Elevated levels of STAT1 in Fanconi anemia group A lymphoblasts correlate with the cells' sensitivity to DNA interstrand crosslinking drugs

Prieto-Remón, Inés; Sánchez-Carrera, Dámaso; López‐Duarte, Mónica; Richard, Carlos; Pipaón, Carlos

doi:10.3324/haematol.2012.074187

Cited by 3 publications

(3 citation statements)

References 32 publications

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“…Cycloheximide had no effect on CD3 + T cells STAT1 (Figure 8D) or CD3 receptor levels (data not shown), whereas CD14 + positive cells showed a fast and significant decrease in both STAT1 (Figures 8A–C) and CD14 receptor (Data not shown) levels under cycloheximide treatment. A previous report of cycloheximide and STAT1 levels in lymphoblastoid cell lines (27) found significant STAT1 degradation within 3 h of cycloheximide treatment, while in cells carrying a Fanconi anemia gene, STAT1 protein levels stayed stable for 17 h after cycloheximide treatment. The lack of decrease in CD3 + receptor levels suggests that primary peripheral CD3 + cells are not terribly sensitive to cycloheximide for up to 16 h, while CD14 + monocytes are more rapidly susceptible.…”

Section: Discussionmentioning

confidence: 71%

STAT1 Gain-of-Function Mutations Cause High Total STAT1 Levels With Normal Dephosphorylation

et al. 2019

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Signal transducer and activator of transcription (STAT1)1 gain of function (GOF) pathogenic variants have been associated with increased levels of phosphorylated STAT1 and STAT1-dependent cellular responses. Delayed dephosphorylation was proposed as the underlying mechanism leading to the characteristically raised pSTAT1 levels. We examined the levels of STAT1 protein and message as well as rates of STAT1 phosphorylation, dephosphorylation, and degradation associated with STAT1 GOF pathogenic variants. Fresh peripheral blood mononuclear cells (PBMC) from 14 STAT1 GOF patients carrying 10 different pathogenic variants in the coiled-coil, DNA binding, and SH2 domains and healthy donors were used to study STAT1 levels and phosphorylation (pSTAT1) following IFNγ and IFNα stimulation. STAT1 protein levels were measured by flow cytometry and immunoblot. STAT1 mRNA levels were measured using quantitative reverse transcription PCR. STAT1 protein degradation was studied using cycloheximide. Patient IFNγ and IFNα induced peak pSTAT1 was higher than in healthy controls. The velocity of pSTAT1 dephosphorylation after treatment of IFNγ stimulated CD14 + monocytes with the Janus Kinase (JAK)-inhibitor ruxolitinib was significantly faster in patient cells. STAT1 protein levels in patient CD14 + monocytes and CD3 + T cells were higher than in healthy donors. There was a strong and positive correlation between CD14 + STAT1 protein levels and peak pSTAT1 levels. Patient fresh PBMC STAT1 mRNA levels were increased at rest and after 16 h of incubation. STAT1 protein degradation was similar in patient and healthy volunteer cells. Patient IFNγ receptors 1 and 2 and JAK2 levels were normal. One patient in our cohort was treated with the oral JAK inhibitor ruxolitinib. Treatment was associated with normalization of both STAT1 protein and peak pSTAT1 levels. After JAK inhibitor treatment was stopped the patient's CD14 + monocyte STAT1 protein and peak phosphorylation levels increased proportionally. These findings suggest that patients with STAT1 GOF mutations have higher levels of total STAT1 protein, leading to high levels of pSTAT1 after stimulation, despite rapid STAT1 dephosphorylation and normal degradation.

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Section: Discussionmentioning

confidence: 71%

STAT1 Gain-of-Function Mutations Cause High Total STAT1 Levels With Normal Dephosphorylation

et al. 2019

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“…ERK interacts with and phosphorylates FOXO3a predominantly at residues Ser-294, Ser-344, and Ser-425, which are different from the Akt phosphorylation sites at Thr-32, Ser-253, and Ser-315, leading to FOXO3a nuclear exportation. Several groups have reported constitutive activation of ERK in FA-deficient cells (38,39). Thus, the constitutively activated Erk could act on the non-Akt phosphorylation sites leading to increased cytoplasmic localization of CA-FOXO3a in the Fancd2 Ϫ/Ϫ HSCs.…”

Section: Vation Of Erk In Fancd2mentioning

confidence: 99%

Fancd2 Is Required for Nuclear Retention of Foxo3a in Hematopoietic Stem Cell Maintenance

Wilson

et al. 2015

Journal of Biological Chemistry

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Background: Maintenance of HSCs is challenged by DNA damage and oxidative stress. Results: Fancd2 deficiency promoted cytoplasmic localization of Foxo3a in HSCs. Re-expression of Fancd2 restored nuclear Foxo3a localization and prevented HSC exhaustion. Conclusion: Fancd2 is required for nuclear retention of Foxo3a and maintaining hematopoietic repopulation of HSCs. Significance: Our results implicate an interaction between FA DNA repair and FOXO3a pathways in HSC maintenance.

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“…IFN-/STAT1-related signatures promote resistance to chemotherapy and ɣ-irradiation in cancer cells (Ah-Koon et al, 2016;Kaowinn et al, 2017;Khodarev et al, 2012;Malilas et al, 2013). Intriguingly, STAT1 can though promote sensitivity to DNA crosslinking agents (Prieto-Remon et al, 2013) and proapoptotic gene expression (Khodarev et al, 2012;Wieczorek et al, 2012). Hence, modulators of STAT1 may be novel and innovative context-dependent anti-cancer drugs (Khodarev et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Impact of the STAT1 N-terminal domain for fibrosarcoma cell responses to ɣ-irradiation

Göder

Ginter²,

Kröhnert³

et al. 2020

Exp Results

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Abstract Type I/II interferons (IFNα,β/IFNɣ) are cytokines that activate signal-transducer-and-activator-of-transcription-1 (STAT1). The STAT1 N-terminal domain (NTD) mediates dimerization and cooperative DNA-binding. The STAT1 DNA-binding domain (DBD) confers sequence-specific DNA-recognition. STAT1 has been connected to growth inhibition, replication stress and DNA-damage. We investigated how STAT1 and NTD/DBD mutants thereof affect fibrosarcoma cells. STAT1 and indicated mutants do not affect proliferation of resting and IFNα-treated cells as well as checkpoint kinase signaling, and phosphorylation of the tumor-suppressive transcription factor p53 ensuing ɣ-irradiation. Of the STAT1 reconstituted U3A cells those with STAT1 NTD mutants accumulate the highest levels of the replication stress/DNA-damage marker S139-phosphorylated histone H2AX (ɣH2AX). This is similarly seen with a STAT1 NTD/DBD double mutant, indicating transcription-independent effects. Furthermore, U3A cells with STAT1 NTD mutants are most susceptible to apoptotic DNA fragmentation and cleavage of the DNA repair protein PARP1. These data provide novel insights into the relevance of the STAT1 NTD.

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Elevated levels of STAT1 in Fanconi anemia group A lymphoblasts correlate with the cells' sensitivity to DNA interstrand crosslinking drugs

Cited by 3 publications

References 32 publications

STAT1 Gain-of-Function Mutations Cause High Total STAT1 Levels With Normal Dephosphorylation

STAT1 Gain-of-Function Mutations Cause High Total STAT1 Levels With Normal Dephosphorylation

Fancd2 Is Required for Nuclear Retention of Foxo3a in Hematopoietic Stem Cell Maintenance

Impact of the STAT1 N-terminal domain for fibrosarcoma cell responses to ɣ-irradiation

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