PCNA-interacting peptides reduce Akt phosphorylation and TLR-mediated cytokine secretion suggesting a role of PCNA in cellular signaling

Olaisen, Camilla; Müller, Rebekka; Nedal, Aina; Otterlei, Marit

doi:10.1016/j.cellsig.2015.03.009

Cited by 51 publications

(97 citation statements)

References 80 publications

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“…The association between PCNA and kinases is also studied in primary monocytes isolated from healthy donors in which APIM‐peptide again reduces the MAPK and PI3K/Akt pathways and subsequently reduces the cytokine secretion stimulated by activation of tolllike receptor ligands . This study therefore corroborates our findings in neutrophils by confirming that cytosolic PCNA may have a platform role similar to nuclear PCNA, and APIM–PCNA interactions might be important in cellular stress responses to pathogen‐ and damage‐associated molecular patterns, similar to its importance in response to genotoxic stress.…”

Section: Unravelling Cytosolic Pcna Scaffold In Neutrophils and Othersupporting

confidence: 82%

“…In keeping with our results using the carboxy‐p21 peptide, procaspase 3 co‐immunoprecipitates with PCNA and less procaspase 3 is co‐immunoprecipitated in cells treated with the ATX‐101 peptide. However, ATX‐101 does not induce apoptosis in normal lymphocytes or monocytes despite the fact that monocytes display cytosolic PCNA expression . Interestingly, the authors observe that the immunoprecipitated PCNA with the APIM‐peptide has a different isoelectric distribution than the total PCNA in the cell, suggesting that PCNA interacting with APIM‐peptides has specific post‐translational modifications.…”

Section: Unravelling Cytosolic Pcna Scaffold In Neutrophils and Othermentioning

confidence: 97%

“…In another recent study performed in the human HaCaT keratinocyte cell line, using mass spectrometry analysis of PCNA‐pull downs, it is reported that various cytosolic proteins involved in the MAPK and PI3K/Akt pathways form a complex with PCNA . Given the APIM motif was identified in over 20 kinases and/or associated proteins, targeting PCNA with APIM‐peptide in HaCaT acts to reduce Akt phosphorylation.…”

Section: Unravelling Cytosolic Pcna Scaffold In Neutrophils and Othermentioning

confidence: 99%

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Proliferating cell nuclear antigen in neutrophil fate

Witko‐Sarsat

Ohayon

2016

Immunological Reviews

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The life span of a neutrophil is a tightly regulated process as extended survival is beneficial for pathogen elimination and cell death necessary to prevent cytotoxic content release from activated neutrophils at the inflammatory site. Therefore, the control between survival and death must be a dynamic process. We have previously described that proliferating cell nuclear antigen (PCNA) which is known as a nuclear protein pivotal in DNA synthesis, is a key element in controlling neutrophil survival through its association with procaspases. Contrary to the dogma which asserted that PCNA has a strictly nuclear function, in mature neutrophils, PCNA is present exclusively within the cytosol due to its nuclear export at the end of the granulocytic differentiation. More recent studies are consistent with the notion that the cytosolic scaffold of PCNA is aimed at modulating neutrophil fate rather than simply preventing death. Ultimately, targeting neutrophil survival might have important applications not just in the field of immunology and inflammation, but also in hematology and transfusion. The neutrophil emerges as a unique and powerful cellular model to unravel the basic mechanisms governing the cell cycle-independent functions of PCNA and should be considered as a leader of the pack.

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Section: Unravelling Cytosolic Pcna Scaffold In Neutrophils and Othersupporting

confidence: 82%

Section: Unravelling Cytosolic Pcna Scaffold In Neutrophils and Othermentioning

confidence: 97%

Section: Unravelling Cytosolic Pcna Scaffold In Neutrophils and Othermentioning

confidence: 99%

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Proliferating cell nuclear antigen in neutrophil fate

Witko‐Sarsat

Ohayon

2016

Immunological Reviews

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“…Interestingly, cytosolic PCNA also participates in the activation of the Akt pathway, possibly through its interactions with APIM motif-containing components of this pathway. Indeed, inhibition of these interactions reduces Akt activation and cell growth (Olaisen et al, 2015). …”

Section: Dna Replicationmentioning

confidence: 99%

Forging Ahead through Darkness: PCNA, Still the Principal Conductor at the Replication Fork

2017

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Proliferating Cell Nuclear Antigen (PCNA) lies at the center of the faithful duplication of eukaryotic genomes. With its distinctive doughnut-shaped molecular structure, PCNA was originally studied for its role in stimulating DNA polymerases. However, we now know that PCNA does much more than promote processive DNA synthesis. Because of the complexity of the events involved, cellular DNA replication poses major threats to genomic integrity. Whatever predicament lies ahead for the replication fork, PCNA is there to orchestrate the events necessary to handle it. Through its many protein interactions and various post-translational modifications, PCNA has far-reaching impacts on a myriad of cellular functions.

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“…Moreover, treatment of human monocytes with an APIM‐peptide that blocks the interaction between APIM‐containing proteins and PCNA reduced phosphorylation of AKT and the secretion of several cytokines after stimulation of Toll‐like receptors. Inhibition of p38 MAPK enhanced this effect of the APIM‐peptide .…”

mentioning

confidence: 91%

The role of PCNA as a scaffold protein in cellular signaling is functionally conserved between yeast and humans

et al. 2018

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Proliferating cell nuclear antigen ( PCNA ), a member of the highly conserved DNA sliding clamp family, is an essential protein for cellular processes including DNA replication and repair. A large number of proteins from higher eukaryotes contain one of two PCNA ‐interacting motifs: PCNA ‐interacting protein box ( PIP box) and AlkB homologue 2 PCNA ‐interacting motif ( APIM ). APIM has been shown to be especially important during cellular stress. PIP box is known to be functionally conserved in yeast, and here, we show that this is also the case for APIM . Several of the 84 APIM ‐containing yeast proteins are associated with cellular signaling as hub proteins, which are able to interact with a large number of other proteins. Cellular signaling is highly conserved throughout evolution, and we recently suggested a novel role for PCNA as a scaffold protein in cellular signaling in human cells. A cell‐penetrating peptide containing the APIM sequence increases the sensitivity toward the chemotherapeutic agent cisplatin in both yeast and human cells, and both yeast and human cells become hypersensitive when the Hog1/p38 MAPK pathway is blocked. These results suggest that the interactions between APIM ‐containing signaling proteins and PCNA during the DNA damage response is evolutionary conserved between yeast and mammals and that PCNA has a role in cellular signaling also in yeast.

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PCNA-interacting peptides reduce Akt phosphorylation and TLR-mediated cytokine secretion suggesting a role of PCNA in cellular signaling

Cited by 51 publications

References 80 publications

Proliferating cell nuclear antigen in neutrophil fate

Proliferating cell nuclear antigen in neutrophil fate

Forging Ahead through Darkness: PCNA, Still the Principal Conductor at the Replication Fork

The role of PCNA as a scaffold protein in cellular signaling is functionally conserved between yeast and humans

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