The RAX/PACT-PKR stress response pathway promotes p53 sumoylation and activation, leading to Gâ‚ arrest.
Cellular stresses, including growth factor deprivation, inflammatory cytokines or viral infection promote RAX/PACT-dependent activation of the double-stranded RNA-dependent protein kinase, PKR, to phosphorylate eIF2α, resulting in translation inhibition and apoptosis. In addition, PKR has been reported to regulate p53, STAT1 and NFκB. Here, we report that RAX/PACT interacts with the ... SUMO E2 ligase Ubc9 to stimulate p53-Ubc9 association and reversible p53 sumoylation on lysine 386. In addition, expression of RAX/PACT in a variety of cell lines promotes p53 stability and activity to increase p53 target gene expression. Significantly, while the expression of RAX/PACT, PKR or p53 alone has little effect on the cell cycle of p53-null H1299 cells, co-expression of p53 with either RAX/PACT or PKR promotes a 25-35% increase of cells in Gâ‚. In contrast, co-expression of RAX/PACT with the sumoylation-deficient p53(K386R) mutant or with the desumoylase SENP1 fails to induce such a Gâ‚ arrest. Furthermore, co-expression of p53, RAX/PACT and the dominantnegative PKR(K296R) mutant inhibits RAX/PACT-induced, p53-dependent Gâ‚ growth arrest and expression of RAX/PACT in pkr(+/+) but not pkr(-/-) MEF cells promotes p53 and p21 expression following gamma irradiation. Significantly, p53 stability is decreased in cells with reduced RAX/PACT or PKR following doxorubicin treatment, and expression of exogenous RAX/ PACT promotes phosphorylation of wild-type but not p53(K386R) on serine 392. Collectively, results indicate that, in response to stress, the RAX/PACT-PKR signaling pathway may inhibit p53 protein turnover by a sumoylation-dependent mechanism with promotion of p53 phosphorylation and translational activation leading to Gâ‚ cell cycle arrest.
Mesh Terms:
Cell Line, Tumor, Eukaryotic Initiation Factor-2, Eye Proteins, G1 Phase Cell Cycle Checkpoints, Gene Expression Profiling, Gene Expression Regulation, Homeodomain Proteins, Humans, Phosphorylation, Protein Binding, Protein Biosynthesis, Protein Processing, Post-Translational, RNA-Binding Proteins, Real-Time Polymerase Chain Reaction, Signal Transduction, Stress, Physiological, Sumoylation, Transcription Factors, Transcriptional Activation, Tumor Suppressor Protein p53, Two-Hybrid System Techniques, Ubiquitin-Conjugating Enzymes, eIF-2 Kinase
Cell Line, Tumor, Eukaryotic Initiation Factor-2, Eye Proteins, G1 Phase Cell Cycle Checkpoints, Gene Expression Profiling, Gene Expression Regulation, Homeodomain Proteins, Humans, Phosphorylation, Protein Binding, Protein Biosynthesis, Protein Processing, Post-Translational, RNA-Binding Proteins, Real-Time Polymerase Chain Reaction, Signal Transduction, Stress, Physiological, Sumoylation, Transcription Factors, Transcriptional Activation, Tumor Suppressor Protein p53, Two-Hybrid System Techniques, Ubiquitin-Conjugating Enzymes, eIF-2 Kinase
Cell Cycle
Date: Jan. 15, 2012
PubMed ID: 22214662
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