However, blocking CD32 but not CD64 to inhibit CRP induced FLS proliferation, invasiveness, and proinflammatory cytokine CXCL8 production revealed a major role for CD32 signaling in synovial inflammation, although CRP via CD64, not CD32, to induce MMP9 expression was noticed.

In contrast, blockade of CD16 produced no inhibitory effect on CRP-induced expression of CXCL8, CCL2, MMP9 and IL-6 by RA-FLSs ( xref ), suggesting that CRP may not signal through the CD16 to induce joint inflammation in vitro .

However, CRP- induced expression of CXCL8 was CD32-dependent as it was blunted by the antibody against CD32, whereas CRP-induced MMP9 was blocked by the antibody to CD64, demonstrating that differential signaling mechanisms for CRP in regulating CXCL8 and MMP9 expression in RA-FLSs.

In contrast, blockade of CD16 produced no inhibitory effect on CRP-induced expression of CXCL8, CCL2, MMP9 and IL-6 by RA-FLSs ( xref ), suggesting that CRP may not signal through the CD16 to induce joint inflammation in vitro .

As shown in xref , CRP-induced expression of CCL2 and IL-6 was blocked by either neutralizing antibody to CD32 or CD64 or both, suggesting that CRP signals through both CD32/CD64 to induce expression of CCL2 and IL-6.

As shown in XREF_FIG, CRP induced expression of CCL2 and IL-6 was blocked by either neutralizing antibody to CD32 or CD64 or both, suggesting that CRP signals through both CD32 and CD64 to induce expression of CCL2 and IL-6.

In contrast, blockade of CD16 produced no inhibitory effect on CRP-induced expression of CXCL8, CCL2, MMP9 and IL-6 by RA-FLSs ( xref ), suggesting that CRP may not signal through the CD16 to induce joint inflammation in vitro .

As shown in xref , CRP-induced expression of CCL2 and IL-6 was blocked by either neutralizing antibody to CD32 or CD64 or both, suggesting that CRP signals through both CD32/CD64 to induce expression of CCL2 and IL-6.

As shown in XREF_FIG, CRP induced expression of CCL2 and IL-6 was blocked by either neutralizing antibody to CD32 or CD64 or both, suggesting that CRP signals through both CD32 and CD64 to induce expression of CCL2 and IL-6.

It has been reported that CRP-induced cytokine expression is also regulated by TWIST transcriptionally in myeloma cells ( xref ).

We thus blocked CD32 or CD64 or both with neutralizing antibodies to differentially determine the signaling mechanisms of CRP-induced cytokine expression.

Thus, it is highly possible that high concentration of CRP in synovial fluid in patients with RA may directly bind primarily CD32 to activate p38 MAP kinase and NF-kappaB signaling in RA-FLSs to differentially regulate synovial inflammation.

In vitro studies confirmed this notion and found that CRP was able to upregulate both CD32 and CD64 and induced FLS proliferation, invasion, and pro inflammatory expression by increasing production of CCL2, CXCL8, IL-6, MMP2, MMP9 while suppressing an anti-inflammatory cytokine IL-10 expression.

RA-FLS was a major cell type responsible for CRP production in RA patients, accounting for more than 65% of CRP producing cells as identified by co-expressing CRP and vimentin in the inflamed synovial tissues in patients with RA.

As shown in XREF_FIG, multiplex cytokine assay kits assays showed that addition of CRP dose-dependently upregulated CCL2, CXCL8, IL-6, MMP2, MMP9 in RA-FLS but not in HFLS, although expression of IL-1beta and TNFalpha was not significantly changed (XREF_FIG).

In vitro studies confirmed this notion and found that CRP was able to upregulate both CD32 and CD64 and induced FLS proliferation, invasion, and pro inflammatory expression by increasing production of CCL2, CXCL8, IL-6, MMP2, MMP9 while suppressing an anti-inflammatory cytokine IL-10 expression.

In vitro studies confirmed this notion and found that CRP was able to upregulate both CD32 and CD64 and induced FLS proliferation, invasion, and pro inflammatory expression by increasing production of CCL2, CXCL8, IL-6, MMP2, MMP9 while suppressing an anti-inflammatory cytokine IL-10 expression.

As shown in XREF_FIG, multiplex cytokine assay kits assays showed that addition of CRP dose-dependently upregulated CCL2, CXCL8, IL-6, MMP2, MMP9 in RA-FLS but not in HFLS, although expression of IL-1beta and TNFalpha was not significantly changed (XREF_FIG).

In vitro studies confirmed this notion and found that CRP was able to upregulate both CD32 and CD64 and induced FLS proliferation, invasion, and pro inflammatory expression by increasing production of CCL2, CXCL8, IL-6, MMP2, MMP9 while suppressing an anti-inflammatory cytokine IL-10 expression.

As shown in XREF_FIG, multiplex cytokine assay kits assays showed that addition of CRP dose-dependently upregulated CCL2, CXCL8, IL-6, MMP2, MMP9 in RA-FLS but not in HFLS, although expression of IL-1beta and TNFalpha was not significantly changed (XREF_FIG).

In vitro studies confirmed this notion and found that CRP was able to upregulate both CD32 and CD64 and induced FLS proliferation, invasion, and pro inflammatory expression by increasing production of CCL2, CXCL8, IL-6, MMP2, MMP9 while suppressing an anti-inflammatory cytokine IL-10 expression.

As shown in XREF_FIG, multiplex cytokine assay kits assays showed that addition of CRP dose-dependently upregulated CCL2, CXCL8, IL-6, MMP2, MMP9 in RA-FLS but not in HFLS, although expression of IL-1beta and TNFalpha was not significantly changed (XREF_FIG).

In vitro studies confirmed this notion and found that CRP was able to upregulate both CD32 and CD64 and induced FLS proliferation, invasion, and pro inflammatory expression by increasing production of CCL2, CXCL8, IL-6, MMP2, MMP9 while suppressing an anti-inflammatory cytokine IL-10 expression.

As shown in XREF_FIG, multiplex cytokine assay kits assays showed that addition of CRP dose-dependently upregulated CCL2, CXCL8, IL-6, MMP2, MMP9 in RA-FLS but not in HFLS, although expression of IL-1beta and TNFalpha was not significantly changed (XREF_FIG).

In vitro studies confirmed this notion and found that CRP was able to upregulate both CD32 and CD64 and induced FLS proliferation, invasion, and pro inflammatory expression by increasing production of CCL2, CXCL8, IL-6, MMP2, MMP9 while suppressing an anti-inflammatory cytokine IL-10 expression.

This was further confirmed by the ability of pre-treating RA-FLS with a NF-kappaB inhibitor, PDTC (100 mumol/L) to inhibit CRP induced proliferation (XREF_FIG) and upregulation of CXCL8, CCL2.

CRP can induce synovial inflammation via mechanisms associated with activation of CD32/64-p 38 and NF-kappaB signaling.

Here we tested the hypothesis that CRP may be produced locally by FLSs and functions to induce the synovial inflammation in patients with RA.

CRP may promote synovial inflammation via mechanism associated with activation of CD32/64- p38 and NF-kappaB signaling.

In the present study, we found that CRP signaled primarily through CD32, to a less extent of CD64, to differentially regulate joint inflammation.

CRP Promotes RA-FLS Pro inflammatory Response Differentially via the CD32/64-p 38 and NF-kappaB-Dependent Mechanisms in vitro.

This was supported by the findings that CRP induced activation of p38 MAP kinase and NF-kappaB signaling was blunted by neutralizing antibodies against CD32 but not CD64.

To examine whether CRP induces NF-kappaB nuclear translation, immunofluorescence and subcellular fractionation were performed.

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 C–E).

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

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).

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 C–E).

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

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).

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.

Our study showed that hypoxia increased the production of S100A8 in microglia .

FACS analysis showed that the increase of S100A8 levels in microglia by hypoxia promoted neuronal apoptosis , which was confirmed by immunofluorescence .

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.

In our study , the increase of IL-1beta expression by S100A8 indicated that S100A8 was involved in the priming signal for NLRP3 inflammasome assembly in microglia ( Figure 2B ) .

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.

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

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.

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.

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

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.

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.

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.

S100A8 Knockdown on Microglia Attenuated Neuronal Apoptosis by Hypoxia.

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).

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.

FACS analysis showed that the increase of S100A8 levels in microglia by hypoxia promoted neuronal apoptosis, which was confirmed by immunofluorescence.

Knockdown of S100A8 levels by using shRNA revealed that microglial S100A8 expression activated COX-2 expression, leading to neuronal apoptosis under hypoxia.

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, 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.

The aim of this study was to determine whether S100A8 induced neuronal apoptosis during cerebral hypoxia and elucidate its mechanism of action.

The BMP9 induced phosphorylation of CREB or Smad1/5/9 is also reduced by PTEN, but enhanced by PTEN knockdown.

The BMP9 induced phosphorylation of CREB or Smad1/5/9 is also reduced by PTEN, but enhanced by PTEN knockdown.

PTEN Reduces BMP9 Induced Osteogenic Differentiation Through Inhibiting Wnt10b in Mesenchymal Stem Cells.

On the contrary, knockdown of PTEN potentiated the effects of BMP9 on Runx2 (XREF_FIG), OPN (XREF_FIG), and mineralization (XREF_FIG).

H&E staining results also show that knockdown of PTEN potentiated the effect of BMP9 on increasing trabecular bone, and knockdown of Wnt10b exhibited a reversal effect and almost diminished the effect of PTEN knockdown on enhancing BMP9 induced bone formation (XREF_FIG).

Thus, we speculate that PTEN may reduce the potential of BMP9 on activating Wnt and beta-catenin through inhibiting the expression of Wnt10b in multiple progenitor cells.

As reported, PTEN can reduce the activation of the Wnt and beta-catenin signaling pathway through regulating the phosphorylation of GSK3beta.

PTEN Reduces BMP9-Induced Osteogenic Differentiation Through Inhibiting Wnt10b in Mesenchymal Stem Cells.

The BMP9 increased Wnt10b is decreased by PTEN but enhanced by knockdown of PTEN.

Hence, Wnt10b may be negatively regulated by PTEN through PI3K/Akt/mTOR signaling.

Taken together, our findings suggest that the inhibitory effect of PTEN on BMP9-induced osteogenic differentiation may be mediated through reducing the expression of Wnt10b, and PTEN may inhibit Wnt10b by partly disturbing the interaction between CREB and BMP/Smad signaling.

In this study , we demonstrate that the inhibitory effect of PTEN on BMP9-induced osteogenic differentiation can be partially reversed by Wnt10b , and the expression of Wnt10b can be inhibited by PTEN through disturbing the interaction between CREB and BMP / Smad signaling at least .

We find that PTEN is inhibited by BMP9 in MSCs, but Wnt10b is increased simultaneously.

We find that PTEN is inhibited by BMP9 in MSCs, but Wnt10b is increased simultaneously.

Because BMP9 inhibited PTEN and increased Wnt10b simultaneously, Wnt10b may be implicated in the suppressive effects of PTEN on the osteogenic potential of BMP9.

Our previous study shows that PTEN is downregulated by BMP9 during the osteogenic process in MSCs.

In our previous studies, we find that PTEN is inhibited by BMP9, but Wnt10b is increased concurrently.

In this study, we confirmed that BMP9 inhibits PTEN and increases Wnt10b simultaneously in MSCs.

Our previous study shows that PTEN is downregulated by BMP9 during the osteogenic process in MSCs ( Huang et al ., 2014 ) .

In this study , we confirmed that BMP9 inhibits PTEN and increases Wnt10b simultaneously in MSCs .

Because BMP9 inhibited PTEN and increased Wnt10b simultaneously, Wnt10b may be implicated in the suppressive effects of PTEN on the osteogenic potential of BMP9.

In our previous studies, we find that PTEN is inhibited by BMP9, but Wnt10b is increased concurrently (Huang et al., xref ; Liao et al., xref ).

In this study, we confirmed that BMP9 inhibits PTEN and increases Wnt10b simultaneously in MSCs.

However, knockdown of Wnt10b almost abolished the effect of PTEN knockdown on promoting BMP9 induced bone formation (XREF_FIG).

H&E staining results also show that knockdown of PTEN potentiated the effect of BMP9 on increasing trabecular bone, and knockdown of Wnt10b exhibited a reversal effect and almost diminished the effect of PTEN knockdown on enhancing BMP9 induced bone formation (XREF_FIG).

In this study, we determined whether PTEN could reduce the expression of Wnt10b during the osteogenic process initialized by BMP9 in mesenchymal stem cells (MSCs) and the possible molecular mechanism.

These data suggest that PTEN may negatively regulate the expression of Wnt10b in MSCs at least.

In this study, we demonstrate that the inhibitory effect of PTEN on BMP9 induced osteogenic differentiation can be partially reversed by Wnt10b, and the expression of Wnt10b can be inhibited by PTEN through disturbing the interaction between CREB and BMP and Smad signaling at least.

Meanwhile, PTEN may modulate the activity of Wnt and beta-catenin signaling via a Wnt10b dependent manner although the concrete process needs to be further unveiled.

However, it remains unknown whether PTEN could modulate the activation of Wnt and beta-catenin signaling through regulating the expression of Wnt10b.

Meanwhile, PTEN may modulate the activity of Wnt and beta-catenin signaling via a Wnt10b dependent manner although the concrete process needs to be further unveiled.

However, it remains unknown whether PTEN could modulate the activation of Wnt and beta-catenin signaling through regulating the expression of Wnt10b.

Although Wnt10b may reverse the suppressive effect of PTEN on the osteogenic potential of BMP9, the concrete relationship between them is unclear.

In this study, we determined whether Wnt10b could reverse the inhibitory effect of PTEN on the BMP9 induced osteogenic process in MSCs and dissect the possible relationship between PTEN and Wnt10b during the osteoblastic commitment initialized by BMP9 in progenitor cells.

Chronic S15 phosphorylation of mutant p53 has been found in tumors where DNA damage signaling is constitutively activated ( xref , xref ).

Further, NF-kB inhibition by overexpression of IkB also results in S15 phosphorylation of mutant p53 via GADD45α mediated JNK1 activation ( xref ).

On the contrary , Nanog suppresses p53 activity while Gli activated by Nanog inhibits p53 by activating Mdm2 to promote pluripotency .

p53 loss upregulates CD133 which subsequently promotes CSC marker expression and confers stemness .

For example , p53 repress CD133 by directly binding to its promoter and recruiting HDAC1 ( Figure 2 ) .

With the advent of reprogramming era , it was further highlighted that p53 loss promote dedifferentiation and reprogramming under favorable conditions .

Loss or gain-of-function mutations in TP53 induce dedifferentiation and proliferation of SCs with damaged DNA leading to the generation of CSCs.

TP53 maintains homeostasis between self-renewal and differentiation depending on the cellular and developmental state and prevents the dedifferentiation and reprogramming of somatic cells to stem cells.

With the advent of reprogramming era, it was further highlighted that p53 loss promote dedifferentiation and reprogramming under favorable conditions.

Furthermore, p53 loss was found to trigger dedifferentiation of mature hepatocytes to pluripotent cells by the activation of SC marker Nestin, which remains suppressed in wild-type p53 bearing cells (XREF_FIG).

While wild type p53 suppresses inflammatory response by inhibiting the production of cytokines and antagonizing NF-kB activity, mutant p53 on the other hand enhances NF-kB activity in response to TNF-alpha and promotes inflammation (XREF_FIG).

Mutant p53 can itself disrupt the balance between stem cell proliferation and differentiation as well as sequester p63 or p73 thereby hindering apoptosis, augmenting proliferation, and driving chemoresistance and metastasis typical of cancer stem cells.

Mutant p53 mediated repression of p63 function can also modulate the expression of certain miRNAs involved in invasion and metastasis such as let-7i, miR-155, miR-205, miR-130b, and miR-27a (XREF_FIG).

Hence, loss of NUMB in breast cancer cells leads to decreased p53 levels and increased activity of NOTCH receptor which confers increased chemoresistance.

It may form a complex with mutant p53 and MDM2 to block their ubiquitination mediated degradation or may form a complex with mutant p53 to prevent aggregation of mutant p53 by inhibiting MDM2 and CHIP in multiple cancer cell lines ( xref , xref ).

A recent study by Capaci et al. showed that mutant p53 can interact with HIF1α to induce miR-30d expression which promotes tubulo-vesiculation of Golgi apparatus leading to enhanced vesicular trafficking and secretion ( xref ) ( xref ).

Binding of mutant p53 to ETS2 can promote expression of Pla2g16 or nucleotide synthesis genes required for invasion depending upon the cancer type ( xref ) ( xref , xref ).

Furthermore, the binding of mutant p53 to EGR1 promotes MYO10 expression which drives breast cancer cell invasion ( xref ) ( xref ).

Further, mutant p53 can interact with PELP1 to promote resistance to platinum-based drugs in triple negative breast cancer ( xref ).

A further study reported that mutant p53 enhance the association of mutant p53 and PARP on the replicating DNA ( xref ) ( xref ).

GOF mutant p53 can bind to TopBP1 and attenuate ATR checkpoint response during replication stress ( xref ) ( xref ).

The compound, RETRA disrupts mutant p53-p73 complex restoring p73-dependent transcription and apoptosis ( xref ) ( xref ).

Short Interfering Mutant p53 Peptides (SIMP) can interact with different mutant p53 proteins and release p73, while peptides aptamers (PA) can inhibit mutant p53 transcription ( xref ) ( xref ).

Mutant p53 and p63 complex can increase RAB coupling protein (RCP)-mediated recycling of cell surface growth promoting receptors.

Zhou et al. showed that mutant p53 binds to novel interacting partner AMPKα in glucose starvation conditions and inhibits its activation by other kinases leading to increased aerobic glycolysis, lipid production, and cell growth ( xref ) ( xref ).

This eliminates mitochondria associated p53 which would otherwise be activated by PINK1 to mediate suppression of Nanog (XREF_FIG).

This eliminates mitochondria-associated p53 which would otherwise be activated by PINK1 to mediate suppression of Nanog ( xref ) ( xref ).

Further, the human p53 isoform Delta133p53beta lacking the transactivation domain was observed to promote CSC features in breast cancer cell lines by expression of Sox2, Oct3/4, and Nanog in a Delta133p53beta dependent manner.

Acetylation of p53 at K373 by CBP and p300 leads to dissociation of HDM2 and TRIM24 and subsequent activation of p53 which in turn transcriptionally activates p21, miR-34a, and miR-145 (XREF_FIG).

Further , induction of miR-34a by p53 functionally targets the CSC marker CD44 , thereby inhibiting prostate cancer regeneration and metastasis ( Figure 2 ) ( 74 ) .

Additionally , p53 upregulates miR-34a that represses Notch ( Figure 2 ) and anti-apoptotic Bcl2 thereby promoting differentiation and apoptosis ( 82 ) .

Acetylation of p53 at K373 by CBP and p300 leads to dissociation of HDM2 and TRIM24 and subsequent activation of p53 which in turn transcriptionally activates p21, miR-34a, and miR-145 (XREF_FIG).

Acetylation of p53 at K373 by CBP/p300 leads to dissociation of HDM2 and TRIM24 and subsequent activation of p53 which in turn transcriptionally activates p21, miR-34a, and miR-145 ( xref ).

A recent study by Alam et al. reveals GOF mutant p53 upregulates EFNB2 and activates ephrin B2 reverse signaling to impart enhanced chemoresistance to colorectal cancer cells ( xref ) ( xref ).

Inactivation of p53 disrupts this balance and promotes pluripotency and somatic cell reprogramming .

Inactivation of p53 disrupts this balance and promotes pluripotency and somatic cell reprogramming .

Mutant p53 implicate various context and tissue dependent mechanisms to promote cancer cell invasion and metastasis.

Various transcription factors such as NF-Y, SREBPs, ETS, and EGFR1 play crucial role in mutant p53 driven invasion and metastasis.

Mutant p53 implicate various context and tissue dependent mechanisms to promote cancer cell invasion and metastasis.

Various transcription factors such as NF-Y, SREBPs, ETS, and EGFR1 play crucial role in mutant p53 driven invasion and metastasis.

This suggests that acetylation at K320 and K373 can alter the structure of mutant p53 and restore wild type p53 functions.

Mutant p53 can also induce YAP and TAZ nuclear localization by interacting with SREBP and activating the mevalonate pathway.

Mutant p53 can also promote proliferation by inducing the REG-gamma proteosome pathway in association with p300 (XREF_FIG).

GOF mutant p53 can modify the tumor microenvironment and has been found to support chronic inflammation.

While wild type p53 suppresses inflammatory response by inhibiting the production of cytokines and antagonizing NF-kB activity, mutant p53 on the other hand enhances NF-kB activity in response to TNF-alpha and promotes inflammation (XREF_FIG).

In absence of AMPK, mitochondrial stress augments aerobic glycolysis, also called " Warburg effect " in tumor cells, which is promoted by mutant p53.

Several evidence demonstrate that mutant p53 promotes glycolysis and reprograms the cellular metabolism of cancer cells.

Gain-of function mutant p53 further promotes EMT and stemness phenotypes by activating genes regulating them.

Although these studies highlight that mutant p53 mediated EMT phenotype confer stemness in cancer cells, however, there is still a lot to explore in context of molecular mechanisms of mutant p53 driven stemness through activation of EMT genes.

However, whether mutant p53 induced EMT trigger stemness properties in cancer cells, is still quite unexplored.

While wild type p53 suppresses inflammatory response by inhibiting the production of cytokines and antagonizing NF-kB activity, mutant p53 on the other hand enhances NF-kB activity in response to TNF-alpha and promotes inflammation (XREF_FIG).

The sustained activation of NF-kB signaling by mutant p53 not only elevate inflammatory response but also protects the cancer cells from cytotoxic effects of tumor microenvironment by activating pro survival pathways.

Interaction of mutant p53 to SREBPs activates mevalonate pathway that promotes invasion in breast cancer cells (XREF_FIG).

Mutant p53 can also induce YAP and TAZ nuclear localization by interacting with SREBP and activating the mevalonate pathway.

Similarly, p53 activation by nutlin leads to transcriptional activation of p21 that cause cell cycle arrest and induces differentiation in human ESCs.

Acetylation of p53 at K373 by CBP/p300 leads to dissociation of HDM2 and TRIM24 and subsequent activation of p53 which in turn transcriptionally activates p21, miR-34a, and miR-145 ( xref ).

These findings demonstrated that PLG reduces the calcification in VSMCs by regulating P53, indicating that P53 plays an important role in the calcification of VSMCs.

These experiments demonstrate that PLG attenuates arterial calcification by upregulating the P53 and PTEN signaling pathway and that this inhibitory effect on calcification can be blocked by P53 knockdown.

In various types of cancer cells, PLG significantly enhances the expression of wild-type P53 and PUMA, and it inhibits the expression of many pro survival proteins, such as BCL2, survivin and XIAP.

PLG has antitumour activity and significantly increases the expression of wild-type P53.

Similarly, the expression of P53 in the Vit D group was significantly reduced, and PLG treatment effectively increased the expression of P53 in the aorta (XREF_FIG).

These results showed that PLG upregulated the expression of P53 during vascular calcification by reducing STAT3 phosphorylation.

Western blotting and qRT-PCR analyses showed that high calcium and phosphate treatment reduced the P53 expression level in VSMCs and that PLG significantly increased the P53 expression level compared to the control group.

PTEN is induced by P53 in the early and late stages of cell response, and PTEN and P53 interact ( xref , xref ).

Moreover, P53 regulates PTEN in the early and late stages of cell response, and there PTEN and P53 interact ( xref , xref ).

Activated STAT3 can bind to the P53 promoter, then inhibit P53 expression in a STAT3-dependent manner ( xref , xref ).

Runx2 is a master transcription factor involved in bone formation and vascular calcification, and P53 can interact with Runx2 during osteogenic differentiation ( xref ).

Runx2 is a master transcription factor involved in bone formation and vascular calcification, and P53 can interact with Runx2 during osteogenic differentiation.

In the case of high calcium / phosphate treatment , the expression of P53 was decreased , while PLG increased the expression of PTEN .

PLG promotes PTEN expression by increasing P53 signaling .

The effective PLG concentration used (10 to 15 muM) to induce apoptosis in tumor cells increases P53 by three- to four-fold compared to the level in control cells.

We hypothesize that P53 activation by PLG in VSMCs is mediated by decreased activation of STAT3.

Western blotting and qRT-PCR analyses showed that high calcium / phosphate treatment reduced the P53 expression level in VSMCs and that PLG significantly increased the P53 expression level compared to the control group .

These results showed that PLG upregulated the expression of P53 during vascular calcification by reducing STAT3 phosphorylation .

PLG upregulates P53 signaling in vivo and in vitro .

PTEN is induced by P53 in the early and late stages of cell response, and PTEN and P53 interact.

Deletion of MDM2, an inhibitor of P53, in osteoblast lineage cells leads to increased P53 production, which in turn inhibits bone organogenesis and homeostasis.

In conclusion, PLG attenuates high calcium and phosphate induced vascular calcification by upregulating P53 and PTEN signaling in VSMCs.

The main findings of the present study indicated that (1) PLG is a promising natural herbal extract for the management of vascular calcification and that (2) PLG attenuates high calcium- and phosphate induced vascular calcification by preserving P53 and PTEN signaling in VSMCs.

In conclusion, PLG attenuates high calcium and phosphate induced vascular calcification by upregulating P53 and PTEN signaling in VSMCs.

The main findings of the present study indicated that (1) PLG is a promising natural herbal extract for the management of vascular calcification and that (2) PLG attenuates high calcium- and phosphate induced vascular calcification by preserving P53 and PTEN signaling in VSMCs.

To examine whether FoxO3a is required for PTEN mediated negative regulation of autophagy, we analyzed the mRNA levels of ATG5, ATG7, and ATG12 in the ipsilateral hippocampus post-ICH.

In the present study, PTEN inhibition not only reduced the levels of autophagy related proteins but also activated the PI3K and AKT pathway in the ipsilateral hippocampus after ICH.

Functionally, our findings confirmed that inhibition of PTEN by PTEN siRNA or specific inhibitor not only ameliorated secondary hippocampal injury but also promoted hippocampal-dependent cognition and memory recovery, suggesting important neuroprotective effects against hemorrhagic insults.

Specifically, PTEN antagonized the PI3K and AKT signaling and downstream effector FoxO3a phosphorylation and subsequently enhanced nuclear translocation of FoxO3a to drive proautophagy gene program, but these changes were diminished upon PTEN inhibition.

Mechanistically, blockage of PTEN could enhance FoxO3a phosphorylation modification to restrict its nuclear translocation and ATG transcription via activating the PI3K and AKT pathway, leading to the suppression of the autophagic program.

Inhibition of PTEN Ameliorates Secondary Hippocampal Injury and Cognitive Deficits after Intracerebral Hemorrhage : Involvement of AKT / FoxO3a / ATG-Mediated Autophagy .

Inhibition of PTEN Ameliorates Secondary Hippocampal Injury and Cognitive Deficits after Intracerebral Hemorrhage : Involvement of AKT / FoxO3a / ATG-Mediated Autophagy Spontaneous intracerebral hemorrhage ( ICH ) commonly causes secondary hippocampal damage and delayed cognitive impairments , but the mechanisms remain elusive .

According to these data, we speculate that posthemorrhagic PTEN elevation triggers the nuclear accumulation of FoxO3a and subsequent transcriptional activation of ATGs, resulting in sequential activation of autophagy.

Herein, we identified that ICH induced a significant increase in ATG transcriptional levels including ATG5, ATG7, and ATG12, which was strongly associated with PTEN mediated FoxO3a nuclear translocation.

PTEN Inhibition Reverses Secondary Hippocampal Injury Post-ICH.

Also, inactivation of the PI3K/AKT/mTOR pathway has been implicated in PTEN induced autophagy initiation [XREF_BIBR, XREF_BIBR].

However , blockage of PTEN prominently abolished these ATG transcriptions and subsequent autophagy induction .

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.

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