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PI3K/AKT/PTEN Signaling as a Molecular Target in Leukemia Angiogenesis  [PDF]
Naoko Okumura,Hitomi Yoshida,Yasuko Kitagishi,Mutsumi Murakami,Yuri Nishimura,Satoru Matsuda
Advances in Hematology , 2012, DOI: 10.1155/2012/843085
Abstract: PI3K/AKT/PTEN pathway is important in the regulation of angiogenesis mediated by vascular endothelial growth factor in many tumors including leukemia. The signaling pathway is activated in leukemia patients as well as leukemia cell lines together with a decrease in the expression of PTEN gene. The mechanism by which the signaling pathway regulates angiogenesis remains to be further elucidated. However, it has become an attractive target for drug therapy against leukemia, because angiogenesis is a key process in malignant cell growth. In this paper, we will focus on the roles and mechanisms of PI3K/AKT/PTEN pathway in regulating angiogenesis. 1. Introduction Angiogenesis is the process by which new blood capillaries are generated from the preexisting blood vessels [1, 2]. Tumor angiogenesis is essential for tumor growth, invasion, and metastasis [3, 4]. This process can be triggered by a series of signal pathways including extracellular signals such as growth factors (Figure 1). It is a complex process that is also regulated by pro- and antiangiogenic factors. In other words, the angiogenesis and vasculature are regulated through the change of balance between the collective actions of proangiogenic factors such as vascular endothelial growth factor (VEGF) and angiogenic inhibitors such as thrombospondin-1(TSP-1). These factors can be derived from different sources such as stromal cells, extracellular matrix, and cancer cells. Their relative contribution is likely to be different according to the difference in tumor types. The interaction btween cancer cells and vascular endothelial cells in the tumor microenvironment affects the angiogenesis [5, 6]. Leukemia is an aggressive malignancy characterized by the accumulation of immature leukemia blasts in the bone marrow. Bone marrow angiogenesis is therefore important for both leukemogenesis, and the leukemic bone marrow shows increased microvascular density [7]. Figure 1: Schematic representation of PI3K/AKT/PTEN signaling. Examples of molecules known to act on angiogenesis via PI3K/AKT regulatory pathways are shown. VEGF and VEGF receptor (VEGFR) are major angiogenesis inducer associated with tumor angiogenesis in numerous solid or hematological malignancies. VEGF binds to VEGF receptor, which leads to the activation of phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. In addition to the PI3K/Akt signaling, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) play an important role as a molecular inhibitor of PI3K/Akt signaling in multiple cellular functions such as cell proliferation,
Deficiency of Pten accelerates mammary oncogenesis in MMTV-Wnt-1 transgenic mice
Yi Li, Katrina Podsypanina, Xiufan Liu, Allison Crane, Lee K Tan, Ramon Parsons, Harold E Varmus
BMC Molecular Biology , 2001, DOI: 10.1186/1471-2199-2-2
Abstract: To better understand the role of PTEN in breast tumor development, we have crossed Pten heterozygous mice to MMTV-Wnt-1 transgenic mice that routinely develop ductal carcinomas in the mammary gland. Female Wnt-1 transgenics heterozygous for Pten developed mammary tumors earlier than Wnt-1 transgenics that were wild type for Pten. In most tumors arising in Pten heterozygotes, the Pten wild-type allele was lost, suggesting that cells lacking Pten function have a growth advantage over cells retaining a wild type allele. Tumors with LOH contained high levels of activated AKT/PKB, a downstream target of the PTEN/PI3K pathway.An animal model has been developed in which the absence of Pten collaborates with Wnt-1 to induce ductal carcinoma in the mammary gland. This animal model may be useful for testing therapies specific for tumors deregulated in the PTEN/PI3K/AKT pathway.Cancer evolves from the accumulation of mutations and the deregulation of two classes of genes, oncogenes and tumor suppressor genes. The large majority of breast cancers arise in epithelia of the breast, and they are thought to evolve from hyperplasia with atypia to carcinoma in situ, invasive carcinoma, and, finally, metastatic disease. The molecular mechanisms leading to breast malignancies are unclear, but many genetic abnormalities and epigenetic factors have been implicated, including changes affecting known tumor suppressor genes (p53, BRCA1, BRCA2, PTEN/MMAC1/TEP1) and proto-oncogenes (neu/ErbB2/HER2, ErbB1/EGFR, PRAD-1/cyclin D1, Mdm2, and c-myc) [reviewed in ref. 1].The gene product of PTEN (phosphatase and tensin homolog deleted from chromosome 10) is a lipid phosphatase that reverses the activities of phosphatidylinositol 3-kinase (PI3K) by dephosphorylating the D3 position of its lipid products, phosphatidylinositol-3, 4 bis-phosphate (PtdIns(3,4)P2), phosphatidylinositol-3,5 bis-phosphate (PtdIns(3,5)P2), and 3,4,5-tri-phosphate (PtdIns(3,4,5)P3) [2, 3], the elevated levels of which are li
Roles for PI3K/AKT/PTEN Pathway in Cell Signaling of Nonalcoholic Fatty Liver Disease  [PDF]
Satoru Matsuda,Mayumi Kobayashi,Yasuko Kitagishi
ISRN Endocrinology , 2013, DOI: 10.1155/2013/472432
Abstract: Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver pathologies and is associated with obesity and the metabolic syndrome, which represents a range of fatty liver diseases associated with an increased risk of type 2 diabetes. Molecular mechanisms underlying how to make transition from simple fatty liver to nonalcoholic steatohepatitis (NASH) are not well understood. However, accumulating evidence indicates that deregulation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway in hepatocytes is a common molecular event associated with metabolic dysfunctions including obesity, metabolic syndrome, and the NAFLD. A tumor suppressor PTEN negatively regulates the PI3K/AKT pathways through its lipid phosphatase activity. Molecular studies in the NAFLD support a key role for PTEN in hepatic insulin sensitivity and the development of steatosis, steatohepatitis, and fibrosis. We review recent studies on the features of the PTEN and the PI3K/AKT pathway and discuss the protein functions in the signaling pathways involved in the NAFLD. The molecular mechanisms contributing to the diseases are the subject of considerable investigation, as a better understanding of the pathogenesis will lead to novel therapies for a condition. 1. Introduction Nonalcoholic fatty liver diseases (NAFLD) represent a hepatic metabolic syndrome, which is the common broad-spectrum liver disease, and it is becoming a worldwide health problem. NAFLD ranges from nonalcoholic fatty liver to nonalcoholic steatohepatitis (NASH), which often precedes liver fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD is also associated with obesity, type 2-diabetes, and metabolic syndrome [1–5]. Insulin resistance appears to induce the fat accumulation in hepatocytes and renders the liver more susceptible to diseases [6]. In addition, reactive oxygen species (ROS), endotoxins, and inflammatory cytokines result in the disease development [7]. It is also well known that several stressors like cigarette smoke, pollutants, diabetes, hypertension, and hypercholesterolemia are all risk factors to the disease [8, 9]. The hepatic insulin resistance state of fatty liver infiltration is characterized by increased free fatty acids (FFAs), which causes lipotoxicity, impairs endothelium-dependent vasodilatation, and increases oxidative stresses. Additional metabolic risk factors include leptin, adiponectin, and plasminogen activator inhibitor-1 (PAI-1), which together lead to increased oxidative stress and endothelial dysfunction [10]. Inflammation and fibrogenesis are closely related and
PTEN in liver diseases and cancer  [cached]
Marion Peyrou, Lucie Bourgoin, Michelangelo F
World Journal of Gastroenterology , 2010,
Abstract: The phosphoinositide 3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/Akt axis is a key signal transduction node that regulates crucial cellular functions, including insulin and other growth factors signaling, lipid and glucose metabolism, as well as cell survival and apoptosis. In this pathway, PTEN acts as a phosphoinositide phosphatase, which terminates PI3K-propagated signaling by dephosphorylating PtdIns(3,4)P2 and PtdIns(3,4,5)P3. However, the role of PTEN does not appear to be restricted only to PI3K signaling antagonism, and new functions have been recently discovered for this protein. In addition to the well-established role of PTEN as a tumor suppressor, increasing evidence now suggests that a dysregulated PTEN expression and/or activity is also linked to the development of several hepatic pathologies. Dysregulated PTEN expression/activity is observed with obesity, insulin resistance, diabetes, hepatitis B virus/hepatitis C virus infections, and abusive alcohol consumption, whereas mutations/deletions have also been associated with the occurrence of hepatocellular carcinoma. Thus, it appears that alterations of PTEN expression and activity in hepatocytes are common and recurrent molecular events associated with liver disorders of various etiologies. These recent findings suggest that PTEN might represent a potential common therapeutic target for a number of liver pathologies.
PTEN Negatively Regulates MAPK Signaling during Caenorhabditis elegans Vulval Development  [PDF]
Itay Nakdimon,Michael Walser,Erika Fr?hli,Alex Hajnal
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1002881
Abstract: Vulval development in Caenorhabditis elegans serves as an excellent model to examine the crosstalk between different conserved signaling pathways that are deregulated in human cancer. The concerted action of the RAS/MAPK, NOTCH, and WNT pathways determines an invariant pattern of cell fates in three vulval precursor cells. We have discovered a novel form of crosstalk between components of the Insulin and the RAS/MAPK pathways. The insulin receptor DAF-2 stimulates, while DAF-18 PTEN inhibits, RAS/MAPK signaling in the vulval precursor cells. Surprisingly, the inhibitory activity of DAF-18 PTEN on the RAS/MAPK pathway is partially independent of its PIP3 lipid phosphatase activity and does not involve further downstream components of the insulin pathway, such as AKT and DAF-16 FOXO. Genetic and biochemical analyses indicate that DAF-18 negatively regulates vulval induction by inhibiting MAPK activation. Thus, mutations in the PTEN tumor suppressor gene may result in the simultaneous hyper-activation of two oncogenic signaling pathways.
Human Maf1 negatively regulates RNA Polymerase III transcription via the TFIIB family members Brf1 and Brf2
Janet Rollins, Ingrid Veras, Stephanie Cabarcas, Ian Willis, Laura Schramm
International Journal of Biological Sciences , 2007,
Abstract: RNA polymerase III (RNA pol III) transcribes many of the small structural RNA molecules involved in processing and translation, thereby regulating the growth rate of a cell. Initiation of pol III transcription requires the evolutionarily conserved pol III initiation factor TFIIIB. TFIIIB is the molecular target of regulation by tumor suppressors, including p53, RB and the RB-related pocket proteins. However, our understanding of negative regulation of human TFIIIB-mediated transcription by other proteins is limited. In this study we characterize a RNA pol III luciferase assay and further demonstrate in vivo that a human homolog of yeast Maf1 represses RNA pol III transcription. Additionally, we show that Maf1 repression of RNA pol III transcription occurs via TFIIIB, specifically through the TFIIB family members Brf1 and Brf2.
Clinicopathological Research and Expression of PTEN/PI3K/Akt Signaling Pathway in Non-small Cell Lung Cancer  [PDF]
Hong SHU,HongLan ZHANG,Can XU,Xiaodong ZHAO
Chinese Journal of Lung Cancer , 2009,
Abstract: Background and objective It has been known that abnormality of PTEN/PI3K/Akt signal pathway played an important role in initiation of some malignant tumors. The aim of this study is to examine the expression and clinicopathological significance of PTEN, PI3K and Akt in non-small cell lung cancer (NSCLC). Methods Expression levels of PTEN, PI3K and Akt protein were determined using immunohistochemistry S-P in 61 specimens of NSCLC with follow-up. Results ①The levels of PTEN protein was higher than that of control group, and levels of PI3K and Akt protein were lower than that of control group; ②Expression of PTEN and PI3K were related to histotype, clinical stage, lymphonode metastasis and survival rate; Expression of Akt was related to clinical stage, lymphonode metastasis and survival rate; ③The Cox Monovariable Analyses revealed that both smoking and negative expression of PTEN were the risking factors on the death of the NSCLC patients after surgery; ④The expression of PTEN protein was negatively correlated to that of PI3K and Akt respectively, while the expression of PI3K was positively correlated to that of Akt. Conclusion In NSCLC, the lack of PTEN induced up-regulation of PI3K and Akt, which demonstrated that PTEN/PI3K/Akt signaling pathway contributed to the tumorigenesis and development of NSCLC. They could be used as the indicators of prognosis and targets of therapy.
Oocyte-Specific Deletion of Pten in Mice Reveals a Stage-Specific Function of PTEN/PI3K Signaling in Oocytes in Controlling Follicular Activation
Krishna Jagarlamudi,Lian Liu,Deepak Adhikari,Pradeep Reddy,Annika Idahl,Ulrika Ottander,Eva Lundin,Kui Liu
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0006186
Abstract: Immature ovarian primordial follicles are essential for maintenance of the reproductive lifespan of female mammals. Recently, it was found that overactivation of the phosphatidylinositol 3-kinase (PI3K) signaling in oocytes of primordial follicles by an oocyte-specific deletion of Pten (phosphatase and tensin homolog deleted on chromosome ten), the gene encoding PI3K negative regulator PTEN, results in premature activation of the entire pool of primordial follicles, indicating that activation of the PI3K pathway in oocytes is important for control of follicular activation. To investigate whether PI3K signaling in oocytes of primary and further developed follicles also plays a role at later stages in follicular development and ovulation, we conditionally deleted the Pten gene from oocytes of primary and further developed follicles by using transgenic mice expressing zona pellucida 3 (Zp3) promoter-mediated Cre recombinase. Our results show that Pten was efficiently deleted from oocytes of primary and further developed follicles, as indicated by the elevated phosphorylation of the major PI3K downstream component Akt. However, follicular development was not altered and oocyte maturation was also normal, which led to normal fertility with unaltered litter size in the mutant mice. Our data indicate that properly controlled PTEN/PI3K-Akt signaling in oocytes is essential for control of the development of primordial follicles whereas overactivation of PI3K signaling in oocytes does not appear to affect the development of growing follicles. This suggests that there is a stage-specific function of PTEN/PI3K signaling in mouse oocytes that controls follicular activation.
NO signaling and S-nitrosylation regulate PTEN inhibition in neurodegeneration
Young-Don Kwak, Tao Ma, Shiyong Diao, Xue Zhang, Yaomin Chen, Janet Hsu, Stuart A Lipton, Eliezer Masliah, Huaxi Xu, Francesca-Fang Liao
Molecular Neurodegeneration , 2010, DOI: 10.1186/1750-1326-5-49
Abstract: In this study, we investigated redox regulation of PTEN, namely S-nitrosylation, a covalent modification of cysteine residues by nitric oxide (NO), and H2O2-mediated oxidation. We found that S-nitrosylation of PTEN was markedly elevated in brains in the early stages of AD (MCI). Surprisingly, there was no increase in the H2O2-mediated oxidation of PTEN, a modification common in cancer cell types, in the MCI/AD brains as compared to normal aged control. Using several cultured neuronal models, we further demonstrate that S-nitrosylation, in conjunction with NO-mediated enhanced ubiquitination, regulates both the lipid phosphatase activity and protein stability of PTEN. S-nitrosylation and oxidation occur on overlapping and distinct Cys residues of PTEN. The NO signal induces PTEN protein degradation via the ubiquitin-proteasome system (UPS) through NEDD4-1-mediated ubiquitination.This study demonstrates for the first time that NO-mediated redox regulation is the mechanism of PTEN protein degradation, which is distinguished from the H2O2-mediated PTEN oxidation, known to only inactivate the enzyme. This novel regulatory mechanism likely accounts for the PTEN loss observed in neurodegeneration such as in AD, in which NO plays a critical pathophysiological role.PTEN, the phosphatase and tensin homologue deleted on chromosome 10, is one of the most frequently mutated tumor suppressors in human cancers. The major, and best characterized, function of PTEN is its lipid phosphatase activity which dephosphorylates PIP3 to generate PIP2, and thus antagonizes the PI3K activity in the activation of Akt [1,2]. PTEN is expressed in almost all types of neurons [3] and is critical in multiple CNS functions such as neuronal differentiation and synaptogenesis [3-5], neuronal plasticity [6], neuronal injury (e.g., axonal branching/regeneration) [7,8] myelin thickness of periphery nerves [9], and in drug addiction [10]. Our research has focused on elucidating novel roles for PTEN in neur
MicroRNA-21 Regulates hTERT via PTEN in Hypertrophic Scar Fibroblasts  [PDF]
Hua-Yu Zhu, Chao Li, Wen-Dong Bai, Lin-Lin Su, Jia-Qi Liu, Yan Li, Ji-Hong Shi, Wei-Xia Cai, Xiao-Zhi Bai, Yan-Hui Jia, Bin Zhao, Xue Wu, Jun Li, Da-Hai Hu
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0097114
Abstract: Background As an important oncogenic miRNA, microRNA-21 (miR-21) is associated with various malignant diseases. However, the precise biological function of miR-21 and its molecular mechanism in hypertrophic scar fibroblast cells has not been fully elucidated. Methodology/Principal Findings Quantitative Real-Time PCR (qRT-PCR) analysis revealed significant upregulation of miR-21 in hypertrophic scar fibroblast cells compared with that in normal skin fibroblast cells. The effects of miR-21 were then assessed in MTT and apoptosis assays through in vitro transfection with a miR-21 mimic or inhibitor. Next, PTEN (phosphatase and tensin homologue deleted on chromosome ten) was identified as a target gene of miR-21 in hypertrophic scar fibroblast cells. Furthermore, Western-blot and qRT-PCR analyses revealed that miR-21 increased the expression of human telomerase reverse transcriptase (hTERT) via the PTEN/PI3K/AKT pathway. Introduction of PTEN cDNA led to a remarkable depletion of hTERT and PI3K/AKT at the protein level as well as inhibition of miR-21-induced proliferation. In addition, Western-blot and qRT-PCR analyses confirmed that hTERT was the downstream target of PTEN. Finally, miR-21 and PTEN RNA expression levels in hypertrophic scar tissue samples were examined. Immunohistochemistry assays revealed an inverse correlation between PTEN and hTERT levels in high miR-21 RNA expressing-hypertrophic scar tissues. Conclusions/Significance These data indicate that miR-21 regulates hTERT expression via the PTEN/PI3K/AKT signaling pathway by directly targeting PTEN, therefore controlling hypertrophic scar fibroblast cell growth. MiR-21 may be a potential novel molecular target for the treatment of hypertrophic scarring.
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