Proliferating cell nuclear antigen acts as a cytoplasmic platform controlling human neutrophil survival

Witko‐Sarsat, Véronique; Mocek, Julie; Bouayad, Dikra; Tamassia, Nicola; Ribeil, Jean-Antoine; Candalh, Céline; Davezac, Noélie; Reuter, Nathalie; Mouthon, Luc; Hermine, Olivier; Pederzoli-Ribeil, Magali; Cassatella, Marco Antonio

doi:10.1083/jcb1913oia6

Cited by 15 publications

(41 citation statements)

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“…Amounts of PCNA are also elevated in cancer cells, and thus it is used as a diagnostic and prognostic marker in tumours [57]. In neutrophils, PCNA exclusively localizes in the cytosol and is expressed in amounts comparable to those expressed in proliferating cells [18]. Only mature neutrophils express cytosolic PCNA; in fact, in CD34 + cells or in myeloblasts isolated from human bone marrow aspirates, PCNA is detected only in the nucleus.…”

Section: Reviewmentioning

confidence: 98%

“…32,No. 3 receptors) or the intrinsic (mitochondria) pathway ( Figure 2) [18]. Inhibitor studies suggest the proteasome is responsible for the apoptosis-induced PCNA degradation [18], although other proteolytic enzymes (including calpain, serine proteinases and caspases) might also be involved.…”

Section: Reviewmentioning

confidence: 98%

“…3 receptors) or the intrinsic (mitochondria) pathway ( Figure 2) [18]. Inhibitor studies suggest the proteasome is responsible for the apoptosis-induced PCNA degradation [18], although other proteolytic enzymes (including calpain, serine proteinases and caspases) might also be involved. The finding that PCNA levels are stably maintained by factors such as G-CSF or IFNg, and that neutrophils isolated from G-CSF-treated donors contain large amounts of PCNA and are resistant to apoptosis [18], reinforces the view that PCNA plays a major role in promoting neutrophil survival.…”

Section: Reviewmentioning

confidence: 98%

“…Nuclear-to-cytoplasmic re-localization of proliferating cell nuclear antigen (PCNA) to inhibit apoptosis in neutrophils PCNA was recently identified as one of the cell cycle regulatory proteins that is expressed by neutrophils to control survival [18]. PCNA was initially characterized in the nucleus of proliferating cells as an auxiliary protein for the DNA polymerases delta and epsilon [55].…”

Section: Reviewmentioning

confidence: 99%

“…Despite this, recent studies have provided insight into the mechanisms that regulate neutrophil lifespan. Unexpectedly, cell cycle regulators, including survivin [16], cyclindependent kinases (CDK) [17] and the proliferating cell nuclear antigen (PCNA) [18], have been found to be expressed in neutrophils and specifically control their survival. In this review, we consider recent findings regarding neutrophil survival and death and discuss the potential for exploiting these targets to manipulate acute or chronic neutrophil-dominated inflammation [15].…”

mentioning

confidence: 99%

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Regulating neutrophil apoptosis: new players enter the game

Witko‐Sarsat

Pederzoli-Ribeil

Hirsch

et al. 2011

Trends in Immunology

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112

137

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Section: Reviewmentioning

confidence: 98%

Section: Reviewmentioning

confidence: 98%

Section: Reviewmentioning

confidence: 98%

Section: Reviewmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Regulating neutrophil apoptosis: new players enter the game

Witko‐Sarsat

Pederzoli-Ribeil

Hirsch

et al. 2011

Trends in Immunology

Self Cite

112

137

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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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Target validation and structure–activity analysis of a series of novel PCNA inhibitors

Dillehay

Seibel

Zhao

et al. 2015

Pharmacology Res & Perspec

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Proliferating cell nuclear antigen (PCNA) plays an essential role in DNA replication and repair. Tumor cells express high levels of PCNA, identifying it as a potentially ideal target for cancer therapy. Previously, we identified nine compounds termed PCNA inhibitors (PCNA-Is) that bind directly to PCNA, stabilize PCNA trimer structure, reduce chromatin-associated PCNA, and selectively inhibit tumor cell growth. Of these compounds, PCNA-I1 was most potent. The purpose of this study is to further establish targeting of PCNA by PCNA-I1 and to identify PCNA-I1 analogs with superior potencies. We found that PCNA-I1 does not affect the level of chromatin-associated PCNA harboring point mutations at the predicted binding site of PCNA-I1. Forty-six PCNA-I1 analogs with structures of 1-hydrazonomethyl-2-hydroxy (scaffold A), 2-hydrazonomethyl-1-hydroxy (scaffold B), 2-hydrazonomethyl-3-hydroxy (scaffold C), and 4-pyridyl hydrazine (scaffold D) were analyzed for their effects on cell growth in four tumor cell lines and PCNA trimer stabilization. Compounds in scaffold group A and group B showed the highest trimer stabilization and the most potent cell growth inhibitory activities with a significant potency advantage observed in the Z isomers of scaffold A. The absence of trimer stabilization and growth inhibitory effects in compounds of scaffold group D confirms the essentiality of the hydroxynaphthyl substructure. Compounds structure–activity relationship (SAR)-6 and SAR-24 were analyzed for their effects on and found to reduce chromatin-associated PCNA in tumor cells. This study led to the identification of SAR-24, a compound with superior potencies and potentially improved solubility, which will be used for future development of PCNA-targeting cancer therapies.

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Proliferating cell nuclear antigen acts as a cytoplasmic platform controlling human neutrophil survival

Cited by 15 publications

References 1 publication

Regulating neutrophil apoptosis: new players enter the game

Regulating neutrophil apoptosis: new players enter the game

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

Target validation and structure–activity analysis of a series of novel PCNA inhibitors

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