The Tyrosine Phosphatase, SHP-1, Is a Negative Regulator of Endothelial Superoxide Formation

Krötz, Florian; Engelbrecht, Barbara; Buerkle, Martin A.; Bassermann, Florian; Bridell, Hanna; Gloe, Torsten; Duyster, Justus; Pohl, Ulrich; Sohn, Hae-Young

doi:10.1016/j.jacc.2005.02.039

Cited by 50 publications

(61 citation statements)

References 35 publications

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“…S6) led us to look for an alternative mechanism for SHP-1/PNKP synthetic lethality. It has been observed previously that SHP-1 depletion causes an increase in ROS production in human umbilical vein endothelial cells through its negative regulation of NAD(P)H-oxidasedependent superoxide production (28). Furthermore, SHP-1, in common with many other protein-tyrosine phosphatases, is susceptible to oxidation of key cysteine residues in its catalytic domain by ROS, including those generated by ionizing radiation (47,48).…”

Section: Discussionmentioning

confidence: 98%

“…One clue provided by the repair assays was the higher level of strand breaks in the unirradiated SHP-1-depleted cells, which, together with reports in the literature about elevated levels of ROS in SHP-1-depleted cells (28), led us to an alternative hypothesis that reduced SHP-1 expression leads to the generation of ROS-induced DNA strand breaks, the repair of which are dependent on PNKP activity. To investigate this supposition, we examined the basal level of ROS (hydroxyl radicals and peroxynitrite together) produced in the wild-type and SHP-1-depleted cells that were used to establish the synthetic lethal partnership between PNKP and SHP-1.…”

Section: Underlying Mechanism Of the Pnkp/shp-1 Synthetic Lethal Partmentioning

confidence: 99%

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Genetic Screening for Synthetic Lethal Partners of Polynucleotide Kinase/Phosphatase: Potential for Targeting SHP-1–Depleted Cancers

et al. 2012

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A genetic screen using a library of 6,961 siRNAs led to the identification of SHP-1 (PTPN6), a tumor suppressor frequently mutated in malignant lymphomas, leukemias, and prostate cancer, as a potential synthetic lethal partner of the DNA repair protein polynucleotide kinase/phosphatase (PNKP). After confirming the partnership with SHP-1, we observed that codepletion of PNKP and SHP-1 induced apoptosis. A T-cell lymphoma cell line that is SHP-1 deficient (Karpas 299) was shown to be sensitive to a chemical inhibitor of PNKP, but resistance was restored by expression of wild-type SHP-1 in these cells. We determined that while SHP-1 depletion does not significantly impact DNA strand-break repair, it does amplify the level of reactive oxygen species (ROS) and elevate endogenous DNA damage. The ROS scavenger WR1065 afforded protection to SHP-1-depleted cells treated with the PNKP inhibitor. We propose that codisruption of SHP-1 and PNKP leads to an increase in DNA damage that escapes repair, resulting in the accumulation of cytotoxic double-strand breaks and induction of apoptosis. This supports an alternative paradigm for synthetic lethal partnerships that could be exploited therapeutically. Cancer Res; 72(22); 5934-44. Ó2012 AACR.

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Section: Discussionmentioning

confidence: 98%

Section: Underlying Mechanism Of the Pnkp/shp-1 Synthetic Lethal Partmentioning

confidence: 99%

Genetic Screening for Synthetic Lethal Partners of Polynucleotide Kinase/Phosphatase: Potential for Targeting SHP-1–Depleted Cancers

et al. 2012

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“…27 MPA (10 mol/L; nϭ7; 24-hour incubation) not only reduced the amount of membrane-bound Rac1 ( Figure 5A), but also led to a marked attenuation of Rac1 activation as indicated by binding of activated Rac1 to GST-PAK in a specific pull-down assay (Figure 5B Ϫ formation by the use of 2 independent methods ( Figure 6 and Table 1; results obtained by the cytochrome c method are not shown).…”

Section: Mpa Attenuates Endothelial Activation Of the Small Gtpase Rac1mentioning

confidence: 98%

“…25,27 All of the O 2 Ϫ measurements were performed under NO-synthase inhibition using N G -nitro-L-arginine (30 mol/L).…”

Section: Measurement Of Superoxide Radicals and Nad(p)h Oxidase Activitymentioning

confidence: 99%

“…These results further supported the concept that MPA-induced inhibition of endothelial O 2 Ϫ formation was because of NAD(P)H oxidase inactivation, because Rac1 is not only an essential component of endothelial. 25,27 NAD(P)H oxidase, but of several vascular NAD(P)H oxidases isoforms. 36,37 Indeed, there have been reports about MPA (10 mol/L) reducing cellular GTP content in HUVECs.…”

Section: Krötz Et Al Mpa Inhibits Endothelial Nad(p)h Oxidase 205mentioning

confidence: 99%

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Mycophenolate Acid Inhibits Endothelial NAD(P)H Oxidase Activity and Superoxide Formation by a Rac1-Dependent Mechanism

Krötz

Keller²,

Derflinger³

et al. 2007

Hypertension

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Abstract-Endothelial dysfunction precedes hypertension and atherosclerosis and predicts cardiac allograft vasculopathy and death in heart transplant recipients. Endothelial overproduction of reactive oxygen species, such as superoxide anions produced by NAD(P)H oxidase, induces endothelial dysfunction. Because immunosuppressive drugs have been associated with increased reactive oxygen species production and endothelial dysfunction, we sought to elucidate the underlying mechanisms. Reactive oxygen species, release of superoxide anions, and NAD(P)H oxidase activity were studied in human umbilical vein endothelial cells and in polymorphonuclear neutrophils. Gp91ds-tat was used to specifically block NAD(P)H oxidase. Transcriptional activation of different subunits of NAD(P)H oxidase was assessed by real-time RT-PCR. Rac1 subunit translocation and activation were studied by membrane fractionation and pull-down assays. Calcineurin inhibitors significantly increased endothelial superoxide anions production because of NAD(P)H oxidase, whereas mycophenolate acid (MPA) blocked it. MPA also attenuated the respiratory burst induced by neutrophil NAD(P)H oxidase. Because transcriptional activation of NAD(P)H oxidase was not affected, but addition of guanosine restored endothelial superoxide anions formation after MPA treatment, we speculate that the inhibitory effect of MPA was mediated by depletion of cellular guanosine triphosphate content. This prevented activation of Rac1 and, thus, of endothelial NAD(P)H oxidase. Because all heart transplant recipients are at risk for cardiac allograft vasculopathy development, these differential effects of immunosuppressants on endothelial oxidative stress should be considered in the choice of immunosuppressive drugs.

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The control of reactive oxygen species production by SHP-1 in oligodendrocytes

Gruber

LaRocca

Minchenberg

et al. 2015

Glia

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We have previously described reduced myelination and corresponding myelin basic protein (MBP) expression in the CNS of Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) deficient motheaten (me/me) mice compared to normal littermate controls. Deficiency in myelin and MBP expression in both brains and spinal cords of motheaten mice correlated with reduced MBP mRNA expression levels in vivo and in purified oligodendrocytes in vitro. Therefore, SHP-1 activity appears to be a critical regulator of oligodendrocyte gene expression and function. Consistent with this role, the present studies demonstrate that oligodendrocytes of motheaten mice and SHP-1 depleted N20.1 cells produce higher levels of reactive oxygen species (ROS) and exhibit corresponding markers of increased oxidative stress. In agreement with these findings, we demonstrate increased production of ROS coincides with ROS-induced signaling pathways known to affect myelin gene expression in oligodendrocytes. Antioxidant treatment of SHP-1-deficient oligodendrocytes reversed the pathological changes in these cells with increased myelin protein gene expression and decreased expression of nuclear factor (erythroid-2)–related factor 2 (Nrf2) responsive gene, heme oxygenase-1 (HO-1). Furthermore, we demonstrate that SHP-1 is expressed in human white matter oligodendrocytes and there is a subset of multiple sclerosis (MS) subjects that demonstrate a deficiency of SHP-1 in normal appearing white matter (NAWM). These studies reveal critical pathways controlled by SHP-1 in oligodendrocytes that relate to susceptibility of SHP-1-deficient mice to both developmental defects in myelination and to inflammatory demyelinating diseases.

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The Tyrosine Phosphatase, SHP-1, Is a Negative Regulator of Endothelial Superoxide Formation

Abstract: In HUVEC, SHP-1 counteracts basal and stimulated NAD(P)H-oxidase activity by negative regulation of PI3K-dependent Rac1 activation; SHP-1 thus seems to be an important part of endothelial antioxidative defense controlling the activity of the O2(*-)-producing NAD(P)H-oxidase.

Cited by 50 publications

References 35 publications

Genetic Screening for Synthetic Lethal Partners of Polynucleotide Kinase/Phosphatase: Potential for Targeting SHP-1–Depleted Cancers

Genetic Screening for Synthetic Lethal Partners of Polynucleotide Kinase/Phosphatase: Potential for Targeting SHP-1–Depleted Cancers

Mycophenolate Acid Inhibits Endothelial NAD(P)H Oxidase Activity and Superoxide Formation by a Rac1-Dependent Mechanism

The control of reactive oxygen species production by SHP-1 in oligodendrocytes

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