analyses demonstrated that the interaction between p38IP and GCN5 depended on the p38IP N terminus (1-381 amino acids) and GCN5 histone acetyltransferase domain and bromodomain. The p38IP N terminus could effectively reverse p38IP depletion-induced GCN5 degradation, thus recovering -tubulin acetylation and G(2)/M progression. p38IP-mediated suppression of GCN5 ubiquitination most likely occurs via nuclear sequestration of GCN5. Our data indicate that the GCN5-SAGA complex is required for G(2)/M progression, mainly because p38IP promotes the acetylation of -tubulin by preventing the degradation of GCN5, in turn facilitating the formation of the mitotic spindle.