2,013 Matching Annotations
  1. Last 7 days
    1. The precise mechanism of how LASP1 promotes PTEN ubiquitination still remains elusive 53.

      LASP1 leads to the ubiquitination of PTEN.

    2. One study showed that Nuclear Receptor Binding SET Domain Protein 2 (NSD2)-mediated dimethylation of PTEN promotes 53BP1 interactions and subsequent recruitment to sites of DNA-damage sites 75.

      NSD2 methylates PTEN.

    3. By using specific mutants of PTEN lacking lipid phosphatase function, an early study concluded that PTEN may block cell migration through a protein phosphatase mediated function on focal adhesion kinase (FAK) protein 14.

      PTEN inhibits cell migration.

    4. PTEN and PDHK1 were observed to have a synthetic-lethal relationship, as loss of PTEN and upregulation of PDHK1 in cells induced glycolysis and a dependency on PDHK1 100.
    5. This PTEN/ARID4B/PI3K signalling axis identifies a novel player in the PTEN mediated suppression of the PI3K pathway and provides a new opportunity to design novel therapeutics to target this axis to promote the tumour suppressive functions of PTEN.

      PTEN inhibits PI3K.

    6. In one of these studies, Baker et al. reported that Notch1 can mediate transcriptional suppression of PTEN, resulting in the derepression of PI3K signalling and development of trastuzumab resistance 91.

      NOTCH1 inhibits PTEN.

    7. This study was the first to link the Ras-MAPK and PI3K pathways through Notch1 transcriptional suppression of PTEN 91.

      NOTCH1 inhibits PTEN.

    8. It was reported that PTEN could dephosphorylate PGK1, a glycolytic enzyme and protein kinase with a tumorigenic role in glioblastoma 99.

      PTEN dephosphorylates PGK1.

    9. Dephosphorylation of PGK1 by PTEN was found to inhibit its activity, downstream glycolytic functions, and glioblastoma cell proliferation 99, thereby presenting another mechanism in which PTEN functions as a tumour suppressor.

      PTEN dephosphorylates PGK1.

    10. Newer studies add to this small body of data, including an intriguing study where a novel PTEN/ARID4B/PI3K pathway in which PTEN inhibits the expression of ARID4B was characterised.

      PTEN decreases the amount of ARID4B.

    11. PTEN inhibits ARID4B expression and thus prevents the transcriptional activation of ARID4B transcriptional targets PIK3CA and PIK3R2 (PI3K subunits) 79.

      PTEN decreases the amount of ARID4B.

    12. Furthermore, nuclear PTEN directly interacted with and inhibited RNA polymerase II (RNAPII)-mediated transcription, where it was involved in direct downregulation of critical transcriptional control genes including AFF4 and POL2RA 80.

      RNApo_II binds PTEN.

    13. Colocalisation of PTEN and PTENalpha promoted the function of PINK1, a mitochondrial-target kinase, and subsequently promoted energy production 105.

      PTEN activates PINK1.

    14. It is known that AKT signaling plays a critical role in the regulation of pre-mRNA splicing 77 and PTEN has been shown to modulate G6PD pre-mRNA splicing in an AKT independent manner 78.

      PTEN activates AKT.

    15. Numb inhibits Notch1, leading to the downregulation of RBP-Jkappa 94, which upregulates PTEN and anti-EMT effectors, leading to the downregulation of p-FAK and pro EMT effectors 94.

      NOTCH1 activates PTEN.

  2. Jul 2021
    1. Although not yet examined in the context of exercise, nitric oxide has been shown to inhibit IDO activity.

      nitric oxide inhibits IDO1.

    2. 33 Thus, a strong rationale suggests that exercise induced changes in nitric oxide may mediate an inhibition of IDO activity, possibly leading to a chronic downregulation and stabilization of the KYN pathway as reported by Zimmer et al. 23 The mechanisms underlying both acute and chronic exercise induced elevations in the metabolic flux towards KA could be driven by KAT expression in different tissues or cell types.

      nitric oxide inhibits IDO1.

    3. Although not yet examined in the context of exercise, nitric oxide has been shown to inhibit IDO activity.

      nitric oxide inhibits IDO1.

    4. 33 Thus, a strong rationale suggests that exercise induced changes in nitric oxide may mediate an inhibition of IDO activity, possibly leading to a chronic downregulation and stabilization of the KYN pathway as reported by Zimmer et al. 23 The mechanisms underlying both acute and chronic exercise induced elevations in the metabolic flux towards KA could be driven by KAT expression in different tissues or cell types.

      nitric oxide inhibits IDO1.

    1. Previous studies have reported that NO is able to inhibit the activity of IDO by reacting with the heme iron situated in its active site.

      nitric oxide inhibits IDO1.

    2. NO inhibits IDO at the transcriptional level and accelerates the decomposition of IDO protein, thereby affecting its stability.

      nitric oxide inhibits IDO1.

    3. Previous studies have reported that NO is able to inhibit the activity of IDO by reacting with the heme iron situated in its active site.

      nitric oxide inhibits IDO1.

    4. NO inhibits IDO at the transcriptional level and accelerates the decomposition of IDO protein, thereby affecting its stability.

      nitric oxide inhibits IDO1.

    1. For example, nitric oxide (NO) production may block IDO enzyme activity since NO inhibits the activity of heme containing enzymes such as IDO (Thomas et al., 2001).

      nitric oxide inhibits IDO1.

    2. For example, nitric oxide (NO) production may block IDO enzyme activity since NO inhibits the activity of heme containing enzymes such as IDO (Thomas et al., 2001).

      nitric oxide inhibits IDO1.

    3. For example, nitric oxide (NO) production may block IDO enzyme activity since NO inhibits the activity of heme containing enzymes such as IDO (Thomas et al., 2001).

      nitric oxide inhibits IDO1.

    4. For example, nitric oxide (NO) production may block IDO enzyme activity since NO inhibits the activity of heme containing enzymes such as IDO (Thomas et al., 2001).

      nitric oxide inhibits IDO1.

    5. For example, nitric oxide (NO) production may block IDO enzyme activity since NO inhibits the activity of heme containing enzymes such as IDO (Thomas et al., 2001).

      nitric oxide inhibits IDO1.

    6. For example, nitric oxide (NO) production may block IDO enzyme activity since NO inhibits the activity of heme containing enzymes such as IDO (Thomas et al., 2001).

      nitric oxide inhibits IDO1.

    1. In sharp contrast to macrophages, murine microglial cell clones immortalized with the activated c-myc oncogene have been reported to be resistant to NO inhibition of IDO.

      nitric oxide inhibits IDO1.

    2. In conclusion, results of the present series of experiments indicate that IDO in primary murine microglia costimulated with IFNgamma + LPS is not impaired by the production of NO, as is known to occur in murine macrophages.

      nitric oxide inhibits IDO1.

    3. Conversely, induction of NO by activation of iNOS down-regulates IDO activity in cell types as diverse as human uroepithelial transformed cells, murine bone marrow derived myeloid dendritic cells, human transformed and primary macrophages and mouse peritoneal cells.

      nitric oxide inhibits IDO1.

    4. As a result of this crosstalk, NO is well known to inhibit IDO activity in many types of cells.

      nitric oxide inhibits IDO1.

    5. In addition, direct binding of NO to heme iron in IDO, which is one of the mechanisms by which NO inhibits IDO at the post-translational level, is dependent on a number of cellular factors, including NO abundance, pH, redox environment and tryptophan availability.

      nitric oxide inhibits IDO1.

    6. NO inhibition of IDO is apparently specific to both certain species and cell types.

      nitric oxide inhibits IDO1.

    7. In macrophages, the inhibition of IDO by NO occurs at both the transcriptional and post-transcriptional levels.

      nitric oxide inhibits IDO1.

    8. In sharp contrast to macrophages, murine microglial cell clones immortalized with the activated c-myc oncogene have been reported to be resistant to NO inhibition of IDO.

      nitric oxide inhibits IDO1.

    9. In conclusion, results of the present series of experiments indicate that IDO in primary murine microglia costimulated with IFNgamma + LPS is not impaired by the production of NO, as is known to occur in murine macrophages.

      nitric oxide inhibits IDO1.

    10. Conversely, induction of NO by activation of iNOS down-regulates IDO activity in cell types as diverse as human uroepithelial transformed cells, murine bone marrow derived myeloid dendritic cells, human transformed and primary macrophages and mouse peritoneal cells.

      nitric oxide inhibits IDO1.

    11. As a result of this crosstalk, NO is well known to inhibit IDO activity in many types of cells.

      nitric oxide inhibits IDO1.

    12. In addition, direct binding of NO to heme iron in IDO, which is one of the mechanisms by which NO inhibits IDO at the post-translational level, is dependent on a number of cellular factors, including NO abundance, pH, redox environment and tryptophan availability.

      nitric oxide inhibits IDO1.

    13. NO inhibition of IDO is apparently specific to both certain species and cell types.

      nitric oxide inhibits IDO1.

    14. In macrophages, the inhibition of IDO by NO occurs at both the transcriptional and post-transcriptional levels.

      nitric oxide inhibits IDO1.

    15. In sharp contrast to macrophages, murine microglial cell clones immortalized with the activated c-myc oncogene have been reported to be resistant to NO inhibition of IDO.

      nitric oxide inhibits IDO1.

    16. In conclusion, results of the present series of experiments indicate that IDO in primary murine microglia costimulated with IFNgamma + LPS is not impaired by the production of NO, as is known to occur in murine macrophages.

      nitric oxide inhibits IDO1.

    17. Conversely, induction of NO by activation of iNOS down-regulates IDO activity in cell types as diverse as human uroepithelial transformed cells, murine bone marrow derived myeloid dendritic cells, human transformed and primary macrophages and mouse peritoneal cells.

      nitric oxide inhibits IDO1.

    18. As a result of this crosstalk, NO is well known to inhibit IDO activity in many types of cells.

      nitric oxide inhibits IDO1.

    19. In addition, direct binding of NO to heme iron in IDO, which is one of the mechanisms by which NO inhibits IDO at the post-translational level, is dependent on a number of cellular factors, including NO abundance, pH, redox environment and tryptophan availability.

      nitric oxide inhibits IDO1.

    20. NO inhibition of IDO is apparently specific to both certain species and cell types.

      nitric oxide inhibits IDO1.

    21. In macrophages, the inhibition of IDO by NO occurs at both the transcriptional and post-transcriptional levels.

      nitric oxide inhibits IDO1.

    1. S100A8 Induced Pro Inflammatory Cytokine Production Via Phosphorylation of ERK and JNK in BV-2 Cells.

      S100A8 leads to the phosphorylation of JNK.

    2. Also, the phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular-signal-regulated kinase (ERK) were stimulated by S100A8, which had an analogous effect to the lipopolysaccharide (LPS) treatment (XREF_FIG C-E).

      S100A8 leads to the phosphorylation of JNK.

    3. S100A8 Induced Pro Inflammatory Cytokine Production Via Phosphorylation of ERK and JNK in BV-2 Cells.

      S100A8 leads to the phosphorylation of ERK.

    4. Also, the phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular-signal-regulated kinase (ERK) were stimulated by S100A8, which had an analogous effect to the lipopolysaccharide (LPS) treatment (XREF_FIG C-E).

      S100A8 leads to the phosphorylation of ERK.

    5. The S100A8 knockdown using shRNA revealed that COX-2 and PGE 2 expression was regulated by S100A8, which suggested that the intracellular increase of microglial S100A8 levels upregulated COX-2 expression and PGE2 secretion, contributing to neuronal death under hypoxic conditions.

      S100A8 increases the amount of PTGS2.

    6. In agreement with previous reports, the results of this study confirmed that S100A8 significantly increased the production of IL-6, TNF-alpha, and IL-1beta.

      S100A8 activates IL6.

    7. In agreement with previous reports, the results of this study confirmed that S100A8 significantly increased the production of IL-6, TNF-alpha, and IL-1beta.

      S100A8 activates IL1B.

    8. These results strongly suggested that S100A8 induced the NLRP3 inflammasome priming via NF-kappaB activation.

      S100A8 activates NLRP3.

    9. The results suggested that S100A8, secreted by neuronal cells under hypoxic conditions, triggered the priming of NLRP3 in microglial cells, through the TLR4 and NF-kappaB signaling.

      S100A8 activates NLRP3.

    10. In addition, the translocation of NF-kB, which played a pivotal role in regulating the expression and activation of NLRP3, was also increased when cells were treated with S100A8.

      S100A8 activates NLRP3.

    11. These results suggested that S100A8, secreted by neuronal cells under hypoxic conditions, combined with TLR4 of microglia cells, activated the NLRP3 inflammasome priming.

      S100A8 activates NLRP3.

    12. In agreement with previous reports, the results of this study confirmed that S100A8 significantly increased the production of IL-6, TNF-alpha, and IL-1beta.

      S100A8 activates TNF.

    13. Therefore, this study determined whether S100A8 induced neuronal apoptosis during cerebral hypoxia and elucidated its mechanism of action using in vitro systems, including astrocytes and microglial and neuronal cells, under hypoxic conditions.
    14. S100A8 Knockdown on Microglia Attenuated Neuronal Apoptosis by Hypoxia.
    15. To investigate whether S100A8 expression in microglia induced apoptosis of neuronal cells under hypoxic condition, SH-SY5Y cells were co-cultured with BV-2 cells transfected with S100A8 shRNA for 48 h in a 0.4 mum pore transwell system and under hypoxic conditions (XREF_FIG A, B).
    16. These findings indicated that the expression of S100A8, induced in microglia cells under hypoxic conditions, activated COX-2 expression and PGE 2 secretion to induce the apoptosis of neurons.
    17. FACS analysis showed that the increase of S100A8 levels in microglia by hypoxia promoted neuronal apoptosis, which was confirmed by immunofluorescence.
    18. However, for the first time, we showed that up-regulation of microglial S100A8 levels increased neuronal apoptosis after hypoxia, in primary multicellular cultures consisting of neurons, astrocytes, and microglia.
    1. Knockdown of S100A8 levels by using shRNA revealed that microglial S100A8 expression activated COX-2 expression, leading to neuronal apoptosis under hypoxia.

      S100A8 increases the amount of PTGS2.

    2. S100A8, secreted from neurons under hypoxia, activated the secretion of tumor necrosis factor (TNF-alpha) and interleukin-6 (IL-6) through phosphorylation of extracellular-signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) in microglia.

      S100A8 activates IL6.

    3. S100A8, secreted from neurons under hypoxia, activated the secretion of tumor necrosis factor (TNF-alpha) and interleukin-6 (IL-6) through phosphorylation of extracellular-signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) in microglia.

      S100A8 activates TNF.

    4. The aim of this study was to determine whether S100A8 induced neuronal apoptosis during cerebral hypoxia and elucidate its mechanism of action.
    1. The enhancer of zeste homolog 2 (EZH2) is a catalytic subunit of the polycomb repressive complex 2 (PRC2), acts as a histone methyltransferase and induces the trimethylation of histone H3 lysine 27 (H3K27me3) in the promoter of many key genes.

      EZH2 leads to the methylation of Histone_H3 at position 27.

    2. The enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and induces the trimethylation of histone H3 lysine 27 (H3K27me3) in the promoter of many key genes; EZH2 acts as a transcriptional repressor and is an epigenetic regulator for several cancers.

      EZH2 leads to the methylation of Histone_H3 at position 27.

    3. The enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and induces the trimethylation of histone H3 lysine 27 (H3K27me3) in the promoter of many key genes; EZH2 acts as a transcriptional repressor and is an epigenetic regulator for several cancers.

      EZH2 leads to the methylation of Histone_H3 at position 27.

    4. The enhancer of zeste homolog 2 (EZH2) is a catalytic subunit of the polycomb repressive complex 2 (PRC2), acts as a histone methyltransferase and induces the trimethylation of histone H3 lysine 27 (H3K27me3) in the promoter of many key genes.

      EZH2 leads to the methylation of Histone_H3 on lysine.

    5. The enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and induces the trimethylation of histone H3 lysine 27 (H3K27me3) in the promoter of many key genes; EZH2 acts as a transcriptional repressor and is an epigenetic regulator for several cancers.

      EZH2 leads to the methylation of Histone_H3 on lysine.

    6. The inhibition of EZH2 aggravated cisplatin induced injury in renal tubular cells by inactivating mTOR complexes.

      EZH2 inhibits MTOR.

    7. In cancer cells, EZH2 epigenetically represses Deptor, an inhibitor of the mammalian target of rapamycin (mTOR) pathway [XREF_BIBR].

      EZH2 inhibits DEPTOR.

    8. The present study showed that the inhibition of EZH2 induced apparent apoptosis in cultured NRK-52E cells, as demonstrated by flow cytometry and the concomitant increase of a pro apoptosis protein (cleaved-caspase 3) and decrease of anti-apoptosis proteins (Bcl-2 and HuR).
    9. These data suggested that EZH2 inhibition induced notable apoptosis in NRK-52E cells.
    10. Inhibition of EZH2 induced apoptosis in NRK-52E cells.
    11. Thus, the regulation of Deptor expression by EZH2 may control cell growth and proliferation through mTOR complex pathways.

      EZH2 increases the amount of DEPTOR.

    12. These data indicated that EZH2 inhibition decreased mTORC1 and mTORC2 activity by up-regulating Deptor expression.

      EZH2 increases the amount of DEPTOR.

    13. In the present study, we identified that the inhibition of EZH2 with 3-deazaneplanocin A (DZNep) upregulated the transcription of Deptor by decreasing the H3K27me3 methylation level in its promoter region and reduced the activity of mTORC1 and mTORC2, resulting in apoptosis of NRK-52E cells.

      EZH2 decreases the amount of DEPTOR.

    14. These data suggested that EZH2 inhibition increased the transcription of Deptor by modifying H3K27me3 in its promoter region, subsequently inhibited mTORC1 and mTORC2 activities, downregulated the expression of apoptosis suppressor genes, and finally led to apoptosis in renal tubular cells.

      EZH2 decreases the amount of DEPTOR.

    15. In summary, our results showed that EZH2 inhibition increased the transcription level of Deptor by decreasing the level of trimethylation of H3K27 in the Deptor promoter region, subsequently inhibited the activities of mTORC1 and mTORC2, downregulated the expression of HuR and Bcl-2, and finally led to apoptosis in renal tubular cells.

      EZH2 decreases the amount of DEPTOR.

    16. EZH2 bound the Deptor promoter region and then regulated its transcriptional level.

      DEPTOR binds EZH2.

    17. A ChIP assay demonstrated that EZH2 bound the promoter region of Deptor, an endogenous inhibitor of mTORC1 and mTORC2, and regulated the transcription of Deptor by modulating H3K27me3 in its promoter region.

      DEPTOR binds EZH2.

    18. The binding of EZH2 to the Deptor promoter was determined by ChIPassay.

      DEPTOR binds EZH2.

    19. EZH2 epigenetically represses several negative regulators of the mTOR pathway in tumors, including Deptor [XREF_BIBR].

      EZH2 activates MTOR.

    1. It was also suggested that CBX5 silencing suppressed cell proliferation and migration.
    1. Our data indicate that genetic deficiency or topical inhibition of GzmB in PDs reduces disease severity, prevents hemidesmosomal protein loss, impedes neutrophil infiltration, and impairs lesional neutrophil elastase activity.
    2. Further, granzyme B mediates IL-8 and macrophage inflammatory protein-2 secretion, lesional neutrophil infiltration, and lesional neutrophil elastase activity.

      GZMB activates CXCL8.

    3. In our current study, GzmB stimulation increased IL-8 and MIP-2 secretion by pHEKs and primary mouse epidermal keratinocytes, respectively.

      GZMB activates CXCL8.

    4. As GzmB induces COL17 loss in keratinocytes and keratinocyte secretion of IL-8 correlates to COL17 loss 38, GzmB may induce IL-8 secretion from keratinocytes in response to COL17 degradation.

      GZMB activates CXCL8.

    5. To further test if GzmB positively regulated MIP-2 production and to ascertain keratinocytes as a cell source of MIP-2, MIP-2 was quantified in the supernatants of primary mouse epidermal keratinocytes after GzmB stimulation for 16h.

      GZMB activates CXCL2.

    6. MIP-2 levels in the supernatant were increased in a GzmB-dose dependent manner while GzmB inhibitor VTI-1002 attenuated GzmB induced MIP-2 secretion.

      GZMB activates CXCL2.

    7. Consistent with GzmB dependent elevation of neutrophil elastase activity in EBA, we identified GzmB dependent infiltration of neutrophils, a predominant source of neutrophil elastase 32, in EBA mice and GzmB dependent elevation of strong neutrophil chemoattractant MIP-2, a mouse homolog of human IL-8 33.

      GZMB activates CXCL2.

    8. In our current study, GzmB stimulation increased IL-8 and MIP-2 secretion by pHEKs and primary mouse epidermal keratinocytes, respectively.

      GZMB activates CXCL2.

    9. As GzmB did not directly degrade alpha6 integrin in pHEKs, we postulated that GzmB modulated alpha6 integrin loss in WT EBA mice by promoting neutrophil infiltration and neutrophil elastase activity.

      GZMB activates ELANE.

    10. Consistent with GzmB dependent elevation of neutrophil elastase activity in EBA, we identified GzmB dependent infiltration of neutrophils, a predominant source of neutrophil elastase 32, in EBA mice and GzmB dependent elevation of strong neutrophil chemoattractant MIP-2, a mouse homolog of human IL-8 33.

      GZMB activates ELANE.

    11. Further, granzyme B mediates IL-8 and macrophage inflammatory protein-2 secretion, lesional neutrophil infiltration, and lesional neutrophil elastase activity.

      GZMB activates ELANE.

    12. Indeed, a recent work revealed that GzmB activates caspase 3 in secretory lysosomes of mast cells, a mechanism which possibly contributes to enhanced caspase 3 dependent proteolytic cleavage in the extracellular space 39.

      GZMB activates CASP3.

    13. As proteolytic degradation of alpha6 integrin by other proteases has been reported 31, we hypothesized that GzmB augments inflammation to increase the activity of other proteases to degrade alpha6 integrin.
    14. Further, granzyme B mediates IL-8 and macrophage inflammatory protein-2 secretion, lesional neutrophil infiltration, and lesional neutrophil elastase activity.
    15. As GzmB did not directly degrade alpha6 integrin in pHEKs, we postulated that GzmB modulated alpha6 integrin loss in WT EBA mice by promoting neutrophil infiltration and neutrophil elastase activity.
    1. Therefore, simultaneous induction of nitric oxide, respiratory burst and tryptophan degradation responses would antagonize PKC and thus NADPH oxidase activation and the IDO enzyme.

      nitric oxide inhibits IDO1.

    1. Previous studies have suggested nitric oxide (NO) can inhibit IDO activity and expression [XREF_BIBR, XREF_BIBR] most likely through post-translational regulation leading to proteasomal degradation of IDO rather than transcriptional regulation [XREF_BIBR].

      nitric oxide inhibits IDO1.

    2. Previous studies have suggested nitric oxide (NO) can inhibit IDO activity and expression [XREF_BIBR, XREF_BIBR] most likely through post-translational regulation leading to proteasomal degradation of IDO rather than transcriptional regulation [XREF_BIBR].

      nitric oxide inhibits IDO1.

    1. Several findings have demonstrated that NO is able to inhibit the IDO enzyme by direct interaction or accelerating proteasomal degradation [XREF_BIBR, XREF_BIBR].

      nitric oxide inhibits IDO1.

    1. Cells expressing IDO can co-express iNOS in response to IFN-gamma, which produces NO that inhibits, in turn, IDO.

      nitric oxide inhibits IDO1.

  3. May 2021
    1. Repression of AR signaling increases the NGF and is associated with NEPC differentiation.

      AR inhibits NGF.

    2. We found that CSS treated cells had increased levels of the NGF and were associated with higher neuroendocrine marker expressions compared to cells cultured in fetal bovine serum (FBS)-containing medium; however, AR ligand (dihydrotestosterone (DHT))-treated cells had reduced levels of NGF and neuroendocrine markers.

      AR inhibits NGF.

    3. AR inhibition by CSS or enzalutamide upregulates the NGF possibly because ADT inhibits the AR.

      AR inhibits NGF.

    4. The AR may act upstream of both ZBTB46 and the NGF, and downregulates ZBTB46 and the NGF before ADT.

      AR inhibits NGF.

    5. These findings suggest a mechanism whereby ADT upregulated ZBTB46 enhances NGF transcription through direct physical interaction with the NGF-regulatory sequence.

      NGF increases the amount of ZBTB46.

    6. We hypothesized that ZBTB46 upregulates NGF expression in prostate cancer cells by acting as a transcriptional activator and binding to a ZBTB46 binding element (ZBE) in the NGF regulatory sequence.

      ZBTB46 increases the amount of NGF.

    7. Moreover, ZBTB46 binding signals were enriched in C4-2 and LNCaP cells in response to CSS containing medium or MDV3100, supporting the hypothesis that ADT increased ZBTB46 upregulates NGF expression.

      ZBTB46 increases the amount of NGF.

    8. These findings suggest a mechanism whereby ADT upregulated ZBTB46 enhances NGF transcription through direct physical interaction with the NGF-regulatory sequence.

      ZBTB46 increases the amount of NGF.

    9. We further knocked-down AR in AR positive LNCaP cells using AR small interfering RNA, and found that knockdown of AR increased ZBTB46 and NGF expressions.

      AR decreases the amount of NGF.

    10. NGF physically interacts with CHRM4 after ADT.

      CHRM4 binds NGF.

    11. To determine the possible interaction between NGF and CHRM4, AR positive cells were subjected to ADT followed by an immunoprecipitation (IP)-Western blot analysis.

      CHRM4 binds NGF.

    12. These observations confirm that the NGF physically interacts with CHRM4.

      CHRM4 binds NGF.

    13. We demonstrated that the NGF physically interacts with CHRM4 and that the NGF mediates NEPC differentiation dependent on CHRM4.

      CHRM4 binds NGF.

    14. The NGF was reported to promote prostate cancer cell metastasis XREF_BIBR, XREF_BIBR, yet the mechanisms and functions of NGF in NEPC differentiation have not been clearly elucidated.
    15. In prostate cancer, the NGF stimulates NTRK1 downstream of p38-MAPK activation to promote cell migration, invasion, and metastasis 11.
    16. In prostate cancer, the NGF stimulates NTRK1 downstream of p38-MAPK activation to promote cell migration, invasion, and metastasis 11.
    17. In prostate cancer, the NGF stimulates NTRK1 downstream of p38-MAPK activation to promote cell migration, invasion, and metastasis 11.

      NGF activates NTRK1.

    18. Pharmacologic NGF blockade and NGF knockdown markedly inhibited CHRM4 mediated NEPC differentiation and AKT-MYCN signaling activation.

      NGF activates CHRM4.

    19. These results are consistent with the notion that the NGF upregulates CHRM4, through which it activates AKT-MYCN signaling after ADT.

      NGF activates CHRM4.

    20. Taken together, our findings support a model wherein ADT or AR inhibitor treatment stimulates ZBTB46 expression, which upregulates NGF mediated CHRM4 stimulation; this plays a pivotal role in integrating AKT and MYCN signals to promote therapeutic resistance and neuroendocrine differentiation of prostate cancer.

      NGF activates CHRM4.

    21. Activated NGF upregulates CHRM4 and links AKT signaling activation and MYCN stimulation to enhance NEPC reprogramming.

      NGF activates CHRM4.

    22. In prostate cancer, the NGF stimulates NTRK1 downstream of p38-MAPK activation to promote cell migration, invasion, and metastasis 11.

      NGF activates cell migration.

    23. Indeed, involvement of the NGF in pancreatic cancer was demonstrated to increase cell proliferation and survival through activation of mitogen activated protein kinase (MAPK) via the NTRK1 receptor 8.
    24. Notably, overexpression of the NGF in cells promoted cell proliferation regardless of CSS containing medium treatment, whereas NGF-knockdown in AR negative PC3 and ADT-resistance C4-2-MDVR cells reduced cell proliferation and colony formation compared to cells carrying the control vector.
    25. In prostate cancer, the NGF stimulates NTRK1 downstream of p38-MAPK activation to promote cell migration, invasion, and metastasis 11.

      NGF activates p38.

    26. Indeed, it is clear that many types of tumors have the potential to secrete NGF, which induces peripheral nerve infiltration into the tumor microenvironment, thereby promoting tumor growth and metastasis XREF_BIBR, XREF_BIBR.
    27. In addition, the NGF stimulates nerve infiltration into solid tumors and acts as a mediator of pain through activation of NTRK1 in the endings of sensory neurons 65.
    28. Here, we show that an androgen deprivation therapy (ADT)-stimulated transcription factor, ZBTB46, upregulated NGF via ZBTB46 mediated-transcriptional activation of NGF.

      ZBTB46 activates NGF.

    29. ZBTB46 upregulated NGF is associated with NEPC differentiation.

      ZBTB46 activates NGF.

    30. These results indicate that ADT increased NGF promotes NEPC differentiation and suggest that NGF expression is likely regulated by ZBTB46.
    1. Pharmacologic NGF blockade and NGF knockdown markedly inhibited CHRM4 mediated NEPC differentiation and AKT-MYCN signaling activation.

      NGF activates CHRM4.

    2. Here, we show that an androgen deprivation therapy (ADT)-stimulated transcription factor, ZBTB46, upregulated NGF via ZBTB46 mediated-transcriptional activation of NGF.

      ZBTB46 activates NGF.

    3. Here, we show that an androgen deprivation therapy (ADT)-stimulated transcription factor, ZBTB46, upregulated NGF via ZBTB46 mediated-transcriptional activation of NGF.
    1. It was recently shown that MAVS recruits NLRP3 to the mitochondria for activation in response to non crystalline activators and that microtubule driven trafficking of the mitochondria is necessary for NLRP3 and ASC complex assembly and activation.

      MAVS translocates to the mitochondrion.

    2. It was recently shown that MAVS recruits NLRP3 to the mitochondria for activation in response to non crystalline activators and that microtubule driven trafficking of the mitochondria is necessary for NLRP3 and ASC complex assembly and activation.

      NLRP3 translocates to the mitochondrion.

    3. By triggering the phosphorylation of the autophagy inducer ULK1, RIPK2 induces autophagy of disrupted mitochondria (mitophagy), preventing the accumulation of ROS and NLRP3 inflammasome activation.

      RIPK2 leads to the phosphorylation of ULK1.

    4. Conversely, others have shown that overexpression of NLRP7 inhibited pro-IL-1beta synthesis and secretion.

      NLRP7 inhibits IL1B.

    5. Some studies have suggested that NLRP12 may negatively regulate the NF-kappaB pathway.

      NLRP12 inhibits NFkappaB.

    6. IFNgamma functions via signal transducer and activator of transcription 1 (STAT1) and can not induce NLRC5 expression in the absence of STAT1.

      IFNG increases the amount of NLRC5.

    7. It was recently shown that MAVS recruits NLRP3 to the mitochondria for activation in response to non crystalline activators and that microtubule driven trafficking of the mitochondria is necessary for NLRP3 and ASC complex assembly and activation.

      STS binds NLRP3.

    8. NOD1 and 2 both interact with RIPK2, via a CARD-CARD homotypic interaction.

      RIPK2 binds NOD1.

    9. In Alzheimer 's disease, amyloid-beta aggregates were shown to activate NLRP3 ex vivo in primary macrophages and microglia.

      APP activates NLRP3.

    10. The possibility of a role for NOD2 in non bacterial infections has also been suggested, with NOD2 having been shown to induce an IFNbeta driven antiviral response following recognition of single stranded viral RNA.

      NOD2 activates IFNB1.

    11. IL-1beta produced downstream of the NLRP3 inflammasome, which is also stimulated by islet amyloid polypeptide, promotes beta-cell dysfunction, and cell death, linking NLRP3 activation to insulin resistance.

      IAPP activates NLRP3.

    12. Moreover, it was recently reported that bacterial acylated lipopeptides (acLP) activated NLRP7 and stimulated formation of an NLRP7-ASC-caspase-1 inflammasome.

      AEBP1 activates NLRP7.

    13. NLRX1 has been shown to enhance ROS production when it is overexpressed, following Chlamydia and Shigella infection, as well as in response to TNFalpha and poly (I : C).
    14. A recent study by Zhong et al. suggested that particulate stimuli might induce mitochondrial production of reactive oxygen species (ROS), which triggers a calcium influx mediated by transient receptor potential melastatin 2 (TRPM2) to activate NLRP3.

      TRPM3 activates NLRP3.

    15. A recent study by Zhong et al. suggested that particulate stimuli might induce mitochondrial production of reactive oxygen species (ROS), which triggers a calcium influx mediated by transient receptor potential melastatin 2 (TRPM2) to activate NLRP3.

      TRPM3 activates calcium(2+).

    16. Ceballos-Olvera et al. demonstrated that while IL-18 and pyroptosis are both essential for host resistance, the production of IL-1beta by NLRP3 was deleterious, as it triggered excessive neutrophil recruitment and exacerbated the disease.

      NLRP3 activates IL1B.

    17. Mutations in NLRP3 were reported to induce an overproduction of IL-1beta that triggers the subsequent development of severe inflammation.

      NLRP3 activates IL1B.

    18. Other NLRs such as NOD1, NOD2, NLRP10, NLRX1, NLRC5, and CIITA do not directly engage the inflammatory caspases, but instead activate nuclear factor-kappaB (NF-kappaB), mitogen activated protein kinases (MAPKs), and interferon (IFN) regulatory factors (IRFs) to stimulate innate immunity.
    19. A recent study by Zhong et al. suggested that particulate stimuli might induce mitochondrial production of reactive oxygen species (ROS), which triggers a calcium influx mediated by transient receptor potential melastatin 2 (TRPM2) to activate NLRP3.

      TRPM2 activates NLRP3.

    20. By triggering the phosphorylation of the autophagy inducer ULK1, RIPK2 induces autophagy of disrupted mitochondria (mitophagy), preventing the accumulation of ROS and NLRP3 inflammasome activation.

      RIPK2 activates autophagy.

    21. Nlrp6 - / - mice had increased numbers of immune cells in their circulation, as well as enhanced activation of MAPK and NF-kappaB signaling, though Toll like receptor (TLR) activation, suggesting that NLRP6 may suppress TLR pathways after the recognition of pathogens to prevent amplified inflammatory pathology.

      TLR activates NFkappaB.

    22. Other NLRs such as NOD1, NOD2, NLRP10, NLRX1, NLRC5, and CIITA do not directly engage the inflammatory caspases, but instead activate nuclear factor-kappaB (NF-kappaB), mitogen activated protein kinases (MAPKs), and interferon (IFN) regulatory factors (IRFs) to stimulate innate immunity.
    23. The exact mechanism of NLRP3 activation by uric acid crystals is still unknown, but monosodium urate and calcium pyrophosphate dihydrate crystals were found to induce NLRP3 and caspase-1 activation and the subsequent processing of IL-1beta and IL-18.
    24. The exact mechanism of NLRP3 activation by uric acid crystals is still unknown, but monosodium urate and calcium pyrophosphate dihydrate crystals were found to induce NLRP3 and caspase-1 activation and the subsequent processing of IL-1beta and IL-18.
    25. The exact mechanism of NLRP3 activation by uric acid crystals is still unknown, but monosodium urate and calcium pyrophosphate dihydrate crystals were found to induce NLRP3 and caspase-1 activation and the subsequent processing of IL-1beta and IL-18.
    26. The exact mechanism of NLRP3 activation by uric acid crystals is still unknown, but monosodium urate and calcium pyrophosphate dihydrate crystals were found to induce NLRP3 and caspase-1 activation and the subsequent processing of IL-1beta and IL-18.
    27. A recent study by Zhong et al. suggested that particulate stimuli might induce mitochondrial production of reactive oxygen species (ROS), which triggers a calcium influx mediated by transient receptor potential melastatin 2 (TRPM2) to activate NLRP3.
    28. The exact mechanism of NLRP3 activation by uric acid crystals is still unknown, but monosodium urate and calcium pyrophosphate dihydrate crystals were found to induce NLRP3 and caspase-1 activation and the subsequent processing of IL-1beta and IL-18.
    29. The exact mechanism of NLRP3 activation by uric acid crystals is still unknown, but monosodium urate and calcium pyrophosphate dihydrate crystals were found to induce NLRP3 and caspase-1 activation and the subsequent processing of IL-1beta and IL-18.
    30. The exact mechanism of NLRP3 activation by uric acid crystals is still unknown, but monosodium urate and calcium pyrophosphate dihydrate crystals were found to induce NLRP3 and caspase-1 activation and the subsequent processing of IL-1beta and IL-18.
    31. The exact mechanism of NLRP3 activation by uric acid crystals is still unknown, but monosodium urate and calcium pyrophosphate dihydrate crystals were found to induce NLRP3 and caspase-1 activation and the subsequent processing of IL-1beta and IL-18.
    32. Ceramide, a specific product from the metabolism of long-chain saturated fatty acids, and the saturated free fatty acid, palmitate, have been shown to induce IL-1beta in an NLRP3 dependent fashion [Ref.

      ceramide activates IL1B.

    33. Crystalline cholesterol was proposed to cause atherosclerosis by acting as a danger signal and initiating inflammation through the NLRP3 inflammasome.
    34. A recent study by Zhong et al. suggested that particulate stimuli might induce mitochondrial production of reactive oxygen species (ROS), which triggers a calcium influx mediated by transient receptor potential melastatin 2 (TRPM2) to activate NLRP3.

      dioxygen activates calcium(2+).

  4. Apr 2021
    1. Translocation of merlin to the nucleus allows merlin to bind and inhibit the E3 ubiquitin ligase CRL4 DCAF1 (DDB1- and Cul4 Associated Factor 1).

      NF2 translocates to the nucleus.

    2. Notably, NF2 transfection into these cells induced YAP1 phosphorylation at Ser127, YAP1 retention in the cytoplasm and consequent reduction of YAP1 nuclear localization.

      NF2 leads to the phosphorylation of YAP1 on S127.

    3. Previously, we showed that activation of ErbB2 and ErbB3 receptors in primary rat Schwann cells by neuregulin-1 induced merlin phosphorylation at Ser518 via PKA.

      ERBB3 leads to the phosphorylation of NF2 on S518.

    4. Previously, we showed that activation of ErbB2 and ErbB3 receptors in primary rat Schwann cells by neuregulin-1 induced merlin phosphorylation at Ser518 via PKA.

      ERBB3 leads to the phosphorylation of NF2 on S518.

    5. Previously, we showed that activation of ErbB2 and ErbB3 receptors in primary rat Schwann cells by neuregulin-1 induced merlin phosphorylation at Ser518 via PKA.

      ERBB2 leads to the phosphorylation of NF2 on S518.

    6. We reported that merlin associates with beta 1 -integrin in primary Schwann cells and undifferentiated Schwann cell and neuron co-cultures, and in primary Schwann cell cultures, laminin-1 stimulated integrin signaled though PAK1 and caused merlin Ser518 phosphorylation and inactivation of its tumor suppressor function.

      Integrins leads to the phosphorylation of NF2 on S518.

    7. Merlin is phosphorylated at Ser10, Thr230 and Ser315 by Akt (also known as protein kinase B, PKB) and controls merlin 's proteasome mediated degradation by ubiquitination to prevent its interaction with binding partners.

      AKT phosphorylates NF2 on T230.

    8. Merlin is phosphorylated at Ser10, Thr230 and Ser315 by Akt (also known as protein kinase B, PKB) and controls merlin 's proteasome mediated degradation by ubiquitination to prevent its interaction with binding partners.

      AKT phosphorylates NF2 on S315.

    9. Merlin is phosphorylated at Ser10, Thr230 and Ser315 by Akt (also known as protein kinase B, PKB) and controls merlin 's proteasome mediated degradation by ubiquitination to prevent its interaction with binding partners.

      AKT phosphorylates NF2 on S10.

    10. Loss of merlin results in integrin mediated activation of mTORC1 through PAK1, which promotes cell cycle progression by inducing translation of cyclin-D1 mRNA and cyclin-D1 expression.

      PAK1 inhibits cell cycle.

    11. Loss of merlin in mesotheliomas has been linked not only to increased proliferation, but also increased invasiveness, spreading and migration.
    12. Adenoviral transduction of NF2 in Meso-17 and Meso-25 cell lines decreased invasion through Matrigel membranes compared to cells transduced with empty vector.
    13. Second, similar to NF2 schwannomas, mesothelioma cells with NF2 inactivation, exhibit activated PAK1 and AKT, and re-expression of merlin in merlin-null human mesothelioma cells (Meso-17) decreases PAK1 activity.

      NF2 inhibits PAK1.

    14. Soon after merlin was cloned, evidence that merlin inhibits another important member of the Rho GTPases family, Ras, was reported in v-Ha-Ras-transformed NIH3T3cells in which merlin overexpression counteracted the oncogenic role of Ras.

      NF2 inhibits RHOA.

    15. Merlin re-expression in Nf2 -/- Schwann cells similarly reduced the transport of growth factor receptors ErbB2 and ErbB3, insulin like growth factor 1 receptor (IGF1R) and platelet derived growth factor receptor (PDGFR).

      NF2 inhibits ERBB3.

    16. Merlin re-expression in Nf2 -/- Schwann cells similarly reduced the transport of growth factor receptors ErbB2 and ErbB3, insulin like growth factor 1 receptor (IGF1R) and platelet derived growth factor receptor (PDGFR).

      NF2 inhibits ERBB2.

    17. In sum, multiple lines of evidence have established a feedback regulation loop with merlin being phosphorylated at Ser518 (growth permissive form) via activated Rho small GTPases Rac1 and Cdc42 through PAK, and in turn, merlin associating with PAK to inhibit Rac1 and Cdc42 signaling (XREF_FIG).

      NF2 inhibits CDC42.

    18. Collectively, these results indicate that merlin inhibits cell growth by contact inhibition in part by binding CD44 and negatively regulating CD44 function (XREF_FIG).

      NF2 inhibits CD44.

    19. Merlin inactivation of Src signaling was also shown in CNS glial cells, where merlin competitively inhibits Src binding to ErbB2 thereby preventing ErbB2 mediated Src phosphorylation and downstream mitogenic signaling.

      NF2 inhibits SRC.

    20. In the NF2 -/- breast cancer MDA-MB-231 cell line, merlin re-expression inhibited YAP and TEAD activity that was eliminated by LATS1/2 silencing.

      NF2 inhibits TEAD.

    21. Loss of merlin results in integrin mediated activation of mTORC1 through PAK1, which promotes cell cycle progression by inducing translation of cyclin-D1 mRNA and cyclin-D1 expression.

      NF2 inhibits Integrins.