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  1. Last 7 days
    1. Moreover, TFRC activated PTEN induced kinase 1 (PINK1) signaling and induced mitophagy; iron-uptake-induced upregulation of acyl-CoA synthetase long chain family member 4 (ACSL4) was required for mitophagy activation and glutathione peroxidase 4 (GPX4) degradation.

      TFRC activates PTEN.

    2. Moreover, TFRC activated PTEN induced kinase 1 (PINK1) signaling and induced mitophagy; iron-uptake-induced upregulation of acyl-CoA synthetase long chain family member 4 (ACSL4) was required for mitophagy activation and glutathione peroxidase 4 (GPX4) degradation.

      TFRC activates PTEN.

    3. Moreover, TFRC activated PTEN induced kinase 1 (PINK1) signaling and induced mitophagy; iron-uptake-induced upregulation of acyl-CoA synthetase long chain family member 4 (ACSL4) was required for mitophagy activation and glutathione peroxidase 4 (GPX4) degradation.

      TFRC activates PTEN.

    4. Moreover, TFRC activated PTEN induced kinase 1 (PINK1) signaling and induced mitophagy; iron-uptake-induced upregulation of acyl-CoA synthetase long chain family member 4 (ACSL4) was required for mitophagy activation and glutathione peroxidase 4 (GPX4) degradation.

      TFRC activates PTEN.

    1. The precise mechanism of how LASP1 promotes PTEN ubiquitination still remains elusive xref .

      LASP1 leads to the ubiquitination of PTEN.

    2. The precise mechanism of how LASP1 promotes PTEN ubiquitination still remains elusive 53.

      LASP1 leads to the ubiquitination of PTEN.

    3. In another study, the heat shock-like protein Clusterin was shown to increase AKT2 activity and promote the motility of both normal and malignant prostate cells via an inhibitory activity on PTEN-S380 phosphorylation and consequent inactivation of PTEN xref .

      PTEN is phosphorylated on S380.

    4. Another study demonstrated that phosphorylation of PTEN on tyrosine 240 by FGFR2 promotes chromatin binding through an interaction with Ki-67, which facilitates the recruitment of RAD51 to promote DNA repair xref . xref summarises these novel functions and signalling axes of nuclear PTEN.

      FGFR2 phosphorylates PTEN on Y240.

    5. 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.

    6. 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 inhibits ARID4B.

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

      PTEN inhibits ARID4B.

    8. 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.

    9. 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.
    10. 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.

    11. 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.

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

      NOTCH1 inhibits PTEN.

    13. In addition to being a dual specificity phosphatase for lipid and protein substrates, PTEN can also be dephosphorylated at serine/threonine and tyrosine residues.

      PTEN is dephosphorylated.

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

      PTEN dephosphorylates PGK1.

    15. 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.

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

      PTEN dephosphorylates PGK1.

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

      PTEN dephosphorylates PGK1.

    18. 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.

    19. 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.

    20. CBP–β-catenin signalling regulated the levels of C-terminal PTEN phosphorylation in TICs and promoted stemness via CD133 induction.

      CREBBP binds CTNNB1.

    21. 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.

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

      PTEN activates PINK1.

    23. 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.

    24. 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.

    1. IL-1beta secretion was not affected by treatment with the NLRP3 inhibitor glyburide XREF_BIBR or parthenolide, which has also been shown to inhibit NLRP3 XREF_BIBR.

      parthenolide inhibits NLRP3.

    2. Glyburide and parthenolide both inhibited NLRP3 activation by LPS and ATP (data not shown).

      parthenolide inhibits NLRP3.

    3. XREF_BIBR have shown that parthenolide directly inhibits caspase-1 by alkylation of certain cysteine residues.

      parthenolide inhibits CASP1.

    4. However, the previous study xref did not test AIM2 activation so perhaps parthenolide only inhibits caspase-1 in response to NLRP3 or NLRC4 activation.

      parthenolide inhibits CASP1.

    5. Our results disagree with this assertion as we did not find that parthenolide inhibited caspase-1 in response to AIM2 stimulation.

      parthenolide inhibits CASP1.

  2. Sep 2021
    1. Nonetheless, transcripts of genes associated with IL-17 production, such as IL17F, RORC, IL23R, and CCR6, were significantly decreased in CD8 + CD103 + CD49a + relative to CD8 + CD103 + CD49a - Trm cells, whereas transcripts for IFN-gamma were elevated (XREF_FIG D-E).

      IL23R inhibits ITGAE.

    2. Nonetheless, transcripts of genes associated with IL-17 production, such as IL17F, RORC, IL23R, and CCR6, were significantly decreased in CD8 + CD103 + CD49a + relative to CD8 + CD103 + CD49a - Trm cells, whereas transcripts for IFN-gamma were elevated (XREF_FIG D-E).

      IL23R inhibits ITGA1.

    3. CD103 binds E-cadherin, which is highly expressed on epithelia, whereas CD69 antagonizes sphingosine 1-phosphate receptor 1 (S1PR1)-mediated egress from tissues.

      CD69 inhibits S1PR1.

    4. Nonetheless, transcripts of genes associated with IL-17 production, such as IL17F, RORC, IL23R, and CCR6, were significantly decreased in CD8 + CD103 + CD49a + relative to CD8 + CD103 + CD49a - Trm cells, whereas transcripts for IFN-gamma were elevated (XREF_FIG D-E).

      IL17F inhibits ITGAE.

    5. Nonetheless, transcripts of genes associated with IL-17 production, such as IL17F, RORC, IL23R, and CCR6, were significantly decreased in CD8 + CD103 + CD49a + relative to CD8 + CD103 + CD49a - Trm cells, whereas transcripts for IFN-gamma were elevated (XREF_FIG D-E).

      IL17F inhibits ITGA1.

    6. Nonetheless, transcripts of genes associated with IL-17 production, such as IL17F, RORC, IL23R, and CCR6, were significantly decreased in CD8 + CD103 + CD49a + relative to CD8 + CD103 + CD49a - Trm cells, whereas transcripts for IFN-gamma were elevated (XREF_FIG D-E).

      CCR6 inhibits ITGAE.

    7. Nonetheless, transcripts of genes associated with IL-17 production, such as IL17F, RORC, IL23R, and CCR6, were significantly decreased in CD8 + CD103 + CD49a + relative to CD8 + CD103 + CD49a - Trm cells, whereas transcripts for IFN-gamma were elevated (XREF_FIG D-E).

      CCR6 inhibits ITGA1.

    8. Further validating transcriptional data, CXCR3 expression was higher on CD8 + CD103 + CD49a + Trm cells, whereas IL-23R and CCR6 were preferentially expressed by CD8 + CD103 + CD49a - Trm cells (XREF_FIG G).

      ITGAE increases the amount of IL23R.

    9. Further validating transcriptional data, CXCR3 expression was higher on CD8 + CD103 + CD49a + Trm cells, whereas IL-23R and CCR6 were preferentially expressed by CD8 + CD103 + CD49a - Trm cells (XREF_FIG G).

      ITGAE increases the amount of CCR6.

    10. In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

      ITGA1 increases the amount of PRF1.

    11. In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

      ITGA1 increases the amount of PRF1.

    12. In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

      ITGA1 increases the amount of GZMB.

    13. Accordingly, IL-15-dependent expression of perforin and granzyme B was augmented by IL-6, but not other cytokine combinations tested (XREF_SUPPLEMENTARY C-S2E).

      IL6 increases the amount of GZMB.

    14. Rather, their cytotoxic capacity was primed through IL-2 and IL-15-mediated induction of perforin and granzyme B expression.

      IL2 increases the amount of PRF1.

    15. Rather, their cytotoxic capacity was primed through IL-2 and IL-15-mediated induction of perforin and granzyme B expression.

      IL2 increases the amount of GZMB.

    16. In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

      CD8 increases the amount of PRF1.

    17. In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

      CD8 increases the amount of PRF1.

    18. Moreover, IL-15 stimulation potentiated TCR dependent expression of IL-17 and IFN-gamma by epidermal CD8 + CD103 + CD49a - and IFN-gamma by CD8 + CD103 + CD49a + Trm cells, respectively (XREF_FIG D), substantiating effectual gamma chain receptor signaling in both subsets.

      CD8 increases the amount of IL17A.

    19. In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

      CD8 increases the amount of GZMB.

    20. Further validating transcriptional data, CXCR3 expression was higher on CD8 + CD103 + CD49a + Trm cells, whereas IL-23R and CCR6 were preferentially expressed by CD8 + CD103 + CD49a - Trm cells (XREF_FIG G).

      CD8 increases the amount of IL23R.

    21. Further validating transcriptional data, CXCR3 expression was higher on CD8 + CD103 + CD49a + Trm cells, whereas IL-23R and CCR6 were preferentially expressed by CD8 + CD103 + CD49a - Trm cells (XREF_FIG G).

      CD8 increases the amount of CCR6.

    22. Moreover, IL-15 stimulation potentiated TCR dependent expression of IL-17 and IFN-gamma by epidermal CD8 + CD103 + CD49a - and IFN-gamma by CD8 + CD103 + CD49a + Trm cells, respectively (XREF_FIG D), substantiating effectual gamma chain receptor signaling in both subsets.

      CD8 increases the amount of TCR.

    23. In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

      Trm increases the amount of PRF1.

    24. In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

      Trm increases the amount of PRF1.

    25. In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

      Trm increases the amount of GZMB.

    26. CD103 binds E-cadherin, which is highly expressed on epithelia, whereas CD69 antagonizes sphingosine 1-phosphate receptor 1 (S1PR1)-mediated egress from tissues.

      CDH1 binds ITGAE.

    27. Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

      IV activates ITGAE.

    28. Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

      IV activates IFNG.

    29. Relative to the epidermal CD8 + CD103 + CD49a - Trm cells, dermal counterparts produced 3.5-fold less IL-17.

      ITGAE activates IL17A.

    30. Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

      ITGA1 activates ITGAE.

    31. Relative to the epidermal CD8 + CD103 + CD49a - Trm cells, dermal counterparts produced 3.5-fold less IL-17.

      ITGA1 activates IL17A.

    32. Thus, CD49a expression delineated a dichotomy in Trm cell cytokine production, augmented by IL-15, with CD8 + CD103 + CD49a - and CD8 + CD103 + CD49a + Trm cells preferentially producing IL-17 and IFN-gamma, respectively.

      ITGA1 activates IL17A.

    33. Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

      ITGA1 activates IFNG.

    34. Thus, CD49a expression delineated a dichotomy in Trm cell cytokine production, augmented by IL-15, with CD8 + CD103 + CD49a - and CD8 + CD103 + CD49a + Trm cells preferentially producing IL-17 and IFN-gamma, respectively.

      ITGA1 activates IFNG.

    35. In human skin epithelia, CD8 + CD49a + Trm cells produced interferon-gamma, whereas CD8 + CD49a - Trm cells produced interleukin-17 (IL-17).

      ITGA1 activates IFNG.

    36. Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

      ITGA1 activates Trm.

    37. IL-2 and IL-15 Induce Cytotoxic Effector Protein Expression in Epidermal CD8 + CD103 + CD49a + Trm Cells.

      IL2 activates Trm.

    38. Conversely, CD8 + CD49a - Trm cells from psoriasis lesions predominantly generated IL-17 responses that promote local inflammation in this skin disease.
    39. This functional dichotomy was evident in the comparison of distinct immune mediated skin diseases, with skin biopsies from vitiligo patients showing a predominance of cytotoxic CD8 + CD103 + CD49a + Trm cells while skin biopsies from psoriasis patients featured the accumulation of the IL-17 producing CD8 + CD103 + CD49a - counterparts.

      IL17A activates CD8.

    40. Thus, CD49a expression delineated a dichotomy in Trm cell cytokine production, augmented by IL-15, with CD8 + CD103 + CD49a - and CD8 + CD103 + CD49a + Trm cells preferentially producing IL-17 and IFN-gamma, respectively.

      IL15 activates ITGAE.

    41. Thus, CD49a expression delineated a dichotomy in Trm cell cytokine production, augmented by IL-15, with CD8 + CD103 + CD49a - and CD8 + CD103 + CD49a + Trm cells preferentially producing IL-17 and IFN-gamma, respectively.

      IL15 activates ITGA1.

    42. Generally, IFN-gamma contributes to immunity toward intracellular infections while IL-17 provides anti-fungal defense and both of these cytokines initiate inflammatory keratinocyte responses.

      IFNG activates immune response.

    43. In line withincreased CD49a frequencies, IFN-gamma producing Trm cells were enriched in vitiligo lesions (XREF_FIG G).

      IFNG activates Trm.

    44. Nonetheless, transcripts of genes associated with IL-17 production, such as IL17F, RORC, IL23R, and CCR6, were significantly decreased in CD8 + CD103 + CD49a + relative to CD8 + CD103 + CD49a - Trm cells, whereas transcripts for IFN-gamma were elevated (XREF_FIG D-E).

      IL23R activates IL17A.

    45. Nonetheless, transcripts of genes associated with IL-17 production, such as IL17F, RORC, IL23R, and CCR6, were significantly decreased in CD8 + CD103 + CD49a + relative to CD8 + CD103 + CD49a - Trm cells, whereas transcripts for IFN-gamma were elevated (XREF_FIG D-E).

      IL17F activates IL17A.

    46. Nonetheless, transcripts of genes associated with IL-17 production, such as IL17F, RORC, IL23R, and CCR6, were significantly decreased in CD8 + CD103 + CD49a + relative to CD8 + CD103 + CD49a - Trm cells, whereas transcripts for IFN-gamma were elevated (XREF_FIG D-E).

      CCR6 activates IL17A.

    47. TCR engagement using anti-CD3 antibodies also preferentially induced IFN-gamma by epidermal CD8 + CD103 + CD49a + Trm cells (XREF_FIG D).

      TCR activates Trm.

    48. Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

      CD8 activates ITGAE.

    49. Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

      CD8 activates ITGA1.

    50. Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

      CD8 activates Trm.

    51. Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

      Collagen activates ITGAE.

    52. Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

      Collagen activates IFNG.

    53. TNF and IL-2 were abundantly produced by dermal and epidermal Trm cell subsets (XREF_FIG B and 6C).

      carbon atom activates IL2.

    54. TNF and IL-2 were abundantly produced by dermal and epidermal Trm cell subsets (XREF_FIG B and 6C).

      carbon atom activates TNF.

    55. TNF and IL-2 were abundantly produced by dermal and epidermal Trm cell subsets (XREF_FIG B and 6C).

      Trm activates IL2.

    56. Moreover, IL-17 or IFN-gamma production by distinct Trm cells subsets was generally maintained even in the context of the vigorous tissue inflammation.

      Trm activates IL17A.

    57. Revealing functional specialization among epidermal Trm cells with respect to CD49a expression, CD8 + CD103 + CD49a - Trm cells preferentially produced IL-17, a cytokine required for control of bacterial and fungal infections.

      Trm activates IL17A.

    58. Corroborating transcriptional profiles, CD8 + CD103 + CD49a - Trm cells produced IL-17 while CD8 + CD103 + CD49a + Trm cells excelled in IFN-gamma production upon stimulation with phorbol 12-myristate 13-acetate and ionomycin (XREF_FIG A-6C).

      Trm activates IL17A.

    59. Thus, CD49a expression delineated a dichotomy in Trm cell cytokine production, augmented by IL-15, with CD8 + CD103 + CD49a - and CD8 + CD103 + CD49a + Trm cells preferentially producing IL-17 and IFN-gamma, respectively.

      Trm activates IL17A.

    60. In human skin epithelia, CD8 + CD49a + Trm cells produced interferon-gamma, whereas CD8 + CD49a - Trm cells produced interleukin-17 (IL-17).

      Trm activates IL17A.

    61. Here, we identify CD49a expression as a marker delineating a subpopulation ofCD8 + Trm cells in human skin that specifically localize to thebasal layer of epidermis, preferentially produce IFN-gamma, and display high cytotoxic capacity upon stimulation.

      Trm activates IFNG.

    62. Moreover, IL-17 or IFN-gamma production by distinct Trm cells subsets was generally maintained even in the context of the vigorous tissue inflammation.

      Trm activates IFNG.

    63. Thus, CD49a expression delineated a dichotomy in Trm cell cytokine production, augmented by IL-15, with CD8 + CD103 + CD49a - and CD8 + CD103 + CD49a + Trm cells preferentially producing IL-17 and IFN-gamma, respectively.

      Trm activates IFNG.

    64. In human skin epithelia, CD8 + CD49a + Trm cells produced interferon-gamma, whereas CD8 + CD49a - Trm cells produced interleukin-17 (IL-17).

      Trm activates IFNG.

    65. TNF and IL-2 were abundantly produced by dermal and epidermal Trm cell subsets (XREF_FIG B and 6C).

      Trm activates TNF.

    1. In summary, our findings establish that NLRP3 inflammasome activation drives the interactions of NLRP3 and ASC with F-actin as well as regulate the amount of cellular F-actin.

      Active NLRP3 activates PYCARD.

    2. Accordingly, we observed that Ca 2+ / FliI dependent severing of F-actin suppresses F-actin/FliI/LRRFIP2-dependent NLRP3 inflammasome inhibition leading to increase IL-1beta production.

      Active calcium(2+) activates NLRP3.

    1. We further demonstrated that SPOP promoted the ubiquitination of LATS1 in cells (XREF_FIG j).

      SPOP leads to the ubiquitination of LATS1.

    2. We further demonstrated that SPOP promoted the ubiquitination of LATS1 in cells ( xref j).

      SPOP leads to the ubiquitination of LATS1.

    3. On the other hand, we observed that depletion of SPOP reduced cell invasion which can be rescued by additional depletion of LATS1 (XREF_FIG e, f).
    4. These results suggest that SPOP downregulates cell invasion partly through modulating LATS1 protein abundance.
    5. Notably, overexpression of SPOP rescued cell invasion inhibition induced by overexpression of LATS1 (XREF_FIG c, d).
    6. Moreover, previous studies have shown that CKIota was involved in SRC-3 and ERG degradation mediated by SPOP [XREF_BIBR, XREF_BIBR].

      SPOP inhibits NCOA3.

    7. Consistently, recent studies have identified that SPOP promoted SRC-3 and ERG degradation in a casein kinase Iota epsilon (CKIotaepsilon) -dependent and casein kinase Iota delta (CKIotadelta)-dependent manner [XREF_BIBR, XREF_BIBR].

      SPOP inhibits NCOA3.

    8. CKIotadelta promotes the interaction and degradation of LATS1 by SPOP.

      SPOP inhibits LATS1.

    9. Cullin3 SPOP is the physiological E3 ubiquitin ligase for LATS1 and negatively regulates the protein stability of LATS1.

      SPOP inhibits LATS1.

    10. 3.4 CKIotadelta promotes the interaction and degradation of LATS1 by SPOP.

      SPOP inhibits LATS1.

    11. In addition, we found that MTS1 kinase that phosphorylates LATS1 did not involve in SPOP mediated degradation of LATS1.

      SPOP inhibits LATS1.

    12. Given that the SPOP recognizable degron in LATS1 contains several putative CKI phosphorylation sites, we aimed to detect whether CKIota also involves in SPOP mediated degradation of LATS1.

      SPOP inhibits LATS1.

    13. Notably, deletion of degron1 (DeltaDeg1), and to a lesser extent of degron2 (DeltaDeg2), largely blocked SPOP mediated degradation of LATS1, whereas deletion of both degron1 and 2 (DeltaDeg1 +2) nearly abolished the LATS1 degradation of SPOP mediated (XREF_FIG b).

      SPOP inhibits LATS1.

    14. Moreover, either loss of MATH or BTB domain of SPOP prevented the degradation of LATS1.

      SPOP inhibits LATS1.

    15. Moreover, the half-life of LATS1 was markedly extended with depleting of endogenous SPOP protein, whereas overexpression of SPOP reduced the protein half-life of LATS1 (XREF_FIG d-g).

      SPOP inhibits LATS1.

    16. 3.2 Cullin3 SPOP E3 ubiquitin ligase negatively regulates the protein stability of LATS1.

      SPOP inhibits LATS1.

    17. Moreover, previous studies have shown that CKIota was involved in SRC-3 and ERG degradation mediated by SPOP [XREF_BIBR, XREF_BIBR].

      SPOP inhibits ERG.

    18. Consistently, recent studies have identified that SPOP promoted SRC-3 and ERG degradation in a casein kinase Iota epsilon (CKIotaepsilon) -dependent and casein kinase Iota delta (CKIotadelta)-dependent manner [XREF_BIBR, XREF_BIBR].

      SPOP inhibits ERG.

    19. To this end, we observed that depletion of SPOP decreased cell proliferation in A498 kidney cancer cells (XREF_FIG a).
    20. Notably, we observed that LATS1 interacted specifically with SPOP in cells (XREF_FIG f and Supplementary Fig. 1g and 1j).

      SPOP binds LATS1.

    21. More importantly, co-overexpression of CKΙδ in cells enhanced the association of LATS1 with SPOP to promote the ubiquitination of LATS1 ( xref d).

      SPOP binds LATS1.

    22. Mutagenesis studies demonstrated that the serine 336-to alanine mutation (S336A) in ΔDeg1 rarely attenuated the interaction of LATS1 with SPOP, but mutating Ser334, Ser335, Ser336 to alanine (LATS1-3A) dramatically attenuated the interaction of LATS1 with SPOP in cells ( xref g).

      SPOP binds LATS1.

    23. Notably, we observed that LATS1 interacted specifically with SPOP in cells ( xref f and Supplementary Fig. 1g and 1j).

      SPOP binds LATS1.

    24. Consistently, deletion of degron 1 or both degrons dramatically attenuated the interaction of LATS1 with SPOP in cells ( xref c).

      SPOP binds LATS1.

    25. In addition, PTEN and ERK governed the expression of beta-catenin, and mediated EMT in human cancer [XREF_BIBR, XREF_BIBR].
    26. In keeping with a critical role of Cullin 3 in regulating LATS1 protein stability, depletion of Cullin 3 promoted the abundance of LATS1 (XREF_FIG c and Supplementary Fig. 1b).

      CUL3 activates LATS1.

    27. Here we identified that the Cullin3 and SPOP E3 ligase mediates the abundance of LATS1 protein through promoting its ubiquitination and subsequent destruction.

      CUL3 activates LATS1.

    28. Mechanistically, SPOP drove EMT and promoted cell invasion via enhancement of beta-catenin protein expression and its nuclear translocation and upregulation of TCF4 in ccRCC XREF_BIBR.
    29. Thus, these studies indicate that SPOP mediated cell invasion in part via targeting PTEN and ERK, and activation of beta-catenin and TCF4 and subsequent upregulation of ZEB1.
    30. On the other hand, SPOP could promote kidney cancer cell invasion in part via regulating LATS1.
    31. Moreover, we found that overexpression of SPOP enhanced cell invasion (XREF_FIG c, d).
    32. One recent study demonstrated that SPOP promoted renal cell carcinoma cell epithelial-mesenchymal transition (EMT) and enhanced cell invasion via activation of beta, catenin, and TCF4 complex [32].
    33. Here we identified that the Cullin3 and SPOP E3 ligase mediates the abundance of LATS1 protein through promoting its ubiquitination and subsequent destruction.

      SPOP activates LATS1.

    34. Consistent with an important role for SPOP in modulating the stability of LATS1, we demonstrated that depletion of endogenous SPOP with several different small hairpin RNA (shRNA) markedly elevated the protein abundance of LATS1 in multiple cell lines (XREF_FIG a).

      SPOP activates LATS1.

    35. Therefore, our studies identified E3 ubiquitin ligase Cullin3 and SPOP mediated the stability of the tumour suppressor LATS1 through poly-ubiquitination and subsequent degradation of LATS1 in kidney cancer in a degron dependent manner.

      SPOP activates LATS1.

    36. CKIotadelta promotes the interaction and degradation of LATS1 by SPOP It has been previously reported that proper substrate phosphorylation is necessary before substrate ubiquitination and degradation by SCF type of E3 ligases including FBW7 and beta-TRCP .

      SPOP activates LATS1.

    37. It is worth noting that SPOP also targets PTEN, DUSP7, Daxx, and Gli2 in ccRCC XREF_BIBR, thereby suggesting that SPOP could exert its oncogenic function in part via LATS1 pathway.

      SPOP activates GLI2.

    38. SPOP promotes kidney cancer cell proliferation, invasion and regulates cell cycle in part via promoting the degradation of LATS1.
    39. Together, these results suggest that SPOP promotes kidney cancer cell proliferation, invasion and regulates cell cycle in part via promoting the degradation of LATS1.
    40. In line with this, we observed that overexpression of SPOP could promote cell proliferation partly through regulating cell cycle distribution in A498 cells and 786-O cells (XREF_FIG b).
    41. On the other hand, overexpression of SPOP promoted cell proliferation in A498 cells and 786-O cells (XREF_FIG b).
    1. We found that LATS1 interacted with Cullin3, and depletion of Cullin 3 upregulated the abundance of LATS1 largely via prolonging LATS1 protein half-life.

      CUL3 binds LATS1.

    2. We found that LATS1 interacted with Cullin3, and depletion of Cullin 3 upregulated the abundance of LATS1 largely via prolonging LATS1 protein half-life.

      CUL3 binds LATS1.

    3. Mechanistically, SPOP specifically interacted with LATS1, and promoted the poly-ubiquitination and subsequent degradation of LATS1 in a degron dependent manner.

      SPOP binds LATS1.

    4. Mechanistically, SPOP specifically interacted with LATS1, and promoted the poly-ubiquitination and subsequent degradation of LATS1 in a degron-dependent manner.

      SPOP binds LATS1.

    5. We found that LATS1 interacted with Cullin3, and depletion of Cullin 3 upregulated the abundance of LATS1 largely via prolonging LATS1 protein half-life.

      CUL3 activates LATS1.

    6. Furthermore, SPOP also promoted kidney cancer cell invasion via degrading LATS1.
    7. As such, over-expression of SPOP promoted cell proliferation partly through regulating cell cycle distribution in kidney cancer cells.
    1. Here we report that TCF19 interacts with a non histone, well-known tumor suppressor protein 53 (p53) and co-regulates a wide array of metabolic genes.

      TCF19 binds TP53.

    2. Interestingly, we observed that TCF19 and p53 complexes either have CBP or HDAC1 to epigenetically program the expression of TIGAR and SCO2 genes depending on short-term high glucose or prolonged high glucose conditions.

      TCF19 binds TP53.

    3. Here we report that TCF19 interacts with a non histone, well-known tumor suppressor protein 53 (p53) and co-regulates a wide array of metabolic genes.

      TCF19 binds TP53.

    4. Interestingly, we observed that TCF19 and p53 complexes either have CBP or HDAC1 to epigenetically program the expression of TIGAR and SCO2 genes depending on short-term high glucose or prolonged high glucose conditions.

      TCF19 binds TP53.

    1. The low nutrient concentrations and high oxygen concentrations measured in these samples support the influence of the Polar Surface Water or the Polar Intermediate water from the EGC.

      dioxygen activates water.

  3. Aug 2021
    1. The knockdown of NLRP3 significantly reduces the proliferation, clonogenicity, invasion and migration in both Ishikawa and HEC-1A cells, while in contrast, NLRP3 overexpression enhances the proliferation, migration and invasion in both Ishikawa and HEC-1A cells and furthermore, increases caspase-1 activation and the release of IL-1beta in endometrial cancer cells.
    2. Inhibition of NLRP3 suppresses the proliferation, migration and invasion, and promotes apoptosis in glioma cells, while in contrast, increased expression of NLRP3 significantly enhances the proliferation, migration and invasion as well as attenuating apoptosis in glioma cells (XREF_TABLE).
    3. Similarly, NLRP3 expression levels are also correlated with the tumor size, lymph node metastatic status and IL-1beta expression in oral squamous cell carcinoma (OSCC), and downregulating NLRP3 expression markedly attenuates the proliferation, migration, and invasion of OSCC.
    4. The knockdown of NLRP3 significantly reduces the proliferation, clonogenicity, invasion and migration in both Ishikawa and HEC-1A cells, while in contrast, NLRP3 overexpression enhances the proliferation, migration and invasion in both Ishikawa and HEC-1A cells and furthermore, increases caspase-1 activation and the release of IL-1beta in endometrial cancer cells.

      NLRP3 inhibits IL1B.

    5. Knockdown of NLRP3 suppresses UVB induced production of IL-1beta and attenuates other inflammatory mediators, such as IL-1alpha, IL-6, TNF-alpha and PGE 2.

      NLRP3 inhibits IL1B.

    6. The knockdown of NLRP3 significantly reduces the proliferation, clonogenicity, invasion and migration in both Ishikawa and HEC-1A cells, while in contrast, NLRP3 overexpression enhances the proliferation, migration and invasion in both Ishikawa and HEC-1A cells and furthermore, increases caspase-1 activation and the release of IL-1beta in endometrial cancer cells.

      NLRP3 inhibits CASP1.

    7. Dong et al. found that NLRP3 inhibits senescence and enables replicative immortality through regulating the Wnt / beta-catenin pathway via the thioredoxin-interacting protein ( TXNIP ) / NLRP3 axis ( 74 ) .
    8. found that NLRP3 inhibits senescence and enables replicative immortality through regulating the Wnt and beta-catenin pathway via the thioredoxin interacting protein (TXNIP)/NLRP3 axis.
    9. Consistently, knockdown of NLRP3 induces cell apoptosis in MCF-7 cells and decreases cell migration; nevertheless, in other cell-types, NLRP3 inflammasome may pharmacologically repress proliferation and metastasis of hepatic cell carcinoma (HCC) (XREF_TABLE).
    10. The knockdown of NLRP3 significantly reduces the proliferation, clonogenicity, invasion and migration in both Ishikawa and HEC-1A cells, while in contrast, NLRP3 overexpression enhances the proliferation, migration and invasion in both Ishikawa and HEC-1A cells and furthermore, increases caspase-1 activation and the release of IL-1beta in endometrial cancer cells.
    11. Inhibition of NLRP3 suppresses the proliferation, migration and invasion, and promotes apoptosis in glioma cells, while in contrast, increased expression of NLRP3 significantly enhances the proliferation, migration and invasion as well as attenuating apoptosis in glioma cells (XREF_TABLE).
    12. found that NLRP3 overexpression inhibits cell proliferation and stimulates apoptosis in leukemic cells.
    13. Similarly, NLRP3 expression levels are also correlated with the tumor size, lymph node metastatic status and IL-1beta expression in oral squamous cell carcinoma (OSCC), and downregulating NLRP3 expression markedly attenuates the proliferation, migration, and invasion of OSCC.
    14. Consistently, knockdown of NLRP3 induces cell apoptosis in MCF-7 cells and decreases cell migration; nevertheless, in other cell-types, NLRP3 inflammasome may pharmacologically repress proliferation and metastasis of hepatic cell carcinoma (HCC) (XREF_TABLE).
    15. NLRP3 inflammasome inactivation, driven by miR-223-3p, increases proliferation, promotes invasion and inhibits apoptosis in breast cancer cells.
    16. The attenuation of the NLRP3 downstream pyroptosis pathway promotes apoptosis.
    17. Similarly, activation of NLRP3 inflammasome in mesothelial cells of lung cancer leads to an inflammatory response that fuels cancer initiation and progression and then activates the NF-kappaB-signaling pathway in lung cancer, consequently increasing proliferation and inhibiting apoptosis.
    18. NLRP3 inflammasomes mediate both suppressions of apoptosis and progression of the cell cycle by leptin dependent ROS production in breast cancer, which is mediated via estrogen receptor alpha (ERalpha)/reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase signaling.
    19. proposed that significant cell death was observed only when P2X7R and NLRP3 inflammasome were both inhibited by ATP and MCC950, a specific inhibitor of NLRP3 inflammasome, and further research into safety manipulation of NLRP3 inflammasome without enhancing significant dose dependent side effects is required.

      ATP inhibits NLRP3.

    20. In addition, inactivation of NLRP3 inflammasome has also been found to reduce IL-1beta expression and halt development of melanoma.

      NLRP3 decreases the amount of IL1B.

    21. Inactivation of NLRP3 inflammasome driven by miR-233-3p has been found to decrease the expression of NLRP3 inflammasome associated proteins, ASC, IL-1beta, and IL-18 in breast cancers and suppress tumor growth.

      NLRP3 decreases the amount of NLRP3.

    22. found that NLRP3 in renal tubular cells re-localizes from the cytosol to the mitochondria during hypoxia and binds to MAVS, which attenuates mtROS production and depolarization of the mitochondrial membrane potential under hypoxia.

      NLRP3 binds MAVS.

    23. Despite the major downstream event of NLRP3 inflammation formation of caspase-1 mediated pyroptosis, NLRP3 seems to mediate the dual-function of apoptosis and survival.

      CASP1 binds NLRP3.

    24. Huang et al. reported that beta-catenin promotes NLRP3 inflammasome activation, and silencing of beta-catenin impairs NLRP3 activation.

      CTNNB1 activates NLRP3.

    25. TXNIP knockdown or targeting by miR-20b resulted in a pro tumorigenic phenotype with increased cell proliferation, inhibited cell senescence reduced cell cycle modulators (p16 and p21), and decreased NLRP3 inflammasome associated proteins (NLRP3 and cleaved caspase-1).

      TXNIP activates NLRP3.

    26. The knockdown of NLRP3 significantly reduces the proliferation , clonogenicity , invasion and migration in both Ishikawa and HEC-1A cells , while in contrast , NLRP3 overexpression enhances the proliferation , migration and invasion in both Ishikawa and HEC-1A cells and furthermore , increases caspase-1 activation and the release of IL-1beta in endometrial cancer cells .
    27. Inhibition of NLRP3 suppresses the proliferation , migration and invasion , and promotes apoptosis in glioma cells , while in contrast , increased expression of NLRP3 significantly enhances the proliferation , migration and invasion as well as attenuating apoptosis in glioma cells ( 56 ) ( Table 2 ) .
    28. The role of NLRP3 in promoting invasion has been demonstrated with human endometrial cancer cell lines such as Ishikawa and HEC-1A cells , where knockdown of NLRP3 significantly reduces proliferation , clonogenicity , invasion and migration .
    29. Increased activation of the NLRP3 inflammasome promotes migration and invasion activities in gastric cancer cells.
    30. The role of NLRP3 in promoting invasion has been demonstrated with human endometrial cancer cell lines such as Ishikawa and HEC-1A cells, where knockdown of NLRP3 significantly reduces proliferation, clonogenicity, invasion and migration.
    31. In contrast, overexpression of NLRP3 enhances the activities of proliferation, migration and invasion as well as increasing caspase-1 activation and IL-1beta secretion in human endometrial cancer cells.
    32. Moreover, the silencing of NLRP3 significantly decreases the migration and invasion in OSCC cells and reduces EMT related protein expression.
    33. The knockdown of NLRP3 significantly reduces the proliferation, clonogenicity, invasion and migration in both Ishikawa and HEC-1A cells, while in contrast, NLRP3 overexpression enhances the proliferation, migration and invasion in both Ishikawa and HEC-1A cells and furthermore, increases caspase-1 activation and the release of IL-1beta in endometrial cancer cells.
    34. NLRP3 inflammasome inactivation, driven by miR-223-3p, increases proliferation, promotes invasion and inhibits apoptosis in breast cancer cells.
    35. Collectively , these results indicate that upregulated NLRP3 expression promotes the progression of endometrial cancer ( 55 ) .

      NLRP3 activates Dientamoebiasis.

    36. Liu et al. concluded that the upregulation of NLRP3 expression promotes the progression of endometrial cancer ; therefore , NLPR3 inflammasome might be a new therapeutic target for endometrial cancer ( 55 ) .

      NLRP3 activates Dientamoebiasis.

    37. NLRP3 in the primary lesion of cancer cells drives the production of pro-IL-1beta, DC maturation, and the secretion of IL-1beta to support the evolution of tumor specific CD8 + T cells.

      NLRP3 activates Dendritic Cells.

    38. In the primary lesion of cancer cells, NLRP3 drives the production of pro-IL-1beta, DC maturation, and the secretion of IL-1beta to support the differentiation of tumor specific CD8 + T cells.

      NLRP3 activates Dendritic Cells.

    39. NLRP3 enhances IL-1beta , subsequently activating NF-kappaB , and initiates JNK signaling to cause proliferation and invasion in gastric cancer ( 21 ) .

      NLRP3 activates IL1B.

    40. In contrast, overexpression of NLRP3 enhances the activities of proliferation, migration and invasion as well as increasing caspase-1 activation and IL-1beta secretion in human endometrial cancer cells.

      NLRP3 activates IL1B.

    41. NLRP3 enhances IL-1beta, subsequently activating NF-kappaB, and initiates JNK signaling to cause proliferation and invasion in gastric cancer.

      NLRP3 activates IL1B.

    42. NLRP3 agonist induces Wnt and beta-catenin activation, whereas inactivation of Wnt and beta-catenin results in the inhibition of NLRP3, IL-1beta.

      NLRP3 activates IL1B.

    43. NLRP3 inflammasome activation induced IL-1beta and IL-18 in lung cancer may work through mechanisms other than the caspase-1 pathway, indicating that NLRP3 inflammasome can mediate the release of IL-1beta and IL-18 through caspase-1-dependent or -independent pathways.

      NLRP3 activates IL1B.

    44. Epistasis analysis revealed that NLRP3 variants together with polymorphisms in inflammasome related genes modulate both the frequency of inflammasome activation and the process of IL-1beta and IL-18 maturation thatinfluence HPV infection outcome and cervical cancer progression (XREF_TABLE).

      NLRP3 activates IL1B.

    45. NLRP3 in the primary lesion of cancer cells drives the production of pro-IL-1beta, DC maturation, and the secretion of IL-1beta to support the evolution of tumor specific CD8 + T cells.

      NLRP3 activates IL1B.

    46. In the primary lesion of cancer cells, NLRP3 drives the production of pro-IL-1beta, DC maturation, and the secretion of IL-1beta to support the differentiation of tumor specific CD8 + T cells.

      NLRP3 activates IL1B.

    47. NLRP3 inflammasome activation induced IL-1beta and IL-18 in lung cancer may work through mechanisms other than the caspase-1 pathway, indicating that NLRP3 inflammasome can mediate the release of IL-1beta and IL-18 through caspase-1-dependent or -independent pathways.

      NLRP3 activates IL18.