Silencing DCAF1 in Meso-33, merlin deficient mesothelioma cells reduced their proliferation by arresting the cell cycle in G1 phase.

Furthermore, Amot silencing attenuated Rac1 and Ras and MAPK signaling pathway.

Silencing of Amot in Nf2 -/- Schwann cells (SC4) selectively reduced cell proliferation because it did not change the proliferation rate of SC4 with merlin re-expression.

Furthermore, Amot silencing attenuated Rac1 and Ras and MAPK signaling pathway.

Furthermore, Amot silencing attenuated Rac1 and Ras and MAPK signaling pathway.

In various cell types, the binding of hyaluronan to CD44 stimulates Tiam1 dependent Rac1 signaling and cytoskeleton mediated tumor cell migration.

In various cell types, the binding of hyaluronan to CD44 stimulates Tiam1 dependent Rac1 signaling and cytoskeleton mediated tumor cell migration.

First, protein kinase C potentiated phosphatase inhibitor (CPI-17), which is frequently overexpressed in mesothelioma tumors, inhibits merlin phosphatase MYPT1-PP1delta, providing one potential pathway by which merlin 's tumor suppressor function might be inactivated through maintenance of phosphorylation at Ser518.

First, protein kinase C potentiated phosphatase inhibitor (CPI-17), which is frequently overexpressed in mesothelioma tumors, inhibits merlin phosphatase MYPT1-PP1delta, providing one potential pathway by which merlin 's tumor suppressor function might be inactivated through maintenance of phosphorylation at Ser518.

In various cell types, the binding of hyaluronan to CD44 stimulates Tiam1 dependent Rac1 signaling and cytoskeleton mediated tumor cell migration.

We recently showed that PI3K inhibition in merlin deficient mouse Schwann cells selectively decreased their proliferation.

In primary rat Schwann cells, CD44 was shown to constitutively associate with the heterodimer receptor tyrosine kinase ErbB2 and ErbB3 and CD44 enhanced neuregulin induced ErbB2 activating phosphorylation.

Moreover, neuregulin survival signaling through the ErbB2 and ErbB3 receptor activates PI3K in rat Schwann cells through the activation of Akt and inhibition of Bad, a pro apoptotic Blc-2 family protein.

In the canonical hippo pathway, mammalian Ste20 like kinases (Mst1/2; hippo homolog) phosphorylate large tumor suppressor kinases (LATS 1/2), which in turn phosphorylate and inactivate YAP and TAZ, blocking their role as TEAD and MEAD transcription factor co-activators.

SOS is a GEF that activates Ras by catalyzing the nucleotide exchange.

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

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

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

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

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

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

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

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

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

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

Loss of merlin in mesotheliomas has been linked not only to increased proliferation, but also increased invasiveness, spreading and migration.

Adenoviral transduction of NF2 in Meso-17 and Meso-25 cell lines decreased invasion through Matrigel membranes compared to cells transduced with empty vector.

Second, similar to NF2 schwannomas, mesothelioma cells with NF2 inactivation, exhibit activated PAK1 and AKT, and re-expression of merlin in merlin-null human mesothelioma cells (Meso-17) decreases PAK1 activity.

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

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

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

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

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

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

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

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

Loss of merlin activated mTORC1 signaling independently of Akt or ERK in these tumor cells; however, the molecular mechanism connecting merlin loss to mTORC1 activation remains to be elucidated.

Loss of merlin activated mTORC1 signaling independently of Akt or ERK in these tumor cells; however, the molecular mechanism connecting merlin loss to mTORC1 activation remains to be elucidated.

Furthermore, merlin overexpression in Tr6BC1 mouse schwannoma cells inhibited the binding of fluorescein labeled hyaluronan to CD44 and inhibited subcutaneous tumor growth in immunocompromised mice, and overexpression of a merlin mutant lacking the CD44 binding domain was unable to inhibit schwannoma growth.

Further studies showed that wild-type merlin is transported throughout the cell by microtubule motors and merlin mutants or depletion of the microtubule motor kinesin-1 suppressed merlin transport and was associated with accumulation of yorkie, a Drosophila homolog of the hippo pathway transcriptional co-activator Yes associated protein (YAP), in the nucleus.

In a similar fashion, NF2 mutations increased the resistance to dihydrofolate reductase inhibitors methotrexalate and pyremethamine as well as the JNK inhibitor JNK-9L.

The disrupted cell-contact inhibition signaling and merlin phosphorylation correlated with increased expression of NOTCH1 and its downstream target gene, HES1, which represses the transcription factor E2F in cell-contact growth arrest.

Binding of merlin unphosphorylated at Ser518 with the cytoplasmic tail of CD44 mediates contact inhibition at high cell density.

Loss of merlin activated mTORC1 signaling independently of Akt or ERK in these tumor cells; however, the molecular mechanism connecting merlin loss to mTORC1 activation remains to be elucidated.

First, protein kinase C potentiated phosphatase inhibitor (CPI-17), which is frequently overexpressed in mesothelioma tumors, inhibits merlin phosphatase MYPT1-PP1delta, providing one potential pathway by which merlin 's tumor suppressor function might be inactivated through maintenance of phosphorylation at Ser518.

First, protein kinase C potentiated phosphatase inhibitor (CPI-17), which is frequently overexpressed in mesothelioma tumors, inhibits merlin phosphatase MYPT1-PP1delta, providing one potential pathway by which merlin 's tumor suppressor function might be inactivated through maintenance of phosphorylation at Ser518.

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

HDAC inhibitors disrupt the PP1-HDAC interaction facilitating Akt dephosphorylation and decrease human meningioma and schwannoma cell proliferation and schwannoma growth in an allograft model and meningioma growth in an intracranial xenograft model.

The mTORC1 inhibitor rapamycin selectively inhibited proliferation of seven merlin-null mesothelioma cell lines, but not merlin positive cell lines, suggesting a potential pharmacological target for merlin deficient mesotheliomas.

Merlin expression in Meso-17 and Meso-25 cells decreased FAK Tyr397 phosphorylation and consequently disrupted FAK-Src and PI3K interaction, providing a mechanism for the observed enhancement of invasion and spreading caused by merlin inactivation.

Accordingly, merlin was shown to reduce the levels of ErbB2 and ErbB3 receptor levels at the plasma membrane.

Accordingly, merlin was shown to reduce the levels of ErbB2 and ErbB3 receptor levels at the plasma membrane.

Accordingly, merlin was shown to reduce the levels of ErbB2 and ErbB3 receptor levels at the plasma membrane.

In sub-confluent primary Schwann cells, we found that merlin binds to paxillin and mediates merlin localization at the plasma membrane and association with beta1-integrin and ErbB2, modifying the organization of the actin cytoskeleton in a cell density dependent manner.

Moreover, in cultured Schwann cells, merlin interaction with Amot was demonstrated by co-immunoprecipitation of the endogenous proteins.

Moreover, co-immunoprecipitation experiments revealed that merlin interacts with YAP1, although the interaction is not direct.

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

Merlin interacts with tubulin and acetylated-tubulin and stabilizes the microtubules by attenuating tubulin turnover -- lowering the rates of microtubule polymerization and depolymerization.

Merlin inhibits PI3K activity by binding phosphatidylinositol 3-kinase enhancer-L (PIKE-L), the GTPase that binds and activates PI3K.

In various cell types, the binding of hyaluronan to CD44 stimulates Tiam1 dependent Rac1 signaling and cytoskeleton mediated tumor cell migration.

In various cell types, the binding of hyaluronan to CD44 stimulates Tiam1 dependent Rac1 signaling and cytoskeleton mediated tumor cell migration.

Pharmacological or genetic inhibition of Rac1 in Nf2 -/- MEFs reduced the Wnt signaling activation to basal levels as assessed by reporter assay of transactivation of the nuclear beta-catenin-dependent T-cell factor 4 transcription factor.

In sub-confluent primary Schwann cells, we found that merlin binds to paxillin and mediates merlin localization at the plasma membrane and association with beta1-integrin and ErbB2, modifying the organization of the actin cytoskeleton in a cell density dependent manner.

In sub-confluent primary Schwann cells, we found that merlin binds to paxillin and mediates merlin localization at the plasma membrane and association with beta1-integrin and ErbB2, modifying the organization of the actin cytoskeleton in a cell density dependent manner.

FAK silencing decreased schwannoma cell proliferation and was associated with increased levels of total and nuclear p53.

In a similar fashion, NF2 mutations increased the resistance to dihydrofolate reductase inhibitors methotrexalate and pyremethamine as well as the JNK inhibitor JNK-9L.

Furthermore, it was shown that overactive PAK and LIMK pathway activity contributed to cell proliferation through cofilin phosphorylation and auroraA activation.

Interestingly, it was shown that schwannoma cells release insulin like growth factor binding protein 1 which in beta1-integrin dependent manner activates Src and FAK signaling.

Interestingly, it was shown that schwannoma cells release insulin like growth factor binding protein 1 which in beta1-integrin dependent manner activates Src and FAK signaling.

Moreover, neuregulin survival signaling through the ErbB2 and ErbB3 receptor activates PI3K in rat Schwann cells through the activation of Akt and inhibition of Bad, a pro apoptotic Blc-2 family protein.

ErbB2 activation in mouse Nf2 deficient spinal cord neural progenitor cells was shown to be caused by Rac mediated retention of the receptor at the plasma membrane.

Silencing DCAF1 in Meso-33, merlin deficient mesothelioma cells reduced their proliferation by arresting the cell cycle in G1 phase.

Significantly, silencing of DCAF1 in schwannoma cells isolated from NF2 patients also reduced their proliferation.

Silencing DCAF1 in Meso-33, merlin deficient mesothelioma cells reduced their proliferation by arresting the cell cycle in G1 phase.

Furthermore, Amot silencing attenuated Rac1 and Ras and MAPK signaling pathway.

Silencing of Amot in Nf2 -/- Schwann cells (SC4) selectively reduced cell proliferation because it did not change the proliferation rate of SC4 with merlin re-expression.

Furthermore, Amot silencing attenuated Rac1 and Ras and MAPK signaling pathway.

Furthermore, Amot silencing attenuated Rac1 and Ras and MAPK signaling pathway.

In various cell types, the binding of hyaluronan to CD44 stimulates Tiam1 dependent Rac1 signaling and cytoskeleton mediated tumor cell migration.

In various cell types, the binding of hyaluronan to CD44 stimulates Tiam1 dependent Rac1 signaling and cytoskeleton mediated tumor cell migration.

First, protein kinase C potentiated phosphatase inhibitor (CPI-17), which is frequently overexpressed in mesothelioma tumors, inhibits merlin phosphatase MYPT1-PP1delta, providing one potential pathway by which merlin 's tumor suppressor function might be inactivated through maintenance of phosphorylation at Ser518.

First, protein kinase C potentiated phosphatase inhibitor (CPI-17), which is frequently overexpressed in mesothelioma tumors, inhibits merlin phosphatase MYPT1-PP1delta, providing one potential pathway by which merlin 's tumor suppressor function might be inactivated through maintenance of phosphorylation at Ser518.

In various cell types, the binding of hyaluronan to CD44 stimulates Tiam1 dependent Rac1 signaling and cytoskeleton mediated tumor cell migration.

We recently showed that PI3K inhibition in merlin deficient mouse Schwann cells selectively decreased their proliferation.

In primary rat Schwann cells, CD44 was shown to constitutively associate with the heterodimer receptor tyrosine kinase ErbB2 and ErbB3 and CD44 enhanced neuregulin induced ErbB2 activating phosphorylation.

Moreover, neuregulin survival signaling through the ErbB2 and ErbB3 receptor activates PI3K in rat Schwann cells through the activation of Akt and inhibition of Bad, a pro apoptotic Blc-2 family protein.

In the canonical hippo pathway, mammalian Ste20 like kinases (Mst1/2; hippo homolog) phosphorylate large tumor suppressor kinases (LATS 1/2), which in turn phosphorylate and inactivate YAP and TAZ, blocking their role as TEAD and MEAD transcription factor co-activators.

SOS is a GEF that activates Ras by catalyzing the nucleotide exchange.

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.

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.

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.

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.

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.

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

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

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).

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).

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.

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.

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.

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].

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.

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

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.

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.

Thus, while p53 deletion and missense mutations can enhance mTOR, emphasizing the functional interplay between AMPK and wild-type p53, some mutants can display effects on the canonical AMPK-mTOR signaling beyond the transcriptional repression.

By promoting glucose uptake, mutant p53 can limit autophagy dependent energy production.

Thus, while mutant p53 enhanced glucose metabolism can correspondingly suppressed autophagy in proliferating cancer cells, it is reasonable that a reduced glycolysis by mutant p53 can induce autophagy in quiescent cells.

This is in fact in line with the observations that CHIP, beyond targeting wild-type p53 by K48 polyubiquitinition, preferentially degrades aggregation prone mutant p53 proteins through K63 polyubiquitinition chains.

Although p21 expression generally contributes to the induction of an irreversible proliferative arrest, transient p53 mediated induction of p21 is reversible, allowing cells to re-enter the cell cycle once stress or damage has been resolved.

Therefore, it is reasonable that some mutant p53 forms may enhance autophagy required to prevent energy crisis and maintain nucleotide pools during starvation in cancer cells caused by hypoxia and nutrition depletion in tumor microenvironment.

Alternatively, the mutant p53 driven autophagy suppressive function might be overridden by additional signaling, mutations or epigenetic changes.

Secondly, while mutant p53 have been linked to promote glycolysis through distinct mechanisms, emerging data supports the notion that not all mutants display enhanced glycolysis.

Therefore, sophisticated animal studies are needed for tumors that have undergone mutant p53 induced EMT program to provide an in vivo correlate in preclinical models.

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

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.

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 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.

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.

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.

Down-regulated of RAC1 expression or loss of its function significantly suppressed cancer cell proliferation and metastasis.

Additionally, IR could enhance the expression and activation of RAC1, positively associated with the up-regulation of PAK1, p-PAK1, LIMK1, p-LIMK1, Cofilin and p-Cofilin.

In this report, we found that IR could induce the up-regulation of RAC1 expression and activity via activating the PI3K and AKT signaling pathway.

IR significantly promoted the expression of GST-RAC1, RAC1, PAK1, p-PAK1, LIMK1, p-LIMK1, Cofilin, and p-Cofilin in the cells treated with IR.

These results indicate that IR increases the expression and activity of Rac1 via activating the PI3K and AKT signaling pathway.

A question is how IR induces Rac1 expression.

In addition, as shown in XREF_FIG, the results of GST-pull down assays showed Rac1 expression and activity was significantly increased after 6 Gy dose of IR in lung cancer cells, suggesting that IR could promote the Rac1 expression and activity.