Aspects Of Cell Growth Research Articles

The NDR/LATS protein kinases in neurobiology: Key regulators of cell proliferation, differentiation and migration in the ocular and central nervous system

Nuclear Dbf2-related (NDR) kinases are a subgroup of evolutionarily conserved AGC protein kinases that regulate various aspects of cell growth and morphogenesis. There are 4 NDR protein kinases in mammals, LATS1, LATS2 and STTK8/NDR1, STK38L/NDR2 protein kinases. LATS1 and 2 are core components of the well-studied Hippo pathway, which play a critical role in the regulation of cell proliferation, differentiation, and cell migration via YAP/TAZ transcription factor. The Hippo pathways play an important role in nervous tissue development and homeostasis, especially with regard to the central nervous system (CNS) and the ocular system. The ocular system is a very complex system generated by the interaction in a very tightly coordinated manner of numerous and diverse developing tissues, such as, but not limited to choroidal and retinal blood vessels, the retinal pigmented epithelium and the retina, a highly polarized neuronal tissue. The retina development and maintenance require precise and coordinated regulation of cell proliferation, cell death, migration, morphogenesis, synaptic connectivity, and balanced homeostasis. This review highlights the emerging roles of NDR1 and NDR2 kinases in the regulation of retinal/neuronal function and homeostasis via a noncanonical branch of the Hippo pathway. We highlight a potential role of NDR1 and NDR2 kinases in regulating neuronal inflammation and as potential therapeutic targets for the treatment of neuronal diseases.

Identification of EGFR inhibitors as potential agents for cancer therapy: pharmacophore-based modeling, molecular docking, and molecular dynamics investigations.

As a member of a large family of proteins that together regulate various aspects of cell growth and development, the epidermal growth factor receptor (EGFR) is a validated target for the development of new drugs. Herein, we compiled a library of 62 compounds from the PubChem database with similar pharmacophores as osimertinib, which to our knowledge represents the only drug capable of overcoming EGFR-T790M-mutated NSCLC until date. Subsequently, we launched a docking-based virtual screening campaign against the EGFR kinase with the compiled chemical entities. The virtual screen identified 3 hit candidates (CID_126667097, CID_137660592, and CID_137659061) with lower binding energy/higher affinity (- 8.7kcal/mol, - 8.6kcal/mol, and - 8.5kcal/mol, respectively) than the standard osimertinib (- 8.4kcal/mol). Molecular dynamics metrics such as RMSD, RMSF, ROG, and intermolecular H-bond were used to substantiate the stability of the promising drug candidates at the binding pocket of EGFR after 100,000ps production run. Overall, our molecular modeling study portrayed CID_126667097, CID_137660592, and CID_137659061 as lead-like drug candidates that may be further developed for the treatment of EGFR-associated cancer disease. Molecular docking was conducted with Autodock Vina. A total of 62 compounds were compiled for the docking screen, which were then downloaded in SMILE format and converted to Protein Data Bank (PDB) format using the Openbabel online server. Finally, Gromacs 2022.3 was used to perform MD simulation to substantiate the stability of the hit candidates.

HPMA copolymer-collagen hybridizing peptide conjugates targeted to breast tumor extracellular matrix.

The extracellular matrix (ECM) is dynamically involved in many aspects of cell growth and survival, and it plays an active role in cancer etiology. In comparison to healthy ECM, tumor associated ECM shows high collagen deposition and remodeling activity, which results in an increased amount of denatured collagen strands in tumor tissues. Capitalizing on this distinguishing feature, we developed tumor-localizing polymeric carriers that selectively bind to denatured collagen in the tumor ECM. We synthesized N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers with their side chains conjugated to collagen hybridizing peptides (CHPs). HPMA copolymer-CHP conjugates exhibited selective affinity to denatured collagen and localized to tumors in an orthotopic MDA-MB-231 murine breast cancer model. The conjugates had increased tumor localization compared to copolymers with scrambled peptides in the side chains, as well as increased retention compared to free CHPs. Such conjugates show promise as carriers for ECM-acting drugs and imaging agents in the management of diseases characterized by high ECM remodeling activity.

Characterization of TGF-β signaling in a human organotypic skin model reveals that loss of TGF-βRII induces invasive tissue growth.

Transforming growth factor-β (TGF-β) signaling regulates various aspects of cell growth and differentiation and is often dysregulated in human cancers. We combined genetic engineering of a human organotypic three-dimensional (3D) skin model with global quantitative proteomics and phosphoproteomics to dissect the importance of essential components of the TGF-β signaling pathway, including the ligands TGF-β1, TGF-β2, and TGF-β3, the receptor TGF-βRII, and the intracellular effector SMAD4. Consistent with the antiproliferative effects of TGF-β signaling, the loss of TGF-β1 or SMAD4 promoted cell cycling and delayed epidermal differentiation. The loss of TGF-βRII, which abrogates both SMAD4-dependent and SMAD4-independent downstream signaling, more strongly affected cell proliferation and differentiation than did loss of SMAD4, and it induced invasive growth. TGF-βRII knockout reduced cell-matrix interactions, and the production of matrix proteins increased the production of cancer-associated cell-cell adhesion proteins and proinflammatory mediators and increased mitogen-activated protein kinase (MAPK) signaling. Inhibiting the activation of the ERK and p38 MAPK pathways blocked the development of the invasive phenotype upon the loss of TGF-βRII. This study provides a framework for exploring TGF-β signaling pathways in human epithelial tissue homeostasis and transformation using genetic engineering, 3D tissue models, and high-throughput quantitative proteomics and phosphoproteomics.

Cancer-associated fibroblasts in non-small cell lung cancer: Recent advances and future perspectives.

Non-small cell lung cancer (NSCLC) constitutes the majority of lung cancer, which is the leading cause of cancer-related deaths in the world. Nearly 70% of NSCLC patients were diagnosed at advanced stage with only 15% of five-year survival rate. Cancer-associated fibroblasts (CAFs) are the major component of tumor microenvironment and account for almost 70% of the cells in tumor tissues. By the crosstalk with cancer cells, CAFs reprogrammed cancer cell metabolism, remodeled extracellular matrix (ECM) and created a supportive niche for cancer stem cells. CAFs lead collective invasion of tumor cells and shape tumor immune microenvironment, promoting tumor metastasis and immune escape. In this review, we have summarized the progress of studies regarding CAFs influences on NSCLC in recent five years from the aspects of cell growth, metabolism, therapy resistance, invasion and metastasis and immune suppression. We have discussed the involved mechanisms and implications for the development of anti-NSCLC therapies. The current strategies of CAFs targeting and elimination have also been generalized. Only better understanding of the molecular biology of CAFs may contribute to the development of novel anti-NSCLC strategies.

Theoretical modeling of tunable vibrations of three-dimensional serpentine structures for simultaneous measurement of adherent cell mass and modulus

Abstract

Abstract IA25: Development of PI3K inhibitors in breast cancer

Abstract The phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway is crucial to many aspects of cell growth and survival. PI3K pathway is frequently deregulated in breast cancer due to genetic or epigenetic alterations in components of this pathway and contributes to treatment resistance. Notably, PIK3CA mutation is the most frequent genetic event in estrogen receptor-positive (ER+) breast cancer, while loss of PTEN expression is commonly observed in triple-negative disease (TNBC). There has been significant interest in developing PI3K inhibitors in breast cancer. Several randomized clinical trials assessing the benefit of adding PI3K inhibitors to fulvestrant in patients with advanced ER+ breast cancer, including BELLE-2, BELLE-3, FERGI, and SANDPIPER, have been reported. Significant improvement in progression-free survival (PFS) has been observed in these trials. However, dose-limiting toxicities of pan-PI3K inhibitors are common, which limit their clinical application. Isoform selective inhibitors, such as alpha selective PI3K inhibitor, are in clinical trials with the hope to reduce toxicity. There is ongoing effect in the investigation of predictors of response and mechanisms of treatment resistance. This presentation will summarize clinical trial data in breast cancer and challenges in the development of PI3K inhibitors in breast cancer. Citation Format: Cynthia X. Ma. Development of PI3K inhibitors in breast cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr IA25.

Abstract 6304: Decrypting EGFR signaling with BRET biosensors: A novel approach to study RTK mutations and the effects of inhibitors

Abstract Receptor tyrosine kinases (RTKs) comprise nodes at the center of complex signaling networks regulating various aspects of cell growth, differentiation and survival. Dysregulated RTK activity can alter many cellular processes, often culminating in cancer. Consequently, RTKs are prime targets for new anti-cancer agents. Yet, the efficacy of these drugs is limited by the development of drug-induced adverse events and acquired resistance. Discovery of novel therapeutics devoid of such limitations requires a deeper understanding of often overlooked determinants of therapeutic efficacy, including kinetics, subcellular localization, signaling bias and drug target mutations. In this study, we present a live-cell BRET-based biosensor platform applicable to studying such key elements, which allows for real-time spatiotemporal monitoring of RTK signaling across more than 10 effector proteins/pathways. Using EGFR and two of its ligands (EGF and Epiregulin) as a model system, we used our platform to highlight spatiotemporal signaling bias. Indeed, Epiregulin-induced engagement of effector protein Grb2 was more efficacious (25%) and displayed faster kinetics relative to that observed with EGF. Interestingly, EGF, but not Epiregulin, promoted a gradual increase in Grb2 levels at early endosomes. These data highlight opportunities for the identification of biased ligands displaying improved therapeutic efficacy. The impact of various glioblastoma-related EGFR mutations on receptor signaling were also profiled. The EGFR(vI) mutant showed constitutive activity on the PLCG1 effector pathway while the EGFR(vV) mutant was uniquely constitutive on SHIP1 and SHIP2 pathways. Further, EGFR(vIII) was devoid of constitutive activity on some effector proteins (PLCG1, Grb2) and highly constitutive on others (PI3K, SHIP1/2). The G598V mutant showed constitutive activity on all pathways except Grb2. This data shows how oncogenic mutations can rewire an RTK's signaling network. Identification and targeting of common signaling nodes exploited by various mutants could enhance drug efficacy and minimize mutation-related drug resistance. Finally, RTK biosensors were used to screen for tyrosine kinase inhibitor (TKI) activity on EGFR kinase domain mutants found in NSCLC (T790M and C797S). 1st generation TKI Gefitinib and 4th generation TKI Osimertinib reversed EGF activation of WT EGFR. However, only Osimertinib could reverse EGF-mediated activation of EGFR(T790M) but was ineffective at inhibiting EGFR(C797S). The platform could thus serve as a tool to assess anti-cancer treatment efficacy against various RTK mutants. These data position our biosensor platform as a versatile technology to study multiple facets of RTK biology and pharmacology. Access to real-time, spatiotemporal readouts across multiple signaling pathways will enable the development of novel RTK-based anti-cancer agents. Citation Format: Florence Gross, Guilhem Dugast, Arturo D. Mancini, Stephan Schann, Xavier Leroy. Decrypting EGFR signaling with BRET biosensors: A novel approach to study RTK mutations and the effects of inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6304.

Polyamine regulation of ion channel assembly and implications for nicotinic acetylcholine receptor pharmacology

Small molecule polyamines are abundant in all life forms and participate in diverse aspects of cell growth and differentiation. Spermidine/spermine acetyltransferase (SAT1) is the rate-limiting enzyme in polyamine catabolism and a primary genetic risk factor for suicidality. Here, using genome-wide screening, we find that SAT1 selectively controls nicotinic acetylcholine receptor (nAChR) biogenesis. SAT1 specifically augments assembly of nAChRs containing α7 or α4β2, but not α6 subunits. Polyamines are classically studied as regulators of ion channel gating that engage the nAChR channel pore. In contrast, we find polyamine effects on assembly involve the nAChR cytosolic loop. Neurological studies link brain polyamines with neurodegenerative conditions. Our pharmacological and transgenic animal studies find that reducing polyamines enhances cortical neuron nAChR expression and augments nicotine-mediated neuroprotection. Taken together, we describe a most unexpected role for polyamines in regulating ion channel assembly, which provides a new avenue for nAChR neuropharmacology.

Icariside II inhibits tumorigenesis via inhibiting AKT/Cyclin E/ CDK 2 pathway and activating mitochondria-dependent pathway

Cervical cancer contributes largely in women cancer-related mortality. Herein, Icariside II, a flavonoid extracted from edible and pharmaceutical plant Epimedium brevicornum Maxim, exhibited significant anticancer activity on cervical cancer. At first, it was observed that Icariside II inhibited Hela cell proliferation at IC50 (9.2 μM) and the growth of Hela-originated xenografts in BALB/c nude mice. Next, we studied the underlying mechanisms of Icariside II from the aspects of cell growth and cell death. As for cell growth, Icariside II arrested cell cycle at G0/G1 phase through AKT/Cyclin E/CDK 2 from transcriptional and translational levels. As for cell death, Flow Cytometry and Immunofluorescence showed that Icariside II promoted cell death in a dose-dependet manner. And, Icariside II turned to activate the mitochondria-dependent pathway Caspase 9/Caspase 3 much more significantly than death receptor pathway Caspase 8/Caspase 3. Taken together, Icariside II presented anticancer effect on cervical cancer both in vitro and in vivo. Our study provides the evidence that Icariside II can be used as a suitable novel agent in cervical cancer treatment.

A Strategy to Identify Compounds that Affect Cell Growth and Survival in Cultured Mammalian Cells at Low-to-Moderate Throughput.

Cytotoxicity is a critical parameter that needs to be quantified when studying drugs that may have therapeutic benefits. Because of this, many drug screening assays utilize cytotoxicity as one of the critical characteristics to be profiled for individual compounds. Cells in culture are a useful model to assess cytotoxicity before proceeding to follow up on promising lead compounds in more costly and labor-intensive animal models. We describe a strategy to identify compounds that affect cell growth in a tdTomato expressing human neural stem cells (NSC) line. The strategy uses two complementary assays to assess cell number. One assay works via the reduction of 3-(4,5-dimethylthizol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) to formazan as a proxy for cell number and the other directly counts the tdTomato expressing NSCs. The two assays can be performed simultaneously in a single experiment and are not labor intensive, rapid, and inexpensive. The strategy described in this demonstration tested 57 compounds in an exploratory primary screen for toxicity in a 96-well plate format. Three of the hits were characterized further in a six-point dose response using the same assay set-up as the primary screen. In addition to providing excellent corroboration for toxicity, comparison of results from the two assays may be effective in identifying compounds affecting other aspects of cell growth.

Protein phosphatases regulate growth, development, cellulases and secondary metabolism in Trichoderma reesei

Trichoderma reesei represents one of the most prolific producers of plant cell wall degrading enzymes. Recent research showed broad regulation by phosphorylation in T. reesei, including important transcription factors involved in cellulase regulation. To evaluate factors crucial for changes in these phosphorylation events, we studied non-essential protein phosphatases (PPs) of T. reesei. Viable deletion strains were tested for growth on different carbon sources, osmotic and oxidative stress response, asexual and sexual development, cellulase and protease production as well as secondary metabolism. Six PPs were found to be positive or negative regulators for cellulase production. A correlation of the effects of PPs on protease activities and cellulase activities was not detected. Hierarchical clustering of regulation patterns and phenotypes of deletion indicated functional specialization within PP classes and common as well as variable effects. Our results confirmed the central role of catalytic and regulatory subunits of PP2A which regulates several aspects of cell growth and metabolism. Moreover we show that the additional homologue of PPH5 in Trichoderma spp., PPH5-2 assumes distinct functions in metabolism, development and stress response, different from PPH5. The influence of PPs on both cellulase gene expression and secondary metabolite production support an interrelationship in the underlying regulation mechanisms.

LC-MS based sphingolipidomic study on A549 human lung adenocarcinoma cell line and its taxol-resistant strain

BackgroundResistance to chemotherapy drugs (e.g. taxol) has been a major obstacle in successful cancer treatment. In A549 human lung adenocarcinoma, acquired resistance to the first-line chemotherapy taxol has been a critical problem in clinics. Sphingolipid (SPL) controls various aspects of cell growth, survival, adhesion, and motility in cancer, and has been gradually regarded as a key factor in drug resistance. To better understand the taxol-resistant mechanism, a comprehensive sphingolipidomic approach was carried out to investigate the sphingolipid metabolism in taxol-resistant strain of A549 cell (A549T).MethodsA549 and A549T cells were extracted according to the procedure with optimal condition for SPLs. Sphingolipidomic analysis was carried out by using an UHPLC coupled with quadrupole time-of-flight (Q-TOF) MS system for qualitative profiling and an UHPLC coupled with triple quadrupole (QQQ) MS system for quantitative analysis. The differentially expressed sphingolipids between taxol-sensitive and -resistant cells were explored by using multivariate analysis.ResultsBased on accurate mass and characteristic fragment ions, 114 SPLs, including 4 new species, were clearly identified. Under the multiple reaction monitoring (MRM) mode of QQQ MS, 75 SPLs were further quantified in both A549 and A549T. Multivariate analysis explored that the levels of 57 sphingolipids significantly altered in A549T comparing to those of A549 (p < 0.001 and VIP > 1), including 35 sphingomyelins (SMs), 14 ceramides (Cers), 3 hexosylceramides (HexCers), 4 lactosylceramides (LacCers) and 1 sphingosine. A significant decrease of SM and Cer levels and overall increase of HexCer and LacCer represent the major SPL metabolic characteristic in A549T.ConclusionsThis study investigated sphingolipid profiles in human lung adenocarcinoma cell lines, which is the most comprehensive sphingolipidomic analysis of A549 and A549T. To some extent, the mechanism of taxol-resistance could be attributed to the aberrant sphingolipid metabolism, “inhibition of the de novo synthesis pathway” and “activation of glycosphingolipid pathway” may play the dominant role for taxol-resistance in A549T. This study provides insights into the strategy for clinical diagnosis and treatment of taxol resistant lung cancer.

Structural insights into lipoprotein N-acylation by Escherichia coli apolipoprotein N-acyltransferase

Gram-negative bacteria express a diverse array of lipoproteins that are essential for various aspects of cell growth and virulence, including nutrient uptake, signal transduction, adhesion, conjugation, sporulation, and outer membrane protein folding. Lipoprotein maturation requires the sequential activity of three enzymes that are embedded in the cytoplasmic membrane. First, phosphatidylglycerol:prolipoprotein diacylglyceryl transferase (Lgt) recognizes a conserved lipobox motif within the prolipoprotein signal sequence and catalyzes the addition of diacylglycerol to an invariant cysteine. The signal sequence is then cleaved by signal peptidase II (LspA) to give an N-terminal S-diacylglyceryl cysteine. Finally, apolipoprotein N-acyltransferase (Lnt) catalyzes the transfer of the sn-1-acyl chain of phosphatidylethanolamine to this N-terminal cysteine, generating a mature, triacylated lipoprotein. Although structural studies of Lgt and LspA have yielded significant mechanistic insights into this essential biosynthetic pathway, the structure of Lnt has remained elusive. Here, we present crystal structures of wild-type and an active-site mutant of Escherichia coli Lnt. The structures reveal a monomeric eight-transmembrane helix fold that supports a periplasmic carbon-nitrogen hydrolase domain containing a Cys-Glu-Lys catalytic triad. Two lipids are bound at the active site in the structures, and we propose a putative phosphate recognition site where a chloride ion is coordinated near the active site. Based on these structures and complementary cell-based, biochemical, and molecular dynamics approaches, we propose a mechanism for substrate engagement and catalysis by E. coli Lnt.

Parasites and cancer: A review of the emergence of protozoan carcinogenesis and novel molecular insights.

The role of infectious agents in the formation of cancers has been long established. However the bulk of the emphasis has been on oncogenic DNA viruses and to a lesser extent, bacteria. However,amidst parasites, only a few metazoans have been linked to cancer, and with feeble molecular bases. This review explores the role of protozoa in cancer formation and highlights new insights into the process of oncogenesis by previously identified helminths with carcinogenic potential. It expounds on the impact of parasites on aspects of cell growth and function, particularly apoptosis, gene expression and cell proliferation.Keywords: Protozoa, Cancer, Oncogenesis, Helminths, Apoptosis

High levels of sphingolipids in human breast cancer

BackgroundSphingolipids, including sphingosine-1-phosphate (S1P) and ceramide, have emerged as key regulatory molecules that control various aspects of cell growth and proliferation in cancer. Although important roles of sphingolipids in breast cancer progression have been reported in experimental models, their roles in human patients have yet to be determined. The aims of this study were to determine the levels of sphingolipids including S1P, ceramides, and other sphingolipids, in breast cancer and normal breast tissue and to compare the difference in levels of each sphingolipid between the two tissues. Materials and methodsTumor and noncancerous breast tissue were obtained from 12 patients with breast cancer. Sphingolipids including S1P, ceramides, and their metabolites of sphingosine, sphingomyelin, and monohexosylceramide were measured by liquid chromatography–electrospray ionization–tandem mass spectrometry. ResultsThe levels of S1P, ceramides, and other sphingolipids in the tumor were significantly higher than those in normal breast tissue. There was a relatively strong correlation in the levels of S1P between the tumor and those of normal breast tissue from the same person. On the other hand, there was no correlation in the levels of most of the ceramide species between the tumor and those of normal breast tissue from the same person. ConclusionsTo our knowledge, this is the first study to reveal that levels of sphingolipids in cancer tissue are generally higher than those of normal breast tissue in patients with breast cancer. The correlation of S1P levels in these tissues implicates the role of S1P in interaction between cancer and the tumor microenvironment.

Beneficial Effects of Early mTORC1 Inhibition after Traumatic Brain Injury.

The mammalian target of rapamycin complex 1 (mTORC1) signaling pathway mediates many aspects of cell growth and regeneration and is upregulated after moderate to severe traumatic brain injury (TBI). The significance of this increased signaling event for recovery of brain function is presently unclear. We analyzed the time course and cell specificity of mTORC1 signal activation in the mouse hippocampus after moderate controlled cortical impact (CCI) and identified an early neuronal peak of activity that occurs within a few hours after injury. We suppressed this peak activity by a single injection of the mTORC1 inhibitor rapamycin 1 h after CCI and showed that this acute treatment significantly diminishes the extent of neuronal death, astrogliosis, and cognitive impairment 1-3 days after injury. Our findings suggest that the early neuronal peak of mTORC1 activity after TBI is deleterious to brain function, and that acute, early intervention with mTORC1 inhibitors after injury may represent an effective form of treatment to improve recovery in human patients.

MiR‐625# and miR‐206 participate to the cellular response to matrix rigidity

The extracellular matrix (ECM) affects many aspects of cell growth and behavior. Not only do cells respond to the composition of the ECM, but they also respond to its physical properties. In a seminal paper, Pelham and Wang observed that cells develop large integrin‐based adhesions on rigid surface, whereas on soft substrate adhesions remain immature and small. Since this cellular response to ECM stiffness is central in various aspects of biology, from physiology to disease, many efforts have been directed recently to understand how cells “sense” and respond to the stiffness of their environment. However this remains, so far, an open question. In this study, we investigated the role of micro RNAs (miRNAs) in the cellular response to matrix rigidity. Comparing miRNAs expression in fibroblast cultured on soft (1kPa) and stiff substrates (25kPa), we observed that ECM rigidity induced a decrease in miR‐625# and miR‐206 expression. Interestingly, inhibition of myosin II increased miR‐625# and miR‐206 expression, indicating that cell‐generated tension regulates miR‐206 and miR‐625# expression. Previous work have shown that fibronectin is a direct target of miR‐206, consistent with this we found that miR‐206 expression in cells cultured on stiff substrates decreased fibronectin expression. Additionally, we found that miR‐625# expression decreased cell spreading and survival on rigid ECM. These data indicate that miR‐206 and miR‐625# regulate the cellular response to ECM rigidity. We are currently pursuing this work to identify miR‐625# targets which impact cell adhesion and survival.

Impact of nuclear factor-κB on restoration of neuron growth and differentiation in hippocampus of degenerative brain.

The mode of action of nuclear factor-κB (NF-κB) has been extensively observed in different aspects of cell growth and proliferation. The transcription factor regulates various genes controlling inflammation and anti-inflammatory responses in different tissues. Thus, NF-κB signal gains a therapeutic prospect. The activation of NF-κB requires nuclear localization of its p65 subunit. Research also indicates an impact of phosphorylated p65 on the transcription of genes during cell growth and the immune response. Following the trends in investigations over decades, different observations suggest that NF-κB activation and phosphorylation of p65 regulate neuronal plasticity. Also, inhibition of NF-κB activation is a well-demonstrated way to attenuate inflammation. In addition to anti-inflammatory drugs, recent researches unwind a way to regulate regeneration and repair tissue damage. Thus, keeping a critical view on NF-κB signals, we propose the importance of natural or synthetic NF-κB activators for neurogenesis.

Feedback regulation on PTEN/AKT pathway by the ER stress kinase PERK mediated by interaction with the Vault complex

The high proliferation rate of cancer cells, together with environmental factors such as hypoxia and nutrient deprivation can cause Endoplasmic Reticulum (ER) stress. The protein kinase PERK is an essential mediator in one of the three ER stress response pathways. Genetic and pharmacological inhibition of PERK has been reported to limit tumor growth in xenograft models. Here we provide evidence that inactive PERK interacts with the nuclear pore-associated Vault complex protein and that this compromises Vault-mediated nuclear transport of PTEN. Pharmacological inhibition of PERK under ER stress results is abnormal sequestration of the Vault complex, leading to increased cytoplasmic PTEN activity and lower AKT activation. As the PI3K/PTEN/AKT pathway is crucial for many aspects of cell growth and survival, this unexpected effect of PERK inhibitors on AKT activity may have implications for their potential use as therapeutic agents.