A study of pulmonary injury induced by intratracheal bleomycin demonstrates the role of HA activation of TLR4 in sterile injury.

Taken together these studies addressing the cellular location of the TLR4 signaling that drives growth and wound repair and the nature of the relevant TLR4 ligand suggest that HA activation of myeloid TLR4 mediates intestinal and colonic growth and wound repair.

This suggests that TLR4 activation by endogenous HA promotes healing in DSS colitis.

TLR4 activation by HA also affects the immune response in ischemia- reperfusion injury in the kidney and in acute allograft rejection in a skin transplant model.

TLR2 and TLR4 activation by HA mediates wound repair in the bleomycin model of lung injury.

Wound repair mediated by HA activation of TLR2 and TLR4 is also seen in the lung.

In this pathway, TLR4, which is usually associated with innate immunity, is activated not by the microbial product LPS, but by HA, a host molecule.

TLR4 activation by HA also plays a role in wound repair ( 22 ) .

TLR4 activation by HA also affects the immune response in ischemia - reperfusion injury in the kidney and in acute allograft rejection in a skin transplant model ( 8) .

Moreover , in contrast to wound repair where activation of TLRs by both microbial PAMPs and non-microbial agents , such as HA , play a role ( 11 , 12 ) , intestinal growth is driven only by TLR4 activation by the nonmicrobial agent , HA ( 17 ) .

In the first pathway ( xref ), intestinal and colonic growth is regulated by endogenous HA activating TLR4 on pericryptal macrophages resulting in the release of PGE₂ which promotes LGR5+ stem cell proliferation, crypt fission and intestinal elongation.

This suggests that TLR4 activation by endogenous HA promotes healing in DSS colitis.

TLR4 activation by HA also plays a role in wound repair ( xref ).

Despite these suggestions there is good evidence that endogenous HA activates TLR4 and promotes growth even though most of the endogenous HA is in the high MW form ( xref , xref , xref ).

Based on the growth studies, it is likely that EGFR activation by PGE2 is also the mechanism of the increased epithelial proliferation in the repair phase of DSS colitis.

In growth EGFR activation by PGE2 accounts for about 30% of LGR5+ cell proliferation.

Although the evidence suggests that EGFR activation in response to TLR4 signaling is mediated by PGE2, it is also possible that TLR4 signaling promotes EGFR activation through the production of amphiregulin, epiregulin or other EGFR ligands.

In accordance with our expectation, over-expressed of PIK3CA could restore the expression level of Snail, beta-catenin, Vimentin, and E-cadherin which decreased by CUX1 knockdown (XREF_FIG).

In accordance with our expectation, over-expressed of PIK3CA could restore the expression level of Snail, beta-catenin, Vimentin, and E-cadherin which decreased by CUX1 knockdown (XREF_FIG).

Gain-of-function and loss-of-function studies showed that PIK3CA expression was facilitated by CUX1, leading to activation of epithelial-mesenchymal transition (EMT), accompanied by upregulated expression of Snail, beta-catenin, Vimentin and downregulated expression of E-cadherin in the bladder cancer cell lines.

Gain-of-function and loss-of-function studies showed that PIK3CA expression was facilitated by CUX1, leading to activation of epithelial-mesenchymal transition (EMT), accompanied by upregulated expression of Snail, beta-catenin, Vimentin and downregulated expression of E-cadherin in the bladder cancer cell lines.

In our research, although we found that over-expression of PIK3CA could upregulate the expression of Snail, beta-catenin, and Vimentin, while downregulate the expression of E-cadherin significantly (XREF_FIG).

In EJ cells and T24T cells, over-expression of PIK3CA could upregulate the expression of Snail, beta-catenin and Vimentin, while downregulate the expression of E-cadherin significantly (XREF_FIG) Consistently, knock down of PIK3CA caused downregulation of Snail, beta-catenin, and Vimentin, while E-cadherin was upregulated significantly (XREF_FIG).

Given that PIK3CA has been reported participating in the proceeding of tumor proliferation, migration, and invasion, and in combination with the evidence that the expression of PIK3CA can be directly regulated by CUX1, the effects of CUX1 knockdown and PIK3CA restoration on bladder cancer was further explored.

The Transcription Levels of PIK3CA Was Increased by CUX1 Regulation.

Besides, over-expressed CUX1 could restore the expression of downregulated Snail, beta-catenin, Vimentin and E-cadherin which was induced by PIK3CA knockdown.

Besides, over-expressed CUX1 could restore the expression of downregulated Snail, beta-catenin, Vimentin and E-cadherin which was induced by PIK3CA knockdown.

Besides, over-expressed CUX1 could restore the expression of downregulated Snail, beta-catenin, Vimentin and E-cadherin which was induced by PIK3CA knockdown.

Besides, over-expressed CUX1 could restore the expression of downregulated Snail, beta-catenin, Vimentin and E-cadherin which was induced by PIK3CA knockdown.

The Ripka study has demonstrated that CUX1 expression was induced by activation of Akt and protein kinase B signaling, and decreased by PI3K inhibitors in pancreatic cancer.

Besides, over-expressed CUX1 could restore the expression of downregulated Snail, beta-catenin, Vimentin and E-cadherin which was induced by PIK3CA knockdown.

Besides, over-expressed CUX1 could restore the expression of downregulated Snail, beta-catenin, Vimentin and E-cadherin which was induced by PIK3CA knockdown.

Besides, over-expressed CUX1 could restore the expression of downregulated Snail, beta-catenin, Vimentin and E-cadherin which was induced by PIK3CA knockdown.

Besides, over-expressed CUX1 could restore the expression of downregulated Snail, beta-catenin, Vimentin and E-cadherin which was induced by PIK3CA knockdown.

PIK3CA functions to promote proliferation and metastasis of bladder cancer by activating EMT.

Here, we propose a model of CUX1-PIK3CA-EMT oncoprotein axis, to illustrate how PIK3CA is activated and contributes to bladder cancer progression and metastasis (XREF_FIG).

Overexpression of PIK3CA Restored the Proliferation, Migration, Invasion, and Angiogenesis of Bladder Cancer Cells Through Knockdown of CUX1.

PIK3CA Promoted the Proliferation, Migration, Invasion, and Angiogenesis of Bladder Cancer In Vitro.

PIK3CA promoted bladder cancer progression by activating EMT related makers - - Snail , beta-catenin , vimentin and E-cadherin .

PIK3CA Promote Bladder Cancer Progression by Activating EMT Related Makers - - Snail , E-cadherin , Vimentin , and beta-Catenin Although the functional role of PIK3CA in EMT has been investigated in several cancers ( 39 ) , there are only a few reports in bladder cancer demonstrating involvement of PIK3CA in the process of EMT .

In our study , we found activation of PIK3CA resulted in an increase in the expression of Snail and a decrease in the expression of E-cadherin at the mRNA and protein level , while inhibition of PIK3CA had the opposite effect .

Our results confirmed a vital regulatory role of CUX1 in PIK3CA induced aggressiveness and angiogenesis of bladder cancer cells PIK3CA Promote Bladder Cancer Progression by Activating EMT Related Makers -- Snail, E-cadherin, Vimentin, and beta-Catenin.

PIK3CA functions to promote proliferation and metastasis of bladder cancer by activating EMT.

Overexpression of PIK3CA Restored the Proliferation, Migration, Invasion, and Angiogenesis of Bladder Cancer Cells Through Knockdown of CUX1.

PIK3CA Promoted the Proliferation, Migration, Invasion, and Angiogenesis of Bladder Cancer In Vitro.

PIK3CA functions to promote proliferation and metastasis of bladder cancer by activating EMT.

Our results confirmed a vital regulatory role of CUX1 in PIK3CA induced aggressiveness and angiogenesis of bladder cancer cells PIK3CA Promote Bladder Cancer Progression by Activating EMT Related Makers -- Snail, E-cadherin, Vimentin, and beta-Catenin.

Our results confirmed a vital regulatory role of CUX1 in PIK3CA induced aggressiveness and angiogenesis of bladder cancer cells PIK3CA Promote Bladder Cancer Progression by Activating EMT Related Makers -- Snail, E-cadherin, Vimentin, and beta-Catenin.

Overexpression of PIK3CA Restored the Proliferation, Migration, Invasion, and Angiogenesis of Bladder Cancer Cells Through Knockdown of CUX1.

PIK3CA Promoted the Proliferation, Migration, Invasion, and Angiogenesis of Bladder Cancer In Vitro.

Transwell analysis showed that CUX1 knockdown attenuated invasion ability of EJ and T24T cells (XREF_FIG).

For example , the conclusion that CUX1 stimulates the expression of PIK3CA requires more experiments to further demonstrate .

These findings suggest that PIK3CA was targeted by CUX1 and the activation of CUX1 and PIK3CA axis and consequently regulation of EMT pathway may contribute to promote bladder cancer cell progression.

As expected, over-expressed of CUX1 could restore the expression level change of Snail, beta-catenin, Vimentin, and E-cadherin which was induced by PIK3CA knockdown (XREF_SUPPLEMENTARY).

Together, the above results demonstrated that CUX1 stimulated transcription activity via direct interaction with the binding site of PIK3CA promoter.

Together , the above results demonstrated that CUX1 stimulated transcription activity via direct interaction with the binding site of PIK3CA promoter .

Our results confirmed a vital regulatory role of CUX1 in PIK3CA induced aggressiveness and angiogenesis of bladder cancer cells PIK3CA Promote Bladder Cancer Progression by Activating EMT Related Makers -- Snail, E-cadherin, Vimentin, and beta-Catenin.

In accordance with the ability of mutant SPOP to repress the function of endogenous wild type SPOP in a dominant negative manner, the over-expression of mutant SPOP (SPOP-Y87C, -F102C, -W131G, -F133S) phenocopied the effect of SPOP knockdown on ERG mediated invasion in PC3 cells.

In line with these findings, gene ontology analysis of AR-ERG co-bound gene signature in VCaP cells indicated that the most striking transcriptional changes were linked to cellular differentiation and cell cycle arrest that are directly induced by DHT and repressed by ERG (e.g., HOXA genes, CDKN1A and p21, Fig.

In line with these findings , gene ontology analysis of AR-ERG co-bound gene signature in VCaP cells indicated that the most striking transcriptional changes were linked to cellular differentiation and cell cycle arrest that are directly induced by DHT and repressed by ERG ( e.g ., HOXA genes , CDKN1A / p21 , Fig. 1d , Fig. 3b , and Supplementary Fig. 5d ) .

In line with these findings, gene ontology analysis of AR-ERG co-bound gene signature in VCaP cells indicated that the most striking transcriptional changes were linked to cellular differentiation and cell cycle arrest that are directly induced by DHT and repressed by ERG (e.g., HOXA genes, CDKN1A and p21, Fig.

Similarly, knockdown of SPOP in VCaP cells reduced cell growth in 3D cell culture and impaired ERG mediated gene transcription.

The oncogenic effect was paralleled by an increase in the expression of the oncogenic transcription factors MYC and HOXB13 and a decrease in the cell cycle inhibitor p21 as seen in an organoid line derived from Spop F133V -mutant transgenic mice 13.

ZMYND11 induces AR signaling pathway and represses ERG activity Next , we assessed if ZMYND11 protein upregulation also contributed to the synthetic sick relationship .

ZMYND11 induces AR signaling pathway and represses ERG activity .

ZMYND11 induces AR signaling pathway and represses ERG activity.

In accordance with the ability of mutant SPOP to repress the function of endogenous wild type SPOP in a dominant negative manner, the over-expression of mutant SPOP (SPOP-Y87C, -F102C, -W131G, -F133S) phenocopied the effect of SPOP knockdown on ERG mediated invasion in PC3 cells.

We found two degron sequences that were required for efficient SPOP mediated ubiquitylation and protein degradation.

Moreover, knockdown of ERG reduced SPOP protein levels in VCaP cells, while forced expression of a DeltaERG led to the upregulation of SPOP mRNA and protein levels in PC3 cells.

Thus, we wondered if ERG itself may directly upregulate SPOP transcription to support its own oncogenic activity.

In contrast, we observed the opposite phenotypic and molecular changes in VCaP human prostate cancer cells harboring the recurrent TMPRSS2-ERG fusion (Fig.  xref & Supplementary Fig.  xref ).

Indeed, knockdown of TRIM24 by two short-hairpin RNAs partially reverted the growth inhibition mediated by mutant-SPOP in VCaP cells and reduced AR signaling, while over-expression of AR was sufficient to decrease cellular growth.

In agreement with the established repressive function of ZMYND11 on ERG, we found that over-expression of HA-ZMNYD11-DM2 was sufficient to repress ERG induced invasion and established target genes in PC3 cells.

We then asked if the elevated SPOP levels in the context of forced DeltaERG expression have a functional impact on the oncogenic activity of DeltaERG in the androgen independent PC3 cells, in which ERG promotes tumor cell invasion 31.

ZMYND11 induces AR signaling pathway and represses ERG activity.

We postulated that ZMYND11 upregulation could contribute to the synthetic sick relationship by repressing the ERG oncogene 's transcriptional activity or enhancing AR signaling.

Mutant SPOP induced androgen receptor signaling antagonizes ERG activity.

Conversely, we assessed the consequence of ERG overexpression in LNCaP cells under low DHT levels where mutant SPOP triggers AR signaling and tumor growth XREF_BIBR, XREF_BIBR.

Taken together, the data imply a mutual incompatibility of mutant SPOP induced AR signaling and the function of the ERG oncogene.

RPL5 and RPL11 delay P53 ubiquitination in breast cancer cells by binding MDM2.

In response to nucleolar stress, RPL4, RPL5, RPL11, RPL23, RPS7, and RPS27 translocate from the nucleolus to the nucleoplasm and bind to MDM2, inhibiting its ubiquitin ligase activity toward p53, which leads to p53 accumulation xref – xref .

RPL11 and RPL5 suppress P53 degradation via binding to MDM2 .

The results showed that the half-life of P53 in cells transfected with RPL11 or RPL5 overexpression vector was prolonged compared with control vector-transfected cells , indicating that RPL11 and RPL5 could inhibit P53 degradation ( Fig. 4e ) .

RPL11 and RPL5 suppress P53 degradation via binding to MDM2 .

The results showed that the half-life of P53 in cells transfected with RPL11 or RPL5 overexpression vector was prolonged compared with control vector-transfected cells , indicating that RPL11 and RPL5 could inhibit P53 degradation ( Fig. 4e ) .

RPL11 and RPL5 suppressed breast cancer cell growth and induced cell apoptosis.

These findings suggested that RPL11 and RPL5 could inhibit breast cancer cell proliferation and induce apoptosis.

Overexpression of RPL11 and RPL5 significantly suppressed MCF7 and ZR-75-1 cell proliferation, as evidenced by both cell viability and colony formation assays.

Cell viability and colony formation assays showed that downregulation of MeCP2 expression led to suppressed cell proliferation, which was rescued by silencing RPL11 or RPL5.

RPL11 and RPL5 may inhibit cancer cell proliferation and induce apoptosis 40.

Our results indicated that overexpression of RPL11 or RPL5 suppressed breast cancer cell proliferation, blocked G1-S cell-cycle transition, and induced cancer cell apoptosis.

MeCP2 inhibited RPL11 and RPL5 transcription by binding to their promoters.

To further confirm that MeCP2 might promote breast cancer cell proliferation by suppressing RPL11 and RPL5 expression and promoting the E3 ubiquitin ligase activity of MDM2, MeCP2 overexpression vector was co-transfected with RPL11 or RPL5 overexpression vectors or MDM2 inhibitor (Nutlin3) into MCF7 cells.

These results suggested that MeCP2 repressed RPL11 and RPL5 expression by binding to their promoters.

MeCP2 inhibited RPL11 and RPL5 transcription by binding to their promoters.

Additionally, our analysis of the specified ribosomal proteins (RPs), which were demonstrated in theas MDM2-P53 pathway mediators or as interacting with MDM2 xref , revealed that MeCP2 expression was correlated with RP expression, including RPL36A, RPS23, RPL15, RPS11, RPL23A, RPL4, RPL14, RPL11, RPL5, RPS6, RPL26, and RPL23 (Fig. xref ).

In addition, silencing MeCP2 remarkably suppressed breast cancer cell migration by inhibiting beta-catenin expression and induced cell apoptosis by downregulating the antiapoptotic gene Bcl-2 and upregulating proapoptotic genes, including Bax, P53, and P21.

To verify that RPL5 and RPL11 promote P53 stability, we treated the breast cancer cells with cycloheximide after transfection with the RPL11 and RPL5 overexpression or control vectors.

The results showed that the half-life of P53 in cells transfected with RPL11 or RPL5 overexpression vector was prolonged compared with control vector transfected cells, indicating that RPL11 and RPL5 could inhibit P53 degradation.

In this study, we observed that RPL11 and RPL5 suppressed ubiquitination mediated P53 degradation by directly binding to MDM2.

The results showed that the half-life of P53 in cells transfected with RPL11 or RPL5 overexpression vector was prolonged compared with control vector transfected cells, indicating that RPL11 and RPL5 could inhibit P53 degradation.

To verify that RPL5 and RPL11 promote P53 stability, we treated the breast cancer cells with cycloheximide after transfection with the RPL11 and RPL5 overexpression or control vectors.

In this study, we observed that RPL11 and RPL5 suppressed ubiquitination mediated P53 degradation by directly binding to MDM2.

These findings suggested that RPL11 and RPL5 could inhibit breast cancer cell proliferation and induce apoptosis.

RPL11 and RPL5 suppressed breast cancer cell growth and induced cell apoptosis.

These findings suggested that RPL11 and RPL5 could inhibit breast cancer cell proliferation and induce apoptosis .

RPL11 and RPL5 inhibits breast cancer cell proliferation and induced apoptosis .

RPL11 and RPL5 may inhibit cancer cell proliferation and induce apoptosis 40.

Our results indicated that overexpression of RPL11 or RPL5 suppressed breast cancer cell proliferation, blocked G1-S cell-cycle transition, and induced cancer cell apoptosis.

MDM2 is an E3 ubiquitin ligase that targets P53 protein for proteasomal degradation XREF_BIBR, XREF_BIBR.

TCGA data revealed significantly lower RPL11 and RPL5 expression in breast cancer tissues; additionally, overexpression of RPL11 and RPL5 significantly suppressed breast cancer cell proliferation and G1-S cell cycle transition and induced apoptosis in vitro.

Investigation of the molecular mechanism showed that MeCP2 repressed RPL11 and RPL5 transcription by binding to their promoter regions.

Investigation of the molecular mechanism showed that MeCP2 repressed RPL11 and RPL5 transcription by binding to their promoter regions.

TCGA data revealed significantly lower RPL11 and RPL5 expression in breast cancer tissues; additionally, overexpression of RPL11 and RPL5 significantly suppressed breast cancer cell proliferation and G1-S cell cycle transition and induced apoptosis in vitro.

Moreover, Rb1 activated the PI3K and AKT pathway, down-regulated Cleaved caspase-3 and Bax, and up-regulated Bcl-2 expression.

Moreover, Rb1 activated the PI3K and AKT pathway, down-regulated Cleaved caspase-3 and Bax, and up-regulated Bcl-2 expression.

Moreover , Rb1 activated the PI3K / AKT pathway , down-regulated Cleaved caspase-3 and Bax , and up-regulated Bcl-2 expression .

Moreover , Rb1 activated the PI3K / AKT pathway , down-regulated Cleaved caspase-3 and Bax , and up-regulated Bcl-2 expression .

Moreover , Rb1 activated the PI3K / AKT pathway , down-regulated Cleaved caspase-3 and Bax , and up-regulated Bcl-2 expression .

Moreover , Rb1 activated the PI3K / AKT pathway , down-regulated Cleaved caspase-3 and Bax , and up-regulated Bcl-2 expression .

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.

Parthenolide has previously been shown to inhibit NLRC4 dependent caspase-1 activation 15, although it did not do so in these experiments (XREF_FIG).

MCC950 blocks NLRP3 induced ASC oligomerization.

Water fluxes through pressurized root systems treated with nitrogen and low oxygen (< 2% O (2)), elevated CO (2) (20% CO (2)), and low O (2) with elevated CO (2) concentrations were reduced to 40, 51 and 58%, respectively, of J (v) of plants aerated with ambient air.

The probability for the occurrence of sulphur plumes is enhanced in years with a lower annual mean of upwelling intensity, decreased oxygen supply associated with decreased lateral ventilation of bottom waters, more southern position of the Angola Benguela Frontal Zone, increased mass fraction of South Atlantic Central Water and stronger downwelling coastal trapped waves.

Heme oxygenase ( HO ) is a stress-inducing enzyme that catalyzes heme to produce free iron , carbon monoxide ( CO ) , and biliverdin [ 7 ] .

Heme oxygenase ( HO ) is a stress-inducing enzyme that catalyzes heme to produce free iron , carbon monoxide ( CO ) , and biliverdin [ 7 ] .

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.

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.

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.

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.

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

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

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 .

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.

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.

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

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 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.

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.

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.

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

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

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

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.

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

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.

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

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

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.

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

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.

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.

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.

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

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

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

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

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).

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).

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

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).

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).

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).

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).

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).

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).

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.

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.

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.

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).

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

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

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.

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.

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.

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.

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).

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).

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.

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.

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.

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.

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

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

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

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

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

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

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.

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

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.

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

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

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

Conversely, CD8 + CD49a - Trm cells from psoriasis lesions predominantly generated IL-17 responses that promote local inflammation in this skin disease.

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.

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.