CD45 Negatively Regulates Monocytic Cell Differentiation by Inhibiting Phorbol 12-Myristate 13-Acetate-dependent Activation and Tyrosine Phosphorylation of Protein Kinase Cδ

Deszo, Eric L.; Brake, Danett K.; Cengel, Keith A.; Kelley, Keith W.; Freund, Gregory G.

doi:10.1074/jbc.m010589200

Cited by 43 publications

(39 citation statements)

References 51 publications

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“…TPA Maturation of U937 Promonocytes to Macrophages-TPA maturation was performed as described previously (44,45). In brief, U937 cells were pelleted and resuspended in growth medium containing 100 nM TPA and incubated for 3 h. Cells were then washed and plated at 5 ϫ 10 5 cells/ml in TPA-free medium and allowed to mature for 2 days prior to experimentation.…”

Section: Methodsmentioning

confidence: 99%

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Insulin Receptor Substrate-2-dependent Interleukin-4 Signaling in Macrophages Is Impaired in Two Models of Type 2 Diabetes Mellitus

Hartman

O’Connor

Godbout

et al. 2004

Journal of Biological Chemistry

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We have shown previously that hyperinsulinemia inhibits interferon-␣-dependent activation of phosphatidylinositol 3-kinase (PI3-kinase) through mammalian target of rapamycin (mTOR)-induced serine phosphorylation of insulin receptor substrate (IRS)-1. Here we report that chronic insulin and high glucose synergistically inhibit interleukin (IL)-4-dependent activation of PI3-kinase in macrophages via the mTOR pathway. Resident peritoneal macrophages (PerM⌽s) from diabetic (db/db) mice showed a 44% reduction in IRS-2-associated PI3-kinase activity stimulated by IL-4 compared with PerM⌽s from heterozygote (db/؉) control mice. IRS-2 from db/db mouse PerM⌽s also showed a 78% increase in Ser/Thr-Pro motif phosphorylation without a difference in IRS-2 mass. To investigate the mechanism of this PI3-kinase inhibition, 12-O-tetradecanoylphorbol-13-acetate-matured U937 cells were treated chronically with insulin (1 nM, 18 h) and high glucose (4.5 g/liter, 48 h). In these cells, IL-4-stimulated IRS-2-associated PI3-kinase activity was reduced by 37.5%. Importantly, chronic insulin or high glucose alone did not impact IL-4-activated IRS-2-associated PI3-kinase. Chronic insulin ؉ high glucose did reduce IL-4-dependent IRS-2 tyrosine phosphorylation and p85 association by 54 and 37%, respectively, but did not effect IL-4-activated JAK/STAT signaling. When IRS-2 Ser/Thr-Pro motif phosphorylation was examined, chronic insulin ؉ high glucose resulted in a 92% increase in IRS-2 Ser/Thr-Pro motif phosphorylation without a change in IRS-2 mass. Pretreatment of matured U937 cells with rapamycin blocked chronic insulin ؉ high glucose-dependent IRS-2 Ser/Thr-Pro motif phosphorylation and restored IL-4-dependent IRS-2-associated PI3-kinase activity. Taken together these results indicate that IRS-2-dependent IL-4 signaling in macrophages is impaired in models of type 2 diabetes mellitus through a mechanism that relies on insulin/ glucose-dependent Ser/Thr-Pro motif serine phosphorylation mediated by the mTOR pathway.The first member of the insulin receptor substrate (IRS) 1 family, IRS-1, was initially discovered in Fao hepatoma cells as a tyrosine-phosphorylated substrate of the insulin receptor (1). In addition to insulin signaling, IRS proteins are integrally linked to intracellular signaling pathways initiated by IGF-I and the cytokines IL-2, 3, 4, 7, 9, 10, 13, 15 and IFN-␣ and IFN-␥ (2-10). Importantly, serine phosphorylation of IRS-1 blocks insulin, IGF-I, and cytokine signaling through IRS-1 (11-15) and appears critical to the initiation of proteasomedependent IRS-1 degradation (16,17). We have shown that chronic insulin in the presence of high glucose leads to serine phosphorylation of IRS-1 through an mTOR-dependent mechanism and that this renders IRS-1 a poorer substrate for JAK1 (18). In addition, we have shown that serine phosphorylation targets IRS-1 for proteasome-dependent degradation in L6 muscle cells (19). However, these same mechanisms have not been investigated in relation to IRS-2-dependent cytokine signaling.IRS-2 is...

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Section: Methodsmentioning

confidence: 99%

“…Chronic Insulin and High Glucose Synergize to Block IL-4-activated IRS-2-associated PI3-Kinase Activity-We have shown previously that maturing promonocytic U937 cells with TPA induces a macrophage phenotype (44,45). Fig.…”

Section: Il-4-activated Irs-2-associated Pi3-kinase Activity Is Impaimentioning

confidence: 99%

Insulin Receptor Substrate-2-dependent Interleukin-4 Signaling in Macrophages Is Impaired in Two Models of Type 2 Diabetes Mellitus

Hartman

O’Connor

Godbout

et al. 2004

Journal of Biological Chemistry

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“…Inhibition of PKC␦ with rottlerin or transfection of a kinasedead mutant of PKC␦ increased apoptosis and potentiated chemotherapy-induced apoptosis in non-small cell lung cancer cells (30). In contrast, overexpression of PKC␦ inhibited the proliferation of fibroblasts (31), induced monocytic differentiation of the myeloid progenitor cell line (17), and enhanced enterocyte-like differentiation of colon cancer cell line Caco-2 (28). PKC␦ has been reported to undergo tyrosine phosphorylation in response to various stimuli such as PMA, epidermal growth factor, and PDGF (17,32,33).…”

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confidence: 99%

“…In contrast, overexpression of PKC␦ inhibited the proliferation of fibroblasts (31), induced monocytic differentiation of the myeloid progenitor cell line (17), and enhanced enterocyte-like differentiation of colon cancer cell line Caco-2 (28). PKC␦ has been reported to undergo tyrosine phosphorylation in response to various stimuli such as PMA, epidermal growth factor, and PDGF (17,32,33). TNF␣ has been shown to induce NF-B activation through PKC␦ in human neutrophils (34).…”

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confidence: 99%

“…The protein kinase C (PKC) family, some isoforms of which are stimulated by phorbol esters such as phorbol-12-myristate-13-acetate (PMA), is responsible for transducing many cellular signals during a variety of cellular processes such as mitogenesis, cellular metabolism, differentiation, tumor promotion, and apoptosis (15)(16)(17)(18). For example, in Fas-induced apoptosis, phorbol esters produce a marked attenuation of the cell death pathway (18).…”

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Induction of cIAP-2 in Human Colon Cancer Cells through PKCδ/NF-κB

Wang

Evers

2003

Journal of Biological Chemistry

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Activation of protein kinase C (PKC) prevents apoptosis in certain cells; however, the mechanisms are largely unknown. Inhibitors of apoptosis (IAP) family members, including NAIP, cIAP-1, cIAP-2, XIAP/hILP, survivin, and BRUCE, block apoptosis by binding and potently inhibiting caspases. Activation of NF-B contributes to cIAP-2 induction; however, the cellular mechanisms regulating cIAP-2 expression have not been entirely defined. In this study, we examined the role of the PKC and NF-B pathways in the regulation of cIAP-2 in human colon cancers. We found that cIAP-2 mRNA levels were markedly increased in human colon cancer cells by treatment with the phorbol ester, phorbol-12-myristate-13-acetate (PMA), or bryostatin 1. Inhibitors of the Ca 2؉ -independent, novel PKC isoforms, but not inhibitors of MAPK, PI3-kinase, or PKA, blocked PMA-stimulated cIAP-2 mRNA expression, suggesting a role of PKC in PMA-mediated cIAP-2 induction. Pretreatment with the PKC␦-selective inhibitor rottlerin or transfection with an antisense PKC␦ oligonucleotide inhibited PMA-induced cIAP-2 expression, whereas cotransfection with a PKC␦ plasmid induced cIAP-2 promoter activity, which, taken together, identifies a role for PKC␦ in cIAP-2 induction. Treatment with the proteasome inhibitor, MG132 or inhibitors of NF-B (e.g. PDTC and gliotoxin), decreased PMA-induced up-regulation of cIAP-2. PMAinduced NF-B activation was blocked by either GF109203x, MG132, PDTC, or gliotoxin. Moreover, overexpression of PKC␦-induced cIAP-2 promoter activity and increased NF-B transactivation, suggesting regulation of cIAP-2 expression by a PKC␦/NF-B pathway. In conclusion, our findings demonstrate a role for a PKC/NF-B-dependent pathway in the regulation of cIAP-2 expression in human colon cancer cells. These data suggest a novel mechanism for the anti-apoptotic function mediated by the PKC␦/NF-B/cIAP-2 pathway in certain cancers.

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Effectiveness of the SurePath liquid‐based Pap test in automated screening and in detection of HSIL

Cengel

Day

Davis-Devine

et al. 2003

Diagnostic Cytopathology

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We have shown that SurePath when compared to conventional Paps fails to increase HSIL detection. In this study, assessment of test performance characteristics for the FocalPoint showed that sensitivity was 96% when manual screening was used as the "gold standard." When cervical biopsy, however, was used as the "gold standard" FocalPoint sensitivity decreased to 93%, which was the same as manual screening. Examination of the FocalPoint "no further review" cases showed that 4/296 were SIL. To understand better the implication of an SIL diagnosis, cervical biopsies generated from SurePath and conventional Paps were compared. Conventional Paps diagnosed as LSIL had a biopsy LSIL:HSIL ratio of 3.1/1, while SurePath Paps had a biopsy LSIL:HSIL ratio of 1.5/1. These results indicate that when cervical biopsy is used as the "gold standard," FocalPoint and manual screening of SurePath Paps have similar test performance but that the FocalPoint can fail to detect LSIL. Importantly, LSIL in a SurePath Pap is 1.6 times more likely to be HSIL on biopsy than LSIL in a conventional Pap.

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CD45 Negatively Regulates Monocytic Cell Differentiation by Inhibiting Phorbol 12-Myristate 13-Acetate-dependent Activation and Tyrosine Phosphorylation of Protein Kinase Cδ

Cited by 43 publications

References 51 publications

Insulin Receptor Substrate-2-dependent Interleukin-4 Signaling in Macrophages Is Impaired in Two Models of Type 2 Diabetes Mellitus

Insulin Receptor Substrate-2-dependent Interleukin-4 Signaling in Macrophages Is Impaired in Two Models of Type 2 Diabetes Mellitus

Induction of cIAP-2 in Human Colon Cancer Cells through PKCδ/NF-κB

Effectiveness of the SurePath liquid‐based Pap test in automated screening and in detection of HSIL

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