ArticleCell cycle (Georgetown, Tex.)2012
The RAX/PACT-PKR stress response pathway promotes p53 sumoylation and activation, leading to G₁ arrest.
Article in Cell cycle (Georgetown, Tex.), 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
30 citing papers in PubMed, 41 citations in OpenAlex.
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- PACT promotes the metastasis of basal-like breast cancer through Rac1 SUMOylation and activation.Oncogene · 2022Article
- Long non-coding RNA DARS-AS1 promotes tumor progression by directly suppressing PACT-mediated cellular stress.Communications biology · 2022Article
- Cell Death and the p53 Enigma During Mammalian Embryonic Development.Stem cells (Dayton, Ohio) · 2022Review
- Developmental Acquisition ofGenes · 2021Review
- Endogenous Double-Stranded RNA.Non-coding RNA · 2021Review
- Identification of key genes and pathways at the downstream of S100PBP in pancreatic cancer cells by integrated bioinformatical analysis.Translational cancer research · 2021Article
- Inhibition of PKR by Viruses.Frontiers in microbiology · 2021Review
- Dystonia 16 (DYT16) mutations in PACT cause dysregulated PKR activation and eIF2α signaling leading to a compromised stress response.Neurobiology of disease · 2020Article
- Glycogen synthase kinase (GSK)-3 and the double-strand RNA-dependent kinase, PKR: When two kinases for the common good turn bad.Biochimica et biophysica acta. Molecular cell research · 2020Review
- The Integrated Stress Response and Phosphorylated Eukaryotic Initiation Factor 2α in Neurodegeneration.Journal of neuropathology and experimental neurology · 2020Review
- PACT/PRKRA and p53 regulate transcriptional activity of DMRT1.Genetics and molecular biology · 2020Article
- eIF2α promotes vascular remodeling via autophagy in monocrotaline-induced pulmonary arterial hypertension rats.Drug design, development and therapy · 2019Article
- The protein activator of protein kinase R, PACT/RAX, negatively regulates protein kinase R during mouse anterior pituitary development.The FEBS journal · 2015Article
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- Protein-Binding Function of RNA-Dependent Protein Kinase Promotes Proliferation through TRAF2/RIP1/NF-κB/c-Myc Pathway in Pancreatic β cells.Molecular medicine (Cambridge, Mass.) · 2015Article
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
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 G₁. In contrast, co-expression of RAX/PACT with the sumoylation-deficient p53(K386R) mutant or with the desumoylase SENP1 fails to induce such a G₁ arrest. Furthermore, co-expression of p53, RAX/PACT and the dominantnegative PKR(K296R) mutant inhibits RAX/PACT-induced, p53-dependent G₁ 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 G₁ cell cycle arrest.
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