scholarly journals p53 loss activates prometastatic secretory vesicle biogenesis in the Golgi

2021 ◽  
Vol 7 (25) ◽  
pp. eabf4885
Author(s):  
Xiaochao Tan ◽  
Priyam Banerjee ◽  
Lei Shi ◽  
Guan-Yu Xiao ◽  
B. Leticia Rodriguez ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Adenosine Diphosphate ◽  
Secretory Vesicle ◽  
Scaffolding Protein ◽  
Receptor Signal ◽  
Vesicle Biogenesis ◽  
Key Driver ◽  
Transcription 3 ◽  
Dependent Pathway ◽  
Pharmacologic Inhibition

Cancer cells exhibit hyperactive secretory states that maintain cancer cell viability and remodel the tumor microenvironment. However, the oncogenic signals that heighten secretion remain unclear. Here, we show that p53 loss activates prometastatic secretory vesicle biogenesis in the Golgi. p53 loss up-regulates the expression of a Golgi scaffolding protein, progestin and adipoQ receptor 11 (PAQR11), which recruits an adenosine diphosphate ribosylation factor 1–containing protein complex that loads cargos into secretory vesicles. PAQR11-dependent secretion of a protease, PLAU, prevents anoikis and initiates autocrine activation of a PLAU receptor/signal transducer and activator of transcription-3-dependent pathway that up-regulates PAQR11 expression, thereby completing a feedforward loop that amplifies prometastatic effector protein secretion. Pharmacologic inhibition of PLAU receptor impairs the growth and metastasis of p53-deficient cancers. Blockade of PAQR11-dependent secretion inhibits immunosuppressive processes in the tumor microenvironment. Thus, Golgi reprogramming by p53 loss is a key driver of hypersecretion in cancer.

scholarly journals RNA interference of PFUS results in inhibition of secretory vesicle biogenesis

2008 ◽  
Vol 22 (S1) ◽  
Author(s):  
Birgit H. Satir ◽  
Li Liu
Keyword(s):  
Rna Interference ◽  
Secretory Vesicle ◽  
Vesicle Biogenesis

scholarly journals PI4KIIIβ is a therapeutic target in chromosome 1q–amplified lung adenocarcinoma

2020 ◽  
Vol 12 (527) ◽  
pp. eaax3772 ◽  
Author(s):  
Xiaochao Tan ◽  
Priyam Banerjee ◽  
Edward A. Pham ◽  
Florentine U. N. Rutaganira ◽  
Kaustabh Basu ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Cell Survival ◽  
Cancer Cell ◽  
Secretory Vesicle ◽  
Effector Proteins ◽  
Therapeutic Implications ◽  
Chromosome 1Q ◽  
Biological Studies ◽  
Cancer Cell Survival ◽  
Vesicle Biogenesis

Heightened secretion of protumorigenic effector proteins is a feature of malignant cells. Yet, the molecular underpinnings and therapeutic implications of this feature remain unclear. Here, we identify a chromosome 1q region that is frequently amplified in diverse cancer types and encodes multiple regulators of secretory vesicle biogenesis and trafficking, including the Golgi-dedicated enzyme phosphatidylinositol (PI)-4-kinase IIIβ (PI4KIIIβ). Molecular, biochemical, and cell biological studies show that PI4KIIIβ-derived PI-4-phosphate (PI4P) synthesis enhances secretion and accelerates lung adenocarcinoma progression by activating Golgi phosphoprotein 3 (GOLPH3)–dependent vesicular release from the Golgi. PI4KIIIβ-dependent secreted factors maintain 1q-amplified cancer cell survival and influence prometastatic processes in the tumor microenvironment. Disruption of this functional circuitry in 1q-amplified cancer cells with selective PI4KIIIβ antagonists induces apoptosis and suppresses tumor growth and metastasis. These results support a model in which chromosome 1q amplifications create a dependency on PI4KIIIβ-dependent secretion for cancer cell survival and tumor progression.

scholarly journals The small GTPases ARL-13 and ARL-3 coordinate intraflagellar transport and ciliogenesis

2010 ◽  
Vol 189 (6) ◽  
pp. 1039-1051 ◽  
Author(s):  
Yujie Li ◽  
Qing Wei ◽  
Yuxia Zhang ◽  
Kun Ling ◽  
Jinghua Hu
Keyword(s):  
Intraflagellar Transport ◽  
Adenosine Diphosphate ◽  
Joubert Syndrome ◽  
Small Gtpases ◽  
Small Gtpase ◽  
Causal Gene ◽  
Guanosine Triphosphatase ◽  
Bidirectional Movement ◽  
Dependent Pathway

Intraflagellar transport (IFT) machinery mediates the bidirectional movement of cargos that are required for the assembly and maintenance of cilia. However, little is known about how IFT is regulated in vivo. In this study, we show that the small guanosine triphosphatase (GTPase) adenosine diphosphate ribosylation factor–like protein 13 (ARL-13) encoded by the Caenorhabditis elegans homologue of the human Joubert syndrome causal gene ARL13B, localizes exclusively to the doublet segment of the cilium. arl-13 mutants have shortened cilia with various ultrastructural deformities and a disrupted association between IFT subcomplexes A and B. Intriguingly, depletion of ARL-3, another ciliary small GTPase, partially suppresses ciliogenesis defects in arl-13 mutants by indirectly restoring binding between IFT subcomplexes A and B. Rescue of arl-13 mutants by ARL-3 depletion is mediated by an HDAC6 deacetylase-dependent pathway. Thus, we propose that two conserved small GTPases, ARL-13 and ARL-3, coordinate to regulate IFT and that perturbing this balance results in cilia deformation.

Regulation and mechanisms of extracellular vesicle biogenesis and secretion

2018 ◽  
Vol 62 (2) ◽  
pp. 125-133 ◽  
Author(s):  
Crislyn D’Souza-Schorey ◽  
Jeffrey S. Schorey
Keyword(s):  
Tumor Microenvironment ◽  
Intercellular Communication ◽  
Membrane Vesicles ◽  
Cell Types ◽  
Extracellular Vesicle ◽  
Systemic Delivery ◽  
Heterogeneous Membrane ◽  
Vesicle Biogenesis ◽  
Infected Cells ◽  
Pathogenic Agents

EV (extracellular vesicle) biology is a rapidly expanding field. These heterogeneous membrane vesicles, which are shed from virtually all cell types, collectively represent a new dimension of intercellular communication in normal physiology and disease. They have been shown to deliver infectious and pathogenic agents to non-infected cells whereas in cancers they are thought to condition the tumor microenvironment. Their presence in body fluids and inherent capacity for systemic delivery point to their clinical promise. All of the above only intensifies the need to better understand the classification, mode of biogenesis, and contents of the different subtypes of EVs. This article focusses on vesicle subtypes labeled as exosomes and MVs (microvesicles) and discusses the biogenesis and release of these vesicles from cells.

Overexpression of FKBP51 in idiopathic myelofibrosis regulates the growth factor independence of megakaryocyte progenitors

Blood ◽  
2002 ◽  
Vol 100 (8) ◽  
pp. 2932-2940 ◽  
Author(s):  
Stéphane Giraudier ◽  
Hédia Chagraoui ◽  
Emiko Komura ◽  
Stéphane Barnache ◽  
Benoit Blanchet ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Idiopathic Myelofibrosis ◽  
Protein Levels ◽  
Cd34 Cells ◽  
Chronic Myeloproliferative Disorder ◽  
Display Technique ◽  
Dependent Pathway ◽  
Calcineurin Activity ◽  
Cytokine Deprivation ◽  
Pharmacologic Inhibition

Idiopathic myelofibrosis (IMF) is a chronic myeloproliferative disorder characterized by megakaryocyte hyperplasia and bone marrow fibrosis. Biologically, an autonomous megakaryocyte growth and differentiation is noticed, which contributes to the megakaryocyte accumulation. To better understand the molecular mechanisms involved in this spontaneous growth, we searched for genes differentially expressed between normal megakaryocytes requiring cytokines to grow and IMF spontaneously proliferating megakaryocytes. Using a differential display technique, we found that the immunophilin FKBP51 was 2 to 8 times overexpressed in megakaryocytes derived from patients' CD34+ cells in comparison to normal megakaryocytes. Overexpression was moderate and confirmed in 8 of 10 patients, both at the mRNA and protein levels. Overexpression of FKBP51 in a UT-7/Mpl cell line and in normal CD34+ cells induced a resistance to apoptosis mediated by cytokine deprivation with no effect on proliferation. FKBP51 interacts with both calcineurin and heat shock protein (HSP)70/HSP90. However, a mutant FKBP51 deleted in the HSP70/HSP90 binding site kept the antiapoptotic effect, suggesting that the calcineurin pathway was responsible for the FKBP51 effect. Overexpression of FKBP51 in UT-7/Mpl cells induced a marked inhibition of calcineurin activity. Pharmacologic inhibition of calcineurin by cyclosporin A mimicked the effect of FKBP51. The data support the conclusion that FKBP51 inhibits apoptosis through a calcineurin-dependent pathway. In conclusion, FKBP51 is overexpressed in IMF megakaryocytes and this overexpression could be, in part, responsible for the megakaryocytic accumulation observed in this disorder by regulating their apoptotic program.

scholarly journals PICK1 Deficiency Impairs Secretory Vesicle Biogenesis and Leads to Growth Retardation and Decreased Glucose Tolerance

PLoS Biology ◽  
2013 ◽  
Vol 11 (4) ◽  
pp. e1001542 ◽  
Author(s):  
Birgitte Holst ◽  
Kenneth L. Madsen ◽  
Anna M. Jansen ◽  
Chunyu Jin ◽  
Mattias Rickhag ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Growth Retardation ◽  
Secretory Vesicle ◽  
Vesicle Biogenesis

scholarly journals Inhibition of Poly(Adenosine Diphosphate–Ribose) Polymerase Attenuates Ventilator-induced Lung Injury

2008 ◽  
Vol 108 (2) ◽  
pp. 261-268 ◽  
Author(s):  
Rosanna Vaschetto ◽  
Jan W. Kuiper ◽  
Shyh Ren Chiang ◽  
Jack J. Haitsma ◽  
Jonathan W. Juco ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Lung Injury ◽  
Tidal Volume ◽  
Interleukin 6 ◽  
Inflammatory Responses ◽  
Adenosine Diphosphate ◽  
High Tidal Volume ◽  
Positive End Expiratory Pressure ◽  
Ventilator Induced Lung Injury ◽  
Pharmacologic Inhibition

Background Mechanical ventilation can induce organ injury associated with overwhelming inflammatory responses. Excessive activation of poly(adenosine diphosphate-ribose) polymerase enzyme after massive DNA damage may aggravate inflammatory responses. Therefore, the authors hypothesized that the pharmacologic inhibition of poly(adenosine diphosphate-ribose) polymerase by PJ-34 would attenuate ventilator-induced lung injury. Methods Anesthetized rats were subjected to intratracheal instillation of lipopolysaccharide at a dose of 6 mg/kg. The animals were then randomly assigned to receive mechanical ventilation at either low tidal volume (6 ml/kg) with 5 cm H2O positive end-expiratory pressure or high tidal volume (15 ml/kg) with zero positive end-expiratory pressure, in the presence and absence of intravenous administration of PJ-34. Results The high-tidal-volume ventilation resulted in an increase in poly(adenosine diphosphate-ribose) polymerase activity in the lung. The treatment with PJ-34 maintained a greater oxygenation and a lower airway plateau pressure than the vehicle control group. This was associated with a decreased level of interleukin 6, active plasminogen activator inhibitor 1 in the lung, attenuated leukocyte lung transmigration, and reduced pulmonary edema and apoptosis. The administration of PJ-34 also decreased the systemic levels of tumor necrosis factor alpha and interleukin 6, and attenuated the degree of apoptosis in the kidney. Conclusion The pharmacologic inhibition of poly(adenosine diphosphate-ribose) polymerase reduces ventilator-induced lung injury and protects kidney function.

scholarly journals Modeling the Tumor Microenvironment of Ovarian Cancer: The Application of Self-Assembling Biomaterials

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5745
Author(s):  
Ana Karen Mendoza-Martinez ◽  
Daniela Loessner ◽  
Alvaro Mata ◽  
Helena S. Azevedo
Keyword(s):  
Ovarian Cancer ◽  
Tumor Microenvironment ◽  
Materials Science ◽  
Treatment Options ◽  
Tumor Biology ◽  
3D Models ◽  
Gynecologic Malignancies ◽  
Cell Behaviors ◽  
Self Assembling ◽  
Key Driver

Ovarian cancer (OvCa) is one of the leading causes of gynecologic malignancies. Despite treatment with surgery and chemotherapy, OvCa disseminates and recurs frequently, reducing the survival rate for patients. There is an urgent need to develop more effective treatment options for women diagnosed with OvCa. The tumor microenvironment (TME) is a key driver of disease progression, metastasis and resistance to treatment. For this reason, 3D models have been designed to represent this specific niche and allow more realistic cell behaviors compared to conventional 2D approaches. In particular, self-assembling peptides represent a promising biomaterial platform to study tumor biology. They form nanofiber networks that resemble the architecture of the extracellular matrix and can be designed to display mechanical properties and biochemical motifs representative of the TME. In this review, we highlight the properties and benefits of emerging 3D platforms used to model the ovarian TME. We also outline the challenges associated with using these 3D systems and provide suggestions for future studies and developments. We conclude that our understanding of OvCa and advances in materials science will progress the engineering of novel 3D approaches, which will enable the development of more effective therapies.

scholarly journals The effect of pharmacologic inhibition of phospholipid methylation on human platelet function

Blood ◽  
1982 ◽  
Vol 59 (5) ◽  
pp. 906-912
Author(s):  
SJ Shattil ◽  
JA Montgomery ◽  
PK Chiang
Keyword(s):  
Platelet Activation ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Adenosine Diphosphate ◽  
Human Platelets ◽  
Serotonin Release ◽  
Platelet Phospholipid ◽  
Biochemical Effect ◽  
Methylation Pathway ◽  
Pharmacologic Inhibition

Human platelets are capable of synthesizing their major membrane phospholipid, phosphatidylcholine, by a methylation pathway. This involves the sequential transfer of methyl groups from S-adenosyl-L- methionine (AdoMet) to phosphatidylethanolamine, and in the process, AdoMet is converted to S-adenosylhomocysteine (AdoHcy). The activity of this methylation pathway is decreased upon stimulation of platelets by various agonists. We inhibited methylation reactions pharmacologically to see whether this inhibition plays any role in the process of platelet activation. Two inhibitors of AdoHcy hydrolase, 3-deaza- adenosine and 3-deaza-(+/-)aristeromycin (500 microM each), were effective in increasing platelets levels of AdoHcy and preventing turnover of AdoMet. Also, these compounds were equipotent in inhibiting platelet phospholipid methylation. However, while 3-deaza-adenosine potentiated platelet aggregation and 14C-serotonin release induced by epinephrine or adenosine diphosphate (ADP) (p less than 0.01), 3-deaza- aristeromycin had no such effect. Neither compound affected platelet responses to thrombin or collagen. Inhibition of methylation reactions was not the only biochemical effect of 3-deaza-adenosine since it also blunted significantly the elevation of platelet cyclic adenosine monophosphate (AMP) levels induced by prostaglandin E1 (p less than 0.02). Therefore, these studies demonstrate that inhibition of platelet phospholipid methylation, per se, has no discernable effect on the function of human platelets. The methylation pathway, though active in platelets, does not appear to be primarily involved in membrane events responsible for platelet activation.

scholarly journals Addiction to Golgi-resident PI4P synthesis in chromosome 1q21.3–amplified lung adenocarcinoma cells

2021 ◽  
Vol 118 (25) ◽  
pp. e2023537118
Author(s):  
Lei Shi ◽  
Xiaochao Tan ◽  
Xin Liu ◽  
Jiang Yu ◽  
Neus Bota-Rabassedas ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Cell Viability ◽  
Protein Secretion ◽  
Secretory Vesicle ◽  
Effector Protein ◽  
Alternative Source ◽  
Adenocarcinoma Cells ◽  
Vesicle Biogenesis ◽  
Competing Endogenous Rna Network ◽  
Cancer Types

A chromosome 1q21.3 region that is frequently amplified in diverse cancer types encodes phosphatidylinositol (PI)-4 kinase IIIβ (PI4KIIIβ), a key regulator of secretory vesicle biogenesis and trafficking. Chromosome 1q21.3–amplified lung adenocarcinoma (1q-LUAD) cells rely on PI4KIIIβ for Golgi-resident PI-4-phosphate (PI4P) synthesis, prosurvival effector protein secretion, and cell viability. Here, we show that 1q-LUAD cells subjected to prolonged PI4KIIIβ antagonist treatment acquire tolerance by activating an miR-218-5p–dependent competing endogenous RNA network that up-regulates PI4KIIα, which provides an alternative source of Golgi-resident PI4P that maintains prosurvival effector protein secretion and cell viability. These findings demonstrate an addiction to Golgi-resident PI4P synthesis in a genetically defined subset of cancers.

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