The p38-interacting protein (p38IP) regulates G2/M progression by promoting α-tubulin acetylation via inhibiting ubiquitination-induced degradation of the acetyltransferase GCN5

J Biol Chem. 2013 Dec 20;288(51):36648-61. doi: 10.1074/jbc.M113.486910. Epub 2013 Nov 12.


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 G2/M phase, exhibiting accumulation of cyclins, shrunken spindles, and hypoacetylation of α-tubulin. Further analysis revealed that knockdown of p38IP led to proteasome-dependent degradation of GCN5. GCN5 associated with and acetylated α-tubulin, and recovering GCN5 protein levels in p38IP knockdown cells by ectopic expression of GCN5 efficiently reversed α-tubulin hypoacetylation and G2/M arrest. During the G2/M transition, the association of α-tubulin with GCN5 increased, and the acetylation of α-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 α-tubulin acetylation and G2/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 G2/M progression, mainly because p38IP promotes the acetylation of α-tubulin by preventing the degradation of GCN5, in turn facilitating the formation of the mitotic spindle.

Keywords: Acetylation; Cell Biology; Cell Cycle; Cell Signaling; Gene Silencing; Molecular Cell Biology; Protein Degradation; gcn5; p38IP; α-Tubulin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Catalytic Domain
  • Cyclins / metabolism
  • G2 Phase Cell Cycle Checkpoints*
  • HeLa Cells
  • Humans
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Proteolysis*
  • Spindle Apparatus / metabolism
  • Transcription Factors / chemistry
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Tubulin / metabolism*
  • Ubiquitination*
  • p300-CBP Transcription Factors / metabolism*


  • Cyclins
  • SUPT20H protein, human
  • Transcription Factors
  • Tubulin
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor
  • Proteasome Endopeptidase Complex