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1.
Sci Signal ; 17(838): eado6266, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38805583

RESUMO

Phosphoinositides are essential signaling molecules. The PI5P4K family of phosphoinositide kinases and their substrates and products, PI5P and PI4,5P2, respectively, are emerging as intracellular metabolic and stress sensors. We performed an unbiased screen to investigate the signals that these kinases relay and the specific upstream regulators controlling this signaling node. We found that the core Hippo pathway kinases MST1/2 phosphorylated PI5P4Ks and inhibited their signaling in vitro and in cells. We further showed that PI5P4K activity regulated several Hippo- and YAP-related phenotypes, specifically decreasing the interaction between the key Hippo proteins MOB1 and LATS and stimulating the YAP-mediated genetic program governing epithelial-to-mesenchymal transition. Mechanistically, we showed that PI5P interacted with MOB1 and enhanced its interaction with LATS, thereby providing a signaling connection between the Hippo pathway and PI5P4Ks. These findings reveal how these two important evolutionarily conserved signaling pathways are integrated to regulate metazoan development and human disease.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Via de Sinalização Hippo , Proteínas Serina-Treonina Quinases , Transdução de Sinais , Fatores de Transcrição , Proteínas de Sinalização YAP , Humanos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Via de Sinalização Hippo/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Proteínas de Sinalização YAP/metabolismo , Proteínas de Sinalização YAP/genética , Ativação Transcricional , Fosforilação , Células HEK293 , Transição Epitelial-Mesenquimal , Fosfoproteínas/metabolismo , Fosfoproteínas/genética , Animais , Serina-Treonina Quinase 3 , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética
2.
Front Cell Dev Biol ; 11: 1297355, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37954209

RESUMO

Phosphoinositides serve as essential players in numerous biological activities and are critical for overall cellular function. Due to their complex chemical structures, localization, and low abundance, current challenges in the phosphoinositide field include the accurate measurement and identification of specific variants, particularly those with acyl chains. Researchers are intensively developing innovative techniques and approaches to address these challenges and advance our understanding of the impact of phosphoinositide signaling on cellular biology. This article provides an overview of recent advances in the study of phosphoinositides, including mass spectrometry, lipid biosensors, and real-time activity assays using fluorometric sensors. These methodologies have proven instrumental for a comprehensive exploration of the cellular distribution and dynamics of phosphoinositides and have shed light on the growing significance of these lipids in human health and various pathological processes, including cancer. To illustrate the importance of phosphoinositide signaling in disease, this perspective also highlights the role of a family of lipid kinases named phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks), which have recently emerged as exciting therapeutic targets for cancer treatment. The ongoing exploration of phosphoinositide signaling not only deepens our understanding of cellular biology but also holds promise for novel interventions in cancer therapy.

3.
Virology ; 585: 1-20, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37257253

RESUMO

The high-risk subtype human papillomaviruses (hrHPVs) infect and oncogenically transform basal epidermal stem cells associated with the development of squamous-cell epithelial cancers. The viral E6 oncoprotein destabilizes the p53 tumor suppressor, inhibits p53 K120-acetylation by the Tat-interacting protein of 60 kDa (TIP60, or Kat5), and prevents p53-dependent apoptosis. Intriguingly, the p53 gene is infrequently mutated in HPV + cervical cancer clinical isolates which suggests a possible paradoxical role for this gatekeeper in viral carcinogenesis. Here, we demonstrate that E6 activates the TP53-induced glycolysis and apoptosis regulator (TIGAR) and protects cells against oncogene-induced oxidative genotoxicity. The E6 oncoprotein induces a Warburg-like stress response and activates PI3K/PI5P4K/AKT-signaling that phosphorylates the TIGAR on serine residues and induces its hypoxia-independent mitochondrial targeting in hrHPV-transformed cells. Primary HPV + cervical cancer tissues contain high levels of TIGAR, p53, and c-Myc and our xenograft studies have further shown that lentiviral-siRNA-knockdown of TIGAR expression inhibits hrHPV-induced tumorigenesis in vivo. These findings suggest the modulation of p53 pro-survival signals and the antioxidant functions of TIGAR could have key ancillary roles during HPV carcinogenesis.


Assuntos
Proteínas Oncogênicas Virais , Infecções por Papillomavirus , Neoplasias do Colo do Útero , Feminino , Humanos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Papillomavirus Humano , Genes p53 , Neoplasias do Colo do Útero/genética , Infecções por Papillomavirus/genética , Proteínas Reguladoras de Apoptose/metabolismo , Glicólise , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/metabolismo , Carcinogênese/genética , Hipóxia
4.
Sci Adv ; 9(5): eade8641, 2023 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-36724278

RESUMO

Phosphatidylinositol (PI)regulating enzymes are frequently altered in cancer and have become a focus for drug development. Here, we explore the phosphatidylinositol-5-phosphate 4-kinases (PI5P4K), a family of lipid kinases that regulate pools of intracellular PI, and demonstrate that the PI5P4Kα isoform influences androgen receptor (AR) signaling, which supports prostate cancer (PCa) cell survival. The regulation of PI becomes increasingly important in the setting of metabolic stress adaptation of PCa during androgen deprivation (AD), as we show that AD influences PI abundance and enhances intracellular pools of PI-4,5-P2. We suggest that this PI5P4Kα-AR relationship is mitigated through mTORC1 dysregulation and show that PI5P4Kα colocalizes to the lysosome, the intracellular site of mTORC1 complex activation. Notably, this relationship becomes prominent in mouse prostate tissue following surgical castration. Finally, multiple PCa cell models demonstrate marked survival vulnerability following stable PI5P4Kα inhibition. These results nominate PI5P4Kα as a target to disrupt PCa metabolic adaptation to castrate resistance.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Receptores Androgênicos , Animais , Humanos , Masculino , Camundongos , Antagonistas de Androgênios , Androgênios/metabolismo , Linhagem Celular Tumoral , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Receptores Androgênicos/metabolismo , Transdução de Sinais
6.
Nat Rev Drug Discov ; 22(5): 357-386, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36376561

RESUMO

Lipid phosphoinositides are master regulators of almost all aspects of a cell's life and death and are generated by the tightly regulated activity of phosphoinositide kinases. Although extensive efforts have focused on drugging class I phosphoinositide 3-kinases (PI3Ks), recent years have revealed opportunities for targeting almost all phosphoinositide kinases in human diseases, including cancer, immunodeficiencies, viral infection and neurodegenerative disease. This has led to widespread efforts in the clinical development of potent and selective inhibitors of phosphoinositide kinases. This Review summarizes our current understanding of the molecular basis for the involvement of phosphoinositide kinases in disease and assesses the preclinical and clinical development of phosphoinositide kinase inhibitors.


Assuntos
Neoplasias , Doenças Neurodegenerativas , Viroses , Humanos , Fosfatidilinositol 3-Quinases , Doenças Neurodegenerativas/tratamento farmacológico , Neoplasias/tratamento farmacológico , Fosfatidilinositóis
7.
Cell Rep Methods ; 2(7): 100239, 2022 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-35880017

RESUMO

We present Multi-miR, a microRNA-embedded shRNA system modeled after endogenous microRNA clusters that enables simultaneous expression of up to three or four short hairpin RNAs (shRNAs) from a single promoter without loss of activity, enabling robust combinatorial RNA interference (RNAi). We further developed complementary all-in-one vectors that are over one log-scale more sensitive to doxycycline-mediated activation in vitro than previous methods and resistant to shRNA inactivation in vivo. We demonstrate the utility of this system for intracranial expression of shRNAs in a glioblastoma model. Additionally, we leverage this platform to target the redundant RAF signaling node in a mouse model of KRAS-mutant cancer and show that robust combinatorial synthetic lethality efficiently abolishes tumor growth.


Assuntos
MicroRNAs , Camundongos , Animais , MicroRNAs/genética , Interferência de RNA , Vetores Genéticos , RNA Interferente Pequeno/genética , Regiões Promotoras Genéticas
8.
Mol Cancer Res ; 20(2): 244-252, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34728552

RESUMO

In this era of precision medicine, numerous workflows for the targeting of high-recurrent mutations in common tumor types have been developed, leaving patients with rare diseases with few options. Here, we implement a functional precision oncology approach utilizing comprehensive genomic profiling in combination with high-throughput drug screening, to identify tumor-specific drug sensitivities for patients with rare tumor types such as myxofibrosarcoma. From a patient with a high-grade myxofibrosarcoma, who was enrolled in the Englander Institute for Precision Medicine (EIPM) program, we established patient-derived 3D sarco-spheres and xenograft models for functional testing. In the absence of a large cohort of clinically similar cases, high-throughput drug screening was performed on the patient-derived cells, and compared with two other myxofibrosarcoma lines and a benign fibroblast line to functionally identify tumor-specific drug sensitivities. The addition of functional drug sensitivity testing to complement genomic profiling identified multiple therapeutic options that were further validated in patient derived xenograft models. Genomic analyses detected the frequently known codeletion of the tumor suppressors CDKN2A/B together with the methylthioadenosine phosphorylase (MTAP) and a TP53 E286fs*50 mutation. High-throughput drug screening demonstrated tumor-specific sensitivity to compounds targeting the cell cycle. Based on genomic analysis and high-throughput drug screening, we show that targeting the cell cycle in these tumors is a powerful approach. IMPLICATIONS: This study demonstrates the potential of functional testing to aid clinical decision making for patients with rare or molecularly complex malignancies when combined with comprehensive genomic profiling.


Assuntos
Biomarcadores Tumorais/metabolismo , Fibrossarcoma/fisiopatologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Oncologia/métodos , Terapia de Alvo Molecular/métodos , Medicina de Precisão/métodos , Animais , Feminino , Humanos , Camundongos , Camundongos Nus , Mutação
9.
Adv Biol Regul ; 83: 100839, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34840111

RESUMO

Metabolic reprogramming of cancer cells by various acquired mutations provides support for rapid proliferation and growth in the tumor microenvironment. Mutations in the TP53 gene are the most common mutation found across all human cancers. Commonly referred to as "the guardian of the genome", p53 has a well-established role as a tumor suppressor by mediating checkpoint integrity and protecting cells from DNA damage. To date, the many functional roles of p53 extending beyond its classical function and exerting control over metabolic processes continues to confound the field. Recently, emerging roles for p53 in mediating lipid metabolism have come to light with intriguing metabolic roles in regulating cholesterol homeostasis and lipid droplet formation. Herein, we will seek to unify the mechanisms by which absence of functional p53, as well as stable mutant forms of p53, exert control over these lipid metabolism programs. Of equal importance, synthetic lethal phenotypes in the context of mutant p53 and aberrant lipid homeostasis offer new possible targets in the therapeutic landscape. This review aims to characterize the mechanisms by which p53 exerts control over these pathways and examine how precision medicine may benefit from tumor subtyping of p53 mutations.


Assuntos
Neoplasias , Proteína Supressora de Tumor p53 , Animais , Genes p53 , Humanos , Metabolismo dos Lipídeos/genética , Mutação , Neoplasias/patologia , Microambiente Tumoral , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
10.
FEBS Lett ; 596(1): 3-16, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34822164

RESUMO

Cancer cells are challenged by a myriad of microenvironmental stresses, and it is their ability to efficiently adapt to the constantly changing nutrient, energy, oxidative, and/or immune landscape that allows them to survive and proliferate. Such adaptations, however, result in distinct vulnerabilities that are attractive therapeutic targets. Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are a family of druggable stress-regulated phosphoinositide kinases that become conditionally essential as a metabolic adaptation, paving the way to targeting cancer cell dependencies. Further, PI5P4Ks have a synthetic lethal interaction with the tumor suppressor p53, the loss of which is one of the most prevalent genetic drivers of malignant transformation. PI5P4K's emergence as a crucial axis in the expanding landscape of phosphoinositide signaling in cancer has already stimulated the development of specific inhibitors. Thus, a better understanding of the biology of the PI5P4Ks will allow for targeted and effective therapeutic interventions. Here, we attempt to summarize the mounting roles of the PI5P4Ks in cancer, including evidence that targeting them is a therapeutic vulnerability and promising next-in-line treatment for multiple cancer subtypes.


Assuntos
Fosfotransferases (Aceptor do Grupo Álcool)
11.
Dev Cell ; 56(11): 1661-1676.e10, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-33984270

RESUMO

PI5P4Ks are a class of phosphoinositide kinases that phosphorylate PI-5-P to PI-4,5-P2. Distinct localization of phosphoinositides is fundamental for a multitude of cellular functions. Here, we identify a role for peroxisomal PI-4,5-P2 generated by the PI5P4Ks in maintaining energy balance. We demonstrate that PI-4,5-P2 regulates peroxisomal fatty acid oxidation by mediating trafficking of lipid droplets to peroxisomes, which is essential for sustaining mitochondrial metabolism. Using fluorescent-tagged lipids and metabolite tracing, we show that loss of the PI5P4Ks significantly impairs lipid uptake and ß-oxidation in the mitochondria. Further, loss of PI5P4Ks results in dramatic alterations in mitochondrial structural and functional integrity, which under nutrient deprivation is further exacerbated, causing cell death. Notably, inhibition of the PI5P4Ks in cancer cells and mouse tumor models leads to decreased cell viability and tumor growth, respectively. Together, these studies reveal an unexplored role for PI5P4Ks in preserving metabolic homeostasis, which is necessary for tumorigenesis.


Assuntos
Carcinogênese/genética , Mitocôndrias/genética , Neoplasias/metabolismo , Peroxissomos/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Animais , Linhagem Celular Tumoral , Metabolismo Energético/genética , Feminino , Homeostase/genética , Humanos , Gotículas Lipídicas/metabolismo , Metabolismo dos Lipídeos/genética , Masculino , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Neoplasias/genética , Neoplasias/patologia , Peroxissomos/genética
12.
Front Cell Dev Biol ; 9: 791758, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35071233

RESUMO

While organelles are individual compartments with specialized functions, it is becoming clear that organellar communication is essential for maintaining cellular homeostasis. This cooperation is carried out by various interactions taking place on the membranes of organelles. The membranes themselves contain a multitude of proteins and lipids that mediate these connections and one such class of molecules facilitating these relations are the phospholipids. There are several phospholipids, but the focus of this perspective is on a minor group called the phosphoinositides and specifically, phosphatidylinositol 4,5-bisphosphate (PI-4,5-P2). This phosphoinositide, on intracellular membranes, is largely generated by the non-canonical Type II PIPKs, namely, Phosphotidylinositol-5-phosphate-4-kinases (PI5P4Ks). These evolutionarily conserved enzymes are emerging as key stress response players in cells. Further, PI5P4Ks have been shown to modulate pathways by regulating organelle crosstalk, revealing roles in preserving metabolic homeostasis. Here we will attempt to summarize the functions of the PI5P4Ks and their product PI-4,5-P2 in facilitating inter-organelle communication and how they impact cellular health as well as their relevance to human diseases.

13.
FEBS J ; 287(2): 222-238, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31693781

RESUMO

Today, the importance of autophagy in physiological processes and pathological conditions is undeniable. Initially, autophagy merely was described as an evolutionarily conserved mechanism to maintain metabolic homeostasis in times of starvation; however, in recent years it is now apparent that autophagy is a powerful regulator of many facets of cellular metabolism, that its deregulation contributes to various human pathologies, including cancer and neurodegeneration, and that its modulation has considerable potential as a therapeutic approach. Different lipid species, including sphingolipids, sterols, and phospholipids, play important roles in the various steps of autophagy. In particular, there is accumulating evidence indicating the minor group of phospholipids called the phosphoinositides as key modulators of autophagy, including the signaling processes underlying autophagy initiation, autophagosome biogenesis and maturation. In this review, we discuss the known functions to date of the phosphoinositides in autophagy and attempt to summarize the kinases and phosphatases that regulate them as well as the proteins that bind to them throughout the autophagy program. We will also provide examples of how the control of phosphoinositides and their metabolizing enzymes is relevant to understanding many human diseases.


Assuntos
Autofagia , Fosfatidilinositóis/metabolismo , Animais , Humanos , Doença de Huntington/genética , Doença de Huntington/metabolismo , Miopatias Congênitas Estruturais/genética , Miopatias Congênitas Estruturais/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Síndrome Oculocerebrorrenal/genética , Síndrome Oculocerebrorrenal/metabolismo , Fosfatidilinositóis/genética
14.
J Cell Biol ; 219(1)2020 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-31868890

RESUMO

How the distinct lipid composition of organelles is determined and maintained is still poorly understood. In this issue, Du et al. (2019. J. Cell Biol.https://doi.org/10.1083/jcb.201905162) show that the lipid transfer protein ORP5 functions at ER-LD contact sites, regulating lipid droplet levels of phosphatidylserine and phosphatidylinositol-4-phosphate.


Assuntos
Gotículas Lipídicas , Membranas Mitocondriais , Fosfatidilserinas
15.
Mol Cell ; 70(3): 531-544.e9, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29727621

RESUMO

While the majority of phosphatidylinositol-4, 5-bisphosphate (PI-4, 5-P2) in mammalian cells is generated by the conversion of phosphatidylinositol-4-phosphate (PI-4-P) to PI-4, 5-P2, a small fraction can be made by phosphorylating phosphatidylinositol-5-phosphate (PI-5-P). The physiological relevance of this second pathway is not clear. Here, we show that deletion of the genes encoding the two most active enzymes in this pathway, Pip4k2a and Pip4k2b, in the liver of mice causes a large enrichment in lipid droplets and in autophagic vesicles during fasting. These changes are due to a defect in the clearance of autophagosomes that halts autophagy and reduces the supply of nutrients salvaged through this pathway. Similar defects in autophagy are seen in nutrient-starved Pip4k2a-/-Pip4k2b-/- mouse embryonic fibroblasts and in C. elegans lacking the PI5P4K ortholog. These results suggest that this alternative pathway for PI-4, 5-P2 synthesis evolved, in part, to enhance the ability of multicellular organisms to survive starvation.


Assuntos
Autofagia/fisiologia , Jejum/metabolismo , Metabolismo dos Lipídeos/fisiologia , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Animais , Autofagossomos/metabolismo , Caenorhabditis elegans/metabolismo , Linhagem Celular , Fibroblastos/metabolismo , Células HEK293 , Humanos , Fígado/metabolismo , Camundongos , Fosfatos de Fosfatidilinositol/metabolismo , Transdução de Sinais/fisiologia
16.
Proc Natl Acad Sci U S A ; 115(4): E743-E752, 2018 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-29311302

RESUMO

The cancer anorexia cachexia syndrome is a systemic metabolic disorder characterized by the catabolism of stored nutrients in skeletal muscle and adipose tissue that is particularly prevalent in nonsmall cell lung cancer (NSCLC). Loss of skeletal muscle results in functional impairments and increased mortality. The aim of the present study was to characterize the changes in systemic metabolism in a genetically engineered mouse model of NSCLC. We show that a portion of these animals develop loss of skeletal muscle, loss of adipose tissue, and increased inflammatory markers mirroring the human cachexia syndrome. Using noncachexic and fasted animals as controls, we report a unique cachexia metabolite phenotype that includes the loss of peroxisome proliferator-activated receptor-α (PPARα) -dependent ketone production by the liver. In this setting, glucocorticoid levels rise and correlate with skeletal muscle degradation and hepatic markers of gluconeogenesis. Restoring ketone production using the PPARα agonist, fenofibrate, prevents the loss of skeletal muscle mass and body weight. These results demonstrate how targeting hepatic metabolism can prevent muscle wasting in lung cancer, and provide evidence for a therapeutic strategy.


Assuntos
Caquexia/prevenção & controle , Carcinoma Pulmonar de Células não Pequenas/complicações , Fenofibrato/uso terapêutico , Neoplasias Pulmonares/complicações , PPAR gama/agonistas , Aminoácidos/metabolismo , Animais , Caquexia/sangue , Caquexia/etiologia , Avaliação Pré-Clínica de Medicamentos , Fenofibrato/farmacologia , Gluconeogênese , Corpos Cetônicos/deficiência , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , PPAR gama/metabolismo
17.
J Exp Med ; 215(1): 17-19, 2018 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-29222106

RESUMO

In this issue of JEM, Kaittanis et al. (https://doi.org/10.1084/jem.20171052) report a new signaling role for prostate-specific membrane antigen (PSMA), providing a mechanistic link between two major oncogenic pathways, as well as promising therapeutic implications for the diagnosis and treatment of prostate cancer.


Assuntos
Fosfatidilinositol 3-Quinases , Receptores de Glutamato Metabotrópico , Antígenos de Superfície , Ácido Fólico , Ácido Glutâmico , Humanos , Masculino , Neoplasias da Próstata
18.
Mol Cell ; 68(3): 471-472, 2017 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-29100049

RESUMO

In this issue of Molecular Cell, Malek et al. (2017) describe a novel HPLC-MS method permitting separation of PI(3,4)P2 and PI(4,5)P2, a technical issue hindering the phosphoinositide signaling field. They use this method to uncover a new target and critical role for PTEN in cancer.


Assuntos
Neoplasias , Fosfatidilinositol 3-Quinases , Humanos , PTEN Fosfo-Hidrolase , Fosfatidilinositóis , Transdução de Sinais
19.
Proc Natl Acad Sci U S A ; 113(27): 7596-601, 2016 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-27313209

RESUMO

Type 2 phosphatidylinositol-5-phosphate 4-kinase (PI5P4K) converts phosphatidylinositol-5-phosphate to phosphatidylinositol-4,5-bisphosphate. Mammals have three enzymes PI5P4Kα, PI5P4Kß, and PI5P4Kγ, and these enzymes have been implicated in metabolic control, growth control, and a variety of stress responses. Here, we show that mice with germline deletion of type 2 phosphatidylinositol-5-phosphate 4-kinase gamma (Pip4k2c), the gene encoding PI5P4Kγ, appear normal in regard to growth and viability but have increased inflammation and T-cell activation as they age. Immune cell infiltrates increased in Pip4k2c(-/-) mouse tissues. Also, there was an increase in proinflammatory cytokines, including IFNγ, interleukin 12, and interleukin 2 in plasma of Pip4k2c(-/-) mice. Pip4k2c(-/-) mice had an increase in T-helper-cell populations and a decrease in regulatory T-cell populations with increased proliferation of T cells. Interestingly, mammalian target of rapamycin complex 1 (mTORC1) signaling was hyperactivated in several tissues from Pip4k2c(-/-) mice and treating Pip4k2c(-/-) mice with rapamycin reduced the inflammatory phenotype, resulting in a decrease in mTORC1 signaling in tissues and a decrease in proinflammatory cytokines in plasma. These results indicate that PI5P4Kγ plays a role in the regulation of the immune system via mTORC1 signaling.


Assuntos
Inflamação/genética , Ativação Linfocitária/genética , Complexos Multiproteicos/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Feminino , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Polimorfismo de Nucleotídeo Único , Sirolimo , Linfócitos T/fisiologia
20.
Mol Cell ; 61(2): 187-98, 2016 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-26774281

RESUMO

While cellular GTP concentration dramatically changes in response to an organism's cellular status, whether it serves as a metabolic cue for biological signaling remains elusive due to the lack of molecular identification of GTP sensors. Here we report that PI5P4Kß, a phosphoinositide kinase that regulates PI(5)P levels, detects GTP concentration and converts them into lipid second messenger signaling. Biochemical analyses show that PI5P4Kß preferentially utilizes GTP, rather than ATP, for PI(5)P phosphorylation, and its activity reflects changes in direct proportion to the physiological GTP concentration. Structural and biological analyses reveal that the GTP-sensing activity of PI5P4Kß is critical for metabolic adaptation and tumorigenesis. These results demonstrate that PI5P4Kß is the missing GTP sensor and that GTP concentration functions as a metabolic cue via PI5P4Kß. The critical role of the GTP-sensing activity of PI5P4Kß in cancer signifies this lipid kinase as a cancer therapeutic target.


Assuntos
Carcinogênese/metabolismo , Carcinogênese/patologia , Guanosina Trifosfato/metabolismo , Espaço Intracelular/enzimologia , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Trifosfato de Adenosina/metabolismo , Sequência de Aminoácidos , Animais , Proliferação de Células , Cristalografia por Raios X , Células HEK293 , Humanos , Hidrólise , Cinética , Camundongos , Dados de Sequência Molecular , Proteínas Mutantes/química , Proteínas Mutantes/metabolismo , Fosfatos de Fosfatidilinositol/metabolismo , Ligação Proteica , Proteômica , Transdução de Sinais
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