Showing papers in "Advances in biological regulation in 2014"
TL;DR: This work summarizes the view of how Akt selectivity is achieved in the context of subcellular localization, isoform-specific substrate phosphorylation and context-dependent functions in normal and pathophysiological settings.
Abstract: Akt/PKB is a key master regulator of a wide range of physiological functions including metabolism, proliferation, survival, growth, angiogenesis and migration and invasion. The Akt protein kinase family comprises three highly related isoforms encoded by different genes. The initial observation that the Akt isoforms share upstream activators as well as several downstream effectors, together with the high sequence homology suggested that their functions were mostly redundant. By contrast, an increasing body of evidence has recently uncovered the concept of Akt isoform signaling specificity, supported by distinct phenotypes displayed by animal strains genetically modified for each of the three genes, as well as by the identification of isoform-specific substrates and association with discrete subcellular locations. Given that Akt is regarded as a promising therapeutic target in a number of pathologies, it is essential to dissect the relative contributions of each isoform, as well as the degree of compensation in pathophysiological function. Here we summarize our view of how Akt selectivity is achieved in the context of subcellular localization, isoform-specific substrate phosphorylation and context-dependent functions in normal and pathophysiological settings.
169 citations
TL;DR: Growing evidence points to roles for eEF2K in neurological processes such as learning and memory and perhaps in depression, as well as cytoprotective in other settings, including hypoxia.
Abstract: Eukaryotic elongation factor 2 kinase (eEF2K) is a member of the small group of atypical 'α-kinases'. It phosphorylates and inhibits eukaryotic elongation factor 2, to slow down the elongation stage of protein synthesis, which normally consumes a great deal of energy and amino acids. The activity of eEF2K is normally dependent on calcium ions and calmodulin. eEF2K is also regulated by a plethora of other inputs, including inhibition by signalling downstream of anabolic signalling pathways such as the mammalian target of rapamycin complex 1. Recent data show that eEF2K helps to protect cancer cells against nutrient starvation and is also cytoprotective in other settings, including hypoxia. Growing evidence points to roles for eEF2K in neurological processes such as learning and memory and perhaps in depression.
148 citations
TL;DR: This review will focus on the current understanding of RAS GAPs in human disease and will highlight important outstanding questions about their potential role(s) in human cancer.
Abstract: The RAS pathway is one of the most commonly deregulated pathways in human cancer. Mutations in RAS genes occur in nearly 30% of all human tumors. However in some tumor types RAS mutations are conspicuously absent or rare, despite the fact that RAS and downstream effector pathways are hyperactivated. Recently, RAS GTPase Activating Proteins (RAS GAPs) have emerged as an expanding class of tumor suppressors that, when inactivated, provide an alternative mechanism of activating RAS. RAS GAPs normally turn off RAS by catalyzing the hydrolysis of RAS-GTP. As such, the loss of a RAS GAP would be expected to promote excessive RAS activation. Indeed, this is the case for the NF1 gene, which plays an established role in a familial tumor predisposition syndrome and a variety of sporadic cancers. However, there are 13 additional RAS GAP family members in the human genome. We are only now beginning to understand why there are so many RAS GAPs, how they differentially function, and what their potential role(s) in human cancer are. This review will focus on our current understanding of RAS GAPs in human disease and will highlight important outstanding questions.
148 citations
TL;DR: The roles of these proteins as markers for stemness in pancreatic cancer as well as recent studies with the c-Met proto-oncogene will be discussed and the ability of these markers to predict survival of pancreaticcancer patients is being examined clinically.
Abstract: In this review, we will discuss the recent advances in understanding the pancreatic cancer stem cells. Identification and characterization of pancreatic cancer stem cells may aid our ability to improve diagnosis and treatment of pancreatic cancer. Novel approaches are necessary for the earlier diagnosis of pancreatic cancer as well as improved treatment to prevent distal metastasis. Key markers for the identification of pancreatic cancer stem cells include CD133, ALDH, side population cells and the triplet combination CD44+ CD24+ESA+. The roles of these proteins as markers for stemness in pancreatic cancer as well as recent studies with the c-Met proto-oncogene will be discussed. The ability of these markers to predict survival of pancreatic cancer patients is being examined clinically. Stemness and resistance to chemotherapy and radiotherapy may be linked. Expression of some of these markers may be associated with distant metastasis. Treatment of pancreatic cancer patients by targeting the pancreatic cancer stem cells holds promise.
93 citations
TL;DR: The role of PTEN expression and function and downstream pathway activation in cancer stem cell biology and regulation of the tumorigenic potential is focused on; the emerging role ofPTEN in mediating the crosstalk between the PI3K and MAPK pathways will also be discussed.
Abstract: Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a non-redundant lipid phosphatase that restrains and fine tunes the phosphatidylinositol-3-kinase (PI3K) signaling pathway. PTEN is involved in inherited syndromes, which predispose to different types of cancers and is among the most frequently inactivated tumor suppressor genes in sporadic cancers. Indeed, loss of PTEN function occurs in a wide spectrum of human cancers through a variety of mechanisms, including mutations, deletions, transcriptional silencing, or protein instability. PTEN prevents tumorigenesis through multiple mechanisms and regulates a plethora of cellular processes, including survival, proliferation, energy metabolism and cellular architecture. Moreover, recent studies have demonstrated that PTEN is able to exit, exist, and function outside the cell, allowing for inhibition of the PI3K pathway in neighboring cells in a paracrine fashion. Most recently, studies have shown that PTEN is also critical for stem cell maintenance and that PTEN loss can lead to the emergence and proliferation of cancer stem cell (CSC) clones. Depending on the cellular and tissue context of origin, PTEN deletion may result in increased self-renewal capacity or normal stem cell exhaustion and PTEN-deficient stem and progenitor cells have been reported in prostate, lung, intestinal, and pancreatic tissues before tumor formation; moreover, reversible or irreversible PTEN loss is frequently observed in CSC from a variety of solid and hematologic malignancies, where it may contribute to the functional phenotype of CSC. In this review, we will focus on the role of PTEN expression and function and downstream pathway activation in cancer stem cell biology and regulation of the tumorigenic potential; the emerging role of PTEN in mediating the crosstalk between the PI3K and MAPK pathways will also be discussed, together with prospects for the therapeutic targeting of tumors lacking PTEN expression.
77 citations
TL;DR: Methylating the phosphate groups of these lipids with TMS-diazomethane is described and this methodology is sensitive, accurate and robust, and also yields fatty-acyl compositions, suggesting it can be used to further the understanding of both the normal and pathophysiological roles of these important lipids.
Abstract: The phosphoinositide family of phospholipids, defined here as PtdIns, PtdIns3P, PtdIns4P, PtdIns5P, PtdIns(3,4)P2, PtdIns(3,5)P2, PtdIns(4,5)P2 and PtdIns(3,4,5)P3, play pivotal roles in organising the location and activity of many different proteins acting on biological membranes, including those involved in vesicle and protein trafficking through the endolysosomal system and receptor signal transduction at the plasma membrane. Accurate measurement of the cellular levels of these lipids, particularly the more highly phosphorylated species, is hampered by their high polarity and low cellular concentrations. Recently, much progress has been made in using mass spectrometry to measure many different lipid classes in parallel, an approach generally referred to as 'lipidomics'. Unfortunately, the acidic nature of highly phosphorylated phosphoinositides makes them difficult to measure using these methods, because they yield low levels of useful ions; this is particularly the case with PtdIns(3,4,5)P3. We have solved some of these problems by methylating the phosphate groups of these lipids with TMS-diazomethane and describe a simple, integrated approach to measuring PtdIns, PtdInsP, PtdInsP2 and PtdInsP3 classes of lipids, in parallel with other phospholipid species, in cell and tissue extracts. This methodology is sensitive, accurate and robust, and also yields fatty-acyl compositions, suggesting it can be used to further our understanding of both the normal and pathophysiological roles of these important lipids.
75 citations
TL;DR: Preclinical studies suggest that FTY720/fingolimod may be useful in treating colon cancer in individuals with ulcerative colitis, and demonstrates the therapeutic value of modulating SphK1 and S1P receptor functions.
Abstract: Sphingosine-1-phosphate (S1P), a pleiotropic bioactive lipid mediator, and the kinase that produces it have now emerged as key regulators of numerous cellular processes involved in inflammation and cancer. Here, we review the importance of S1P in colitis and colitis-associated cancer (CAC) and discuss our recent work demonstrating that S1P produced by upregulation of SphK1 during colitis and associated cancer is essential for production of the multifunctional NF-κB-regulated cytokine IL-6, persistent activation of the transcription factor Stat3, and consequent upregulation of the S1P receptor, S1PR1. The effectiveness of the pro-drug FTY720 (known as fingolimod), approved for the treatment of multiple sclerosis, has become the gold standard for S1P-centric drugs, and will be used to illustrate the therapeutic value of modulating SphK1 and S1P receptor functions. We will discuss our recent results showing that FTY720/fingolimod administration interferes with the SphK1/S1P/S1PR1 axis and suppresses the NF-κB/IL-6/Stat3 malicious amplification loop and CAC. These preclinical studies suggest that FTY720/fingolimod may be useful in treating colon cancer in individuals with ulcerative colitis.
73 citations
TL;DR: Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA Biomedical Department of Internal Medicine and Specialties, University of Palermo, Palerzo, Italy
Abstract: Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA Biomedical Department of Internal Medicine and Specialties, University of Palermo, Palermo, Italy Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare “Alberto Monroy”, Palermo, Italy Department of Medicine, University of Göttingen, Göttingen, Germany e Sanct-Josef-Hospital Cloppenburg, Department of Hematology and Oncology, Cloppenburg, Germany Department of Bio-Medical Sciences, University of Catania, Catania, Italy Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy h Institute of Molecular Genetics, National Research Council-IOR, Bologna, Italy
71 citations
TL;DR: The implication of upstream regulators of the most important isoforms of PI3K in platelets and their downstream effectors such as protein kinase B and its target glycogen synthase kinase 3 (GSK3) will be discussed as well as the impact of PTEN and SHIP phosphatases as modulators of this pathway.
Abstract: Class I phosphoinositide 3-kinases (PI3K) have been extensively studied in different models these last years and several isoforms are now promising drug targets to treat cancer and immune diseases Blood platelets are non-nucleated cells critical for hemostasis and strongly involved in arterial thrombosis, a leading cause of death worldwide Besides their role in hemostasis and thrombosis, platelets provide an interesting model to characterize the implication of the different isoforms of PI3K in signaling They are specialized for regulated adhesion, particularly under high shear stress conditions found in arteries and use highly regulated signaling mechanisms to form and stabilize a thrombus In this review we will highlight the role of class I PI3K in these processes and the pertinence of targeting them in the context of antithrombotic strategies but also the potential consequences on the bleeding risk of inhibiting the PI3K signaling in cancer therapy The implication of upstream regulators of the most important isoforms of PI3K in platelets and their downstream effectors such as protein kinase B (PKB or Akt) and its target glycogen synthase kinase 3 (GSK3) will be discussed as well as the impact of PTEN and SHIP phosphatases as modulators of this pathway
71 citations
TL;DR: Recent progress is highlighted in understanding the mechanism of FASN-induced resistance, which may contribute to resistance to drug and radiation-induced apoptosis.
Abstract: Human FASN is the key enzyme required for de novo synthesis of fatty acids. Up-regulated FASN expression has been reported in various human cancers and was thought to contribute to poor prognosis and recurrence of these cancers. Studies using model cell lines have indicated the role of FASN in both intrinsic and acquired drug and radiation resistance. Recent studies suggest that FASN may play an important role in regulating gene expression such as pro-apoptotic proteins and cellular processes such as DNA repair pathways, which in turn contribute to resistance to drug and radiation-induced apoptosis. In this review, we will highlight our recent progress in understanding the mechanism of FASN-induced resistance.
62 citations
TL;DR: Several examples of the benefit of macrophage plasticity to develop accurate cellular mechanisms of lipid metabolism are summarized, and insights from lipidomic analyses about the differences in eicosanoid pathway enzyme activity in vitro vs. in cells ex vivo are discussed.
Abstract: Macrophages are central to essential physiological processes including the regulation of innate and adaptive immunity, but they are also central to a number of inflammatory disease states. These immune cells also possess remarkable plasticity and display various shades of functionalities based on changes in the surrounding molecular environment. Macrophage biology has defined various phenotypes and roles in inflammation based primarily on cytokine and chemokine profiles of cells in different activation states. Importantly, macrophages are elite producers of eicosanoids and other related lipid mediators during inflammation, but specific roles of these molecules have not generally been incorporated into the larger context of macrophage biology. In this review, we discuss the current classification of macrophage types and their roles in inflammation and disease, along with the practical challenges of studying biologically relevant phenotypes ex vivo. Using the latest advances in eicosanoid lipidomics, we highlight several key studies from our laboratory that provide a comprehensive understanding of how eicosanoid metabolism differs between macrophage phenotypes, along with how this metabolism is altered by changes in membrane fatty acid distribution and varied durations of Toll-like receptor (TLR) priming. In conclusion, we summarize several examples of the benefit of macrophage plasticity to develop accurate cellular mechanisms of lipid metabolism, and insights from lipidomic analyses about the differences in eicosanoid pathway enzyme activity in vitro vs. in cells ex vivo. Examples of new techniques to further understand the role of macrophage eicosanoid signaling in vivo are also discussed.
TL;DR: The classical mammalian PLD’s, PLD1 and PLD2, are introduced, followed by the mechanisms of intracellular regulation and a status of current investigation in the crucial involvement of PLD in cancer, that has grown exponentially in the last few years.
Abstract: Phospholipase D (PLD) is a membrane protein with a double role: maintenance of the structural integrity of cellular or intracellular membranes and involvement in cell signaling through the product of the catalytic reaction, PA, and through protein-protein interaction with a variety of partners. Cross-talk during PLD signaling occurs with other cancer regulators (Ras, PDGF, TGF and kinases). Elevation of either PLD1 or PLD2 (the two mammalian isoforms of PLD) is able to transform fibroblasts and contribute to cancer progression. Elevated total PLD activity, as well as overexpression, is present in a wide variety of cancers such as gastric, colorectal, renal, stomach, esophagus, lung and breast. PLD provides survival signals and is involved in migration, adhesion and invasion of cancer cells, and all are increased during PLD upregulation or, conversely, they are decreased during PLD loss of function. Eventhough the end results of PLD action as relates to downstream signaling mechanisms are still currently being elucidated, invasion, a pre-requisite for metastasis, is directly affected by PLD. This review will introduce the classical mammalian PLD's, PLD1 and PLD2, followed by the mechanisms of intracellular regulation and a status of current investigation in the crucial involvement of PLD in cancer, mostly through its role in cell migration, invasion and metastasis, that has grown exponentially in the last few years.
TL;DR: There is a compelling case for therapeutic targeting of sphingosine kinase, which is predictive markers in inflammatory diseases and cancer as evidenced by data from patients, knockout mice and the use of available molecular and chemical inhibitors.
Abstract: The enzymes that catalyze formation of the bioactive sphingolipid, sphingosine 1-phosphate, sphingosine kinase 1 and 2, are predictive markers in inflammatory diseases and cancer as evidenced by data from patients, knockout mice and the use of available molecular and chemical inhibitors. Thus, there is a compelling case for therapeutic targeting of sphingosine kinase. In addition, there are several examples of functional interaction between sphingosine 1-phosphate receptors and sphingosine kinase 1 that can drive malicious amplification loops that promote cancer cell growth. These novel aspects of sphingosine 1-phosphate pathobiology are reviewed herein.
TL;DR: Collectively, current evidence clearly shows that 2'-hydroxy ceramide and 2'-Hydroxy complex sphingolipids have unique functions in membrane homeostasis and cell signaling that could not be substituted by non-hydroxy counterparts.
Abstract: Ceramide is a precursor of complex sphingolipids and also plays important roles in cell signaling. With the advances in lipid analytical technologies, the structural diversity of ceramide species have become evident, and the complexity of cellular metabolism and function associated with distinct ceramide species is beginning to be revealed. One of the common structural variations of ceramide is 2′-hydroxylation of the N-acyl chain. Fatty acid 2-hydroxylase (FA2H) is one of the enzymes that introduce the hydroxyl group during de novo synthesis of ceramide. FA2H is essential for the normal functioning of the nervous system, as evidenced by demyelinating disorder associated with FA2H mutations in humans and mice. Studies of Fa2h mutant mice indicate that lack of 2′-hydroxy galactosylceramide in the myelin membrane results in loss of long-term stability of myelin and eventual demyelination. FA2H also regulates differentiation of various cell types (epidermal keratinocytes, schwannoma cells, adipocytes). When provided exogenously, ceramide induces apoptosis in many cell types. Interestingly, the effective concentration of 2′-hydroxy ceramide that induces apoptosis is significantly lower compared to non-hydroxy ceramide, and cells die much more rapidly, suggesting that 2′-hydroxy ceramide can mediate proapoptotic signaling distinct from non-hydroxy ceramide. Collectively, current evidence clearly shows that 2′-hydroxy ceramide and 2′-hydroxy complex sphingolipids have unique functions in membrane homeostasis and cell signaling that could not be substituted by non-hydroxy counterparts.
TL;DR: A role for Notch in prostate development and cancer is summarized with an emphasis on how the Notch pathway may intersect with PTEN/PI3K/Akt and mTOR signaling.
Abstract: Over the past decade, our understanding of the role that Notch-signaling has in tumorigenesis has shifted from leukemogenesis into cancers of solid tumors. Emerging data suggests that in addition to direct effects mediated through the canonical Notch pathway, Notch may participate in epithelial tumor development through regulation of pathways such as PTEN/PI3K/Akt. Prostate cancer is a disease for which PTEN gene expression is especially essential. This review will summarize a role for Notch in prostate development and cancer with an emphasis on how the Notch pathway may intersect with PTEN/PI3K/Akt and mTOR signaling.
TL;DR: This review presents the group's recent findings on the role of the GET pathway in the assembly of the 26S proteasome, in addition to its role in mediating the insertion of tail-anchored proteins into the ER membrane.
Abstract: In eukaryotic cells, the ubiquitin proteasome system plays important roles in diverse cellular processes. The 26S proteasome is a large enzyme complex that degrades ubiquitinated proteins. It consists of 33 different subunits that form two subcomplexes, the 20S core particle and the 19S regulatory particle. Recently, several chaperones dedicated to the accurate assembly of this protease complex have been identified, but the complete mechanism of the 26S proteasome assembly is still unclear. In this review, we summarize what is known about the assembly of proteasome to date and present our group's recent findings on the role of the GET pathway in the assembly of the 26S proteasome, in addition to its role in mediating the insertion of tail-anchored (TA) proteins into the ER membrane.
TL;DR: A comparative analysis of the expression patterns of PLC-β1 and DAGL-α is discussed, providing some insight into the potential autocrine role of 2-AG production in the neuronal nuclear compartment that probably subserve additional roles to the recognized activation of the CB1 cannabinoid receptor.
Abstract: Phosphoinositide (PtdIns) signaling involves the generation of lipid second messengers in response to stimuli in a receptor-mediated manner at the plasma membrane. In neuronal cells of adult brain, the standard model proposes that activation of metabotropic receptors coupled to Phospholipase C-β1 (PLC-β1) is linked to endocannabinoid signaling through the production of diacylglycerol (DAG), which could be systematically metabolized by 1,2-diacylglycerol Lipases (DAGL) to produce an increase of 2-arachidonoyl-glycerol (2-AG), the most abundant endocannabinoid in the brain. However, the existence of a nuclear PtdIns metabolism independent from that occurring elsewhere in the cell is now widely accepted, suggesting that the nucleus constitutes both a functional and a distinct compartment for PtdIns metabolism. In this review, we shall highlight the main achievements in the field of neuronal nuclear inositol lipid metabolism with particular attention to progress made linked to the 2-AG biosynthesis. Our aim has been to identify potential sites of 2-AG synthesis other than the neuronal cytoplasmic compartment by determining the subcellular localization of PLC-β1 and DAGL-α, which is much more abundant than DAGL-β in brain. Our data show that PLC-β1 and DAGL-α are detected in discrete brain regions, with a marked predominance of pyramidal morphologies of positive cortical cells, consistent with their role in the biosynthesis and release of 2-AG by pyramidal neurons to control their synaptic inputs. However, as novelty, we showed here an integrated description of the localization of PLC-β1 and DAGL-α in the neuronal nuclear compartment. We discuss our comparative analysis of the expression patterns of PLC-β1 and DAGL-α, providing some insight into the potential autocrine role of 2-AG production in the neuronal nuclear compartment that probably subserve additional roles to the recognized activation of the CB1 cannabinoid receptor.
TL;DR: The existing knowledge of the relevance of Notch1 and PI3K/Akt/mTOR signaling in T-ALL LICs is summarized and the rationale for targeting these key signal transduction networks by means of selective pharmacological inhibitors is examined.
Abstract: Leukemia initiating cells (LICs) represent a reservoir that is believed to drive relapse and resistance to chemotherapy in blood malignant disorders. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive neoplastic disorder of immature hematopoietic precursors committed to the T-cell lineage. T-ALL comprises about 15% of pediatric and 25% of adult ALL cases and is prone to early relapse. Although the prognosis of T-ALL has improved especially in children due to the use of new intensified treatment protocols, the outcome of relapsed T-ALL cases is still poor. Putative LICs have been identified also in T-ALL. LICs are mostly quiescent and for this reason highly resistant to chemotherapy. Therefore, they evade treatment and give rise to disease relapse. At present great interest surrounds the development of targeted therapies against signaling networks aberrantly activated in LICs and important for their survival and drug-resistance. Both the Notch1 pathway and the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) network are involved in T-ALL LIC survival and drug-resistance and could be targeted by small molecules. Thus, Notch1 and PI3K/Akt/mTOR inhibitors are currently being developed for clinical use either as single agents or in combination with conventional chemotherapy for T-ALL patient treatment. In this review, we summarize the existing knowledge of the relevance of Notch1 and PI3K/Akt/mTOR signaling in T-ALL LICs and we examine the rationale for targeting these key signal transduction networks by means of selective pharmacological inhibitors.
TL;DR: Signal transducer and activator of transcription proteins (STATs) are important in maintaining leukemia stem cells and represent a promising target for eradication of this dangerous cell population.
Abstract: Signal transducer and activator of transcription proteins (STATs) play vital roles in the regulation of cellular proliferation and survival in normal hematopoietic cells, including hematopoietic stem cells. However, aberrant activation of STATs is commonly observed in a number of hematologic malignancies, and recent studies indicate that targeting of STATs may have therapeutic benefit in these diseases. Additional studies have provided greater understanding of the cells responsible for leukemia initiation, referred to as leukemia stem cells. Emerging evidence indicates that STATs are important in maintaining leukemia stem cells and represent a promising target for eradication of this dangerous cell population. Here we summarize what is known about normal hematopoietic stem cells and the origin of leukemic stem cells. We further describe the roles of STAT proteins in these cell populations, as well as current progress toward the development of novel agents and strategies for targeting the STAT proteins.
TL;DR: This manuscript summarizes and discusses the characteristics of previously identified GEFs specific to Arf6 and activation machineries of Arf 6, and describes how these machineries could be precisely controlled by its activators, guanine nucleotide exchange factors.
Abstract: The small GTPase ADP-ribosylation factor 6 (Arf6) plays pivotal roles in a wide variety of cellular events, including exocytosis, endocytosis, actin cytoskeleton reorganization and phosphoinositide metabolism, in various types of cells. To control such a wide variety of actions of Arf6, activation of Arf6 could be precisely controlled by its activators, guanine nucleotide exchange factors (GEFs), in spatial and temporal manners. In this manuscript, we summarize and discuss the characteristics of previously identified GEFs specific to Arf6 and activation machineries of Arf6.
TL;DR: The discovery that PTEN regulates L SCs and HSCs through different mechanisms demonstrated that it is possible to identify pathways that differentially impact leukemia and normal stem cell function and opened new therapeutic perspectives for the selective elimination of LSCs.
Abstract: Leukemia stem cells (LSCs) are considered responsible for leukemia initiation, relapse and resistance to chemotherapy. These cells have self-renewal capacity and originate the other cells in the leukemia pool. Therefore, in order to completely eradicate leukemia cells and consequently cure the disease, therapies should in principle necessarily target LSCs. However, the fact that LSCs share functional and phenotypic properties with normal hematopoietic stem cells (HSCs) poses a significant challenge: how to target LSCs without damaging normal HSCs and compromising hematopoiesis? The discovery that PTEN regulates LSCs and HSCs through different mechanisms, demonstrated that it is possible to identify pathways that differentially impact leukemia and normal stem cell function and opened new therapeutic perspectives for the selective elimination of LSCs. In this review, we briefly discuss the mechanisms that regulate PTEN function in LSCs and HSCs and their potential for the development of LSC-targeted therapies.
TL;DR: Basic and clinical research is resulting in novel approaches to improve breast cancer therapy by targeting the breast CICs, which will include discussion of some of the key genes implicated: estrogen receptor (ER), HER2, BRCA1, TP53, PIK3CA, RB, P16INK1 and various miRs.
Abstract: Over the past 10 years there have been significant advances in our understanding of breast cancer and the important roles that breast cancer initiating cells (CICs) play in the development and resistance of breast cancer. Breast CICs endowed with self-renewing and tumor-initiating capacities are believed to be responsible for the relapses which often occur after various breast cancer therapies. In this review, we will summarize some of the key developments in breast CICs which will include discussion of some of the key genes implicated: estrogen receptor (ER), HER2, BRCA1, TP53, PIK3CA, RB, P16INK1 and various miRs as well some drugs which are showing promise in targeting CICs. In addition, the concept of combined therapies will be discussed. Basic and clinical research is resulting in novel approaches to improve breast cancer therapy by targeting the breast CICs.
TL;DR: Together the data point out to a role of SHIP2 in development in normal cells and at least in cell proliferation in some cancer derived cells.
Abstract: Phosphoinositide 5-phosphatases are critical enzymes in modulating the concentrations of PI(3,4,5)P3, PI(4,5)P2 and PI(3,5)P2. The SH2 domain containing inositol 5-phosphatases SHIP1 and SHIP2 belong to this family of enzymes that dephosphorylate the 5 position of PI(3,4,5)P3 to produce PI(3,4)P2. Data obtained in zebrafish and in mice have shown that SHIP2 is critical in development and growth. Exome sequencing identifies mutations in the coding region of SHIP2 as a cause of opsismodysplasia, a severe but rare chondrodysplasia in human. SHIP2 has been reported to have both protumorigenic and tumor suppressor function in human cancer very much depending on the cell model. This could be linked to the relative importance of PI(3,4)P2 (a product of SHIP2 phosphatase activity) which is also controlled by the PI 4-phosphatase and tumor suppressor INPP4B. In the glioblastoma cell line 1321 N1, that do not express PTEN, lowering SHIP2 expression has an impact on the levels of PI(3,4,5)P3, cell morphology and cell proliferation. It positively stimulates cell proliferation by decreasing the expression of key regulatory proteins of the cell cycle such as p27. Together the data point out to a role of SHIP2 in development in normal cells and at least in cell proliferation in some cancer derived cells.
TL;DR: Nuclear PI-PLCβ1 is a key molecule for nuclear inositide signalling, where it plays a role in cell cycle progression, proliferation and differentiation, and here it is reviewed the targets and possible involvement of nuclear PI- PLC β1 in human physiology and pathology.
Abstract: Lipid signalling molecules are essential components of the processes that allow one extracellular signal to be transferred inside the nucleus, where specific lipid second messengers elicit reactions capable of regulating gene transcription, DNA replication or repair and DNA cleavage, eventually resulting in cell growth, differentiation, apoptosis or many other cell functions. Nuclear inositides are independently regulated, suggesting that the nucleus constitutes a functionally distinct compartment of inositol lipids metabolism. Indeed, nuclear inositol lipids themselves can modulate nuclear processes, such as transcription and pre-mRNA splicing, growth, proliferation, cell cycle regulation and differentiation. Nuclear PI-PLCβ1 is a key molecule for nuclear inositide signalling, where it plays a role in cell cycle progression, proliferation and differentiation. Here we review the targets and possible involvement of nuclear PI-PLCβ1 in human physiology and pathology.
TL;DR: DHMEQ was found to be more active in cancer stem cells than in balk cancer cells, and both PI3K-Akt and NF-κB pathways appear in the survival ofcancer stem cells.
Abstract: Recently cancer tissue is considered to consist of large number of balk cancer cells and a small number of cancer stem cells. After surgery, radiotherapy, or chemotherapy, most cancer cells are removed, but if there are still very small number of cancer stem cells left. They may form the similar tumor again. So removal of cancer stem cells is considered to be important for future cancer therapy. In one hand, NF-κB is the transcription factor that promotes expressions of various inflammatory cytokines and apoptosis inhibitory proteins. Cancer cells often possess constitutively activated NF-κB that often provides excess survival and therapeutic resistance in cancer cells. We have discovered DHMEQ as a specific inhibitor of NF-κB. This compound was found to be more active in cancer stem cells than in balk cancer cells. In breast cancer cells both PI3K-Akt and NF-κB pathways appear in the survival of cancer stem cells.
TL;DR: Emerging data from the study of the MDS transcriptome suggests that spliceosomal mutations have effects on specific genes, including some previously shown to play a role in MDS pathogenesis.
Abstract: Accurate pre-mRNA splicing by the spliceosome is a fundamental cellular mechanism required to remove introns that are present in most protein-coding transcripts. The recent discovery of a variety of somatic spliceosomal mutations in the myelodysplastic syndromes (MDS), a heterogeneous group of myeloid malignancies, has revealed a new leukemogenic pathway involving spliceosomal dysfunction. Spliceosome mutations are found in over half of all MDS patients and are likely founder mutations. The spliceosome mutations are highly specific to MDS and closely related conditions and, to some extent, appear to define distinct clinical phenotypes in MDS. The high frequency of mutations in different components of the RNA splicing machinery in MDS suggests that abnormal RNA splicing is the common consequence of these mutations. The identification of the downstream targets of the spliceosome mutations is an active area of research. Emerging data from the study of the MDS transcriptome suggests that spliceosomal mutations have effects on specific genes, including some previously shown to play a role in MDS pathogenesis. The effects of the spliceosomal mutations on RNA splicing and cell growth have been evaluated only in a limited context to date, however, and the determination of the impact of these mutations in primary human hematopoietic cells is essential in order to elucidate fully the molecular mechanism by which they contribute to MDS pathogenesis.
TL;DR: A series of studies on nucleocytoplasmic translocation of DGKζ have been summarized, and the functional implications of this phenomenon in postmitotic neurons and cancer cells under stress conditions are discussed.
Abstract: Eukaryotic cells have evolved to possess a distinct subcellular compartment, the nucleus, separated from the cytoplasm in a manner that allows the precise operation of the chromatin, thereby permitting controlled access to the regulatory elements in the DNA for transcription and replication. In the cytoplasm, genetic information contained in the DNA sequence is translated into proteins, including enzymes that catalyze various reactions, such as metabolic processes, energy control, and responses to changing environments. One mechanism that regulates these events involves phosphoinositide turnover signaling, which generates a lipid second messenger, diacylglycerol (DG). Since DG acts as a potent activator of several signaling molecules, it should be tightly regulated to keep cellular responsiveness within a physiological range. DG kinase (DGK) metabolizes DG by phosphorylating it to generate phosphatidic acid, thus serving as a critical regulator of DG signaling. Phosphoinositide turnover is employed differentially in the nucleus and the cytoplasm. A member of the DGK family, DGKζ, localizes to the nucleus in various cell types and is considered to regulate nuclear DG signaling. Recent studies have provided evidence that DGKζ shuttles between the nucleus and the cytoplasm in neurons under pathophysiological conditions. Transport of a signal regulator between the nucleus and the cytoplasm should be a critical function for maintaining basic processes in the nucleus, such as cell cycle regulation and gene expression, and to ensure communication between nuclear processes and cytoplasmic functions. In this review, a series of studies on nucleocytoplasmic translocation of DGKζ have been summarized, and the functional implications of this phenomenon in postmitotic neurons and cancer cells under stress conditions are discussed.
TL;DR: This work offers insights into the perturbed mechanisms underlying human LCCS-1 and LAAHD disease states and emphasizes the potential impact of altered mRNA transport and gene expression in human disease.
Abstract: A critical step during gene expression is the directional export of nuclear messenger (m)RNA through nuclear pore complexes (NPCs) to the cytoplasm. During export, Gle1 in conjunction with inositol hexakisphosphate (IP6) spatially regulates the activity of the DEAD-box protein Dbp5 at the NPC cytoplasmic face. GLE1 mutations are causally linked to the human diseases lethal congenital contracture syndrome 1 (LCCS-1) and lethal arthrogryposis with anterior horn cell disease (LAAHD). Here, structure prediction and functional analysis provide strong evidence to suggest that the LCCS-1 and LAAHD disease mutations disrupt the function of Gle1 in mRNA export. Strikingly, direct fluorescence microscopy in living cells reveals a dramatic loss of steady-state NPC localization for GFP-gle1 proteins expressed from human gle1 genes harboring LAAHD and LCCS-1 mutations. The potential significance of these residues is further clarified by analyses of sequence and predicted structural conservation. This work offers insights into the perturbed mechanisms underlying human LCCS-1 and LAAHD disease states and emphasizes the potential impact of altered mRNA transport and gene expression in human disease.
TL;DR: The possible general relevance of DGK inhibition to enhanced diacylglycerol signaling is discussed.
Abstract: Diacylglycerol is a key regulator of cell physiology, controlling the membrane recruitment and activation of signaling molecules. Accordingly, diacylglycerol generation and metabolism are strictly controlled, allowing for localized regulation of its concentration. While the increased production of diacylglycerol upon receptor triggering is well recognized, the modulation of diacylglycerol metabolism by diacylglycerol kinases (DGKs) is less characterized. Some agonists induce DGK activation and recruitment to the plasma membrane, promoting diacylglycerol metabolism to phosphatidic acid. Conversely, several reports indicate that signaling pathways that selectively inhibits DGK isoforms can enhance cellular diacylglycerol levels and signal transduction. For example, the impairment of DGKθ activity by RhoA binding to the catalytic domain represents a conserved mechanism controlling diacylglycerol signaling from Caenorhabditis elegans motoneurons to mammalian hepatocytes. Similarly, DGKα activity is inhibited in lymphocytes by TCR signaling, thus contributing to a rise in diacylglycerol concentration for downstream signaling. Finally, DGKμ activity is inhibited by ischemia–reperfusion-generated reactive oxygen species in airway endothelial cells, promoting diacylglycerol-mediated ion channel opening and edema. In those systems, DGKs provide a gatekeeper function by blunting diacylglycerol levels or possibly establishing permissive domains for diacylglycerol signaling. In this review, I discuss the possible general relevance of DGK inhibition to enhanced diacylglycerol signaling.
TL;DR: The potential of the transcription factor Steroidogenic Factor-1 to apply generally to nuclear lipid signaling is discussed, with particular attention given to the nuclear receptor superfamily of transcription factors and their phospholipid ligands.
Abstract: An unresolved problem in biological signal transduction is how particular branches of highly interconnected signaling networks can be decoupled, allowing activation of specific circuits within complex signaling architectures Although signaling dynamics and spatiotemporal mechanisms serve critical roles, it remains unclear if these are the only ways cells achieve specificity within networks The transcription factor Steroidogenic Factor-1 (SF-1) is an excellent model to address this question, as it forms dynamic complexes with several chemically distinct lipid species (phosphatidylinositols, phosphatidylcholines and sphingolipids) This property is important since lipids bound to SF-1 are modified by lipid signaling enzymes (IPMK & PTEN), regulating SF-1 biological activity in gene expression Thus, a particular SF-1/lipid complex can interface with a lipid signaling enzyme only if SF-1 has been loaded with a chemically compatible lipid substrate This mechanism permits dynamic downstream responsiveness to constant upstream input, disentangling specific pathways from the full network The potential of this paradigm to apply generally to nuclear lipid signaling is discussed, with particular attention given to the nuclear receptor superfamily of transcription factors and their phospholipid ligands