関: u-PA、urokinase、urokinase-type plasminogen activator

WordNet

of or relating to the urinary system of the body
of or relating to the function or production or secretion of urine
(biology) any agency bringing about activation; a molecule that increases the activity of an enzyme or a protein that increases the production of a gene product in DNA transcription
an inactive form of plasmin that occurs in plasma and is converted to plasmin by organic solvents

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/05/18 19:58:02」(JST)

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Urokinase (trade name Abbokinase), also called urokinase-type plasminogen activator (uPA), is a serine protease (EC 3.4.21.73). It was discovered in 1947 by McFarlane.^[1] Urokinase was originally isolated from human urine, but is present in several physiological locations, such as blood stream and the extracellular matrix. The primary physiological substrate is plasminogen, which is an inactive form (zymogen) of the serine protease plasmin. Activation of plasmin triggers a proteolysis cascade that, depending on the physiological environment, participates in thrombolysis or extracellular matrix degradation. This links urokinase to vascular diseases and cancer.

Molecular characteristics

Urokinase is a 411-residue protein, consisting of three domains: the serine protease domain, the kringle domain, and the growth factor domain. Urokinase is synthesized as a zymogen form (prourokinase or single-chain urokinase), and is activated by proteolytic cleavage between Lys158 and Ile159. The two resulting chains are kept together by a disulfide bond.

Interaction partners

The most important inhibitors of urokinase are the serpins plasminogen activator inhibitor-1 (PAI-1) and plasminogen activator inhibitor-2 (PAI-2), which inhibit the protease activity irreversibly. In the extracellular matrix, urokinase is tethered to the cell membrane by its interaction to the urokinase receptor.

Fibrinolysis (simplified). Blue arrows denote stimulation, and red arrows inhibition.

The molecular weight of (high molecular weight) urokinase is about 54000 Daltons. Only the Abbokinase = low molecular weight urokinase has a molecular weight of about 31000 Daltons.

Urokinase and cancer

Elevated expression levels of urokinase and several other components of the plasminogen activation system are found to be correlated with tumor malignancy. It is believed that the tissue degradation following plasminogen activation facilitates tissue invasion and, thus, contributes to metastasis. This makes urokinase an attractive drug target, and, so, inhibitors have been sought to be used as anticancer agents.^[2]^[3] However, incompatibilities between the human and murine systems hamper clinical evaluation of these agents. Through its interaction with the urokinase receptor, urokinase affects several other aspects of cancer biology such as cells adhesion, migration, and cellular mitotic pathways.

As of December 7, 2012 Mesupron®, a small molecule serine protease inhibitor developed by the WILEX pharmaceutical company, has completed phase II trials.^[4] Mesupron appears to be safe when combined with chemotherapeutic drug Capecitabine for the progression-free survival in human breast cancer.^[5]

Clinical applications

Urokinase is used clinically as a thrombolytic agent in the treatment of severe or massive deep venous thrombosis, pulmonary embolism, myocardial infarction, and occluded intravenous or dialysis cannulas. It is also administered intrapleurally to improve the drainage of complicated pleural effusions and empyemas. Urokinase is marketed as Kinlytic^TM, and competes with Alteplase^TM as a thrombolytic drug in infarction. It is the most effective drug in myocardial infarction.^{[citation needed]} In contrast to TPA tissue plasminogen activator, it immediately removes the clot. Its injection is very costly.^[vague]

References

^ Nursing grand rounds pdfs.journals.lww.com/.../Nursing_grand_rounds.8.pdf J Vitello-Cicciu - 1987
^ Jankun J, Skrzypczak-Jankun E (July 1999). "Molecular basis of specific inhibition of urokinase plasminogen activator by amiloride". Cancer Biochem. Biophys. 17 (1-2): 109–23. PMID 10738907.
^ Matthews H, Ranson M, Kelso MJ (November 2011). "Anti-tumour/metastasis effects of the potassium-sparing diuretic amiloride: an orally active anti-cancer drug waiting for its call-of-duty?". Int. J. Cancer 129 (9): 2051–61. doi:10.1002/ijc.26156. PMID 21544803.
^ "Gemcitabine With or Without WX-671 in Treating Patients With Locally Advanced Pancreatic Cancer That Cannot Be Removed By Surgery". ClinicalTrials.gov.
^ "Fox Chase Cancer Center : New Small Molecule Inhibitor Could be a Safe and First-Line Treatment for Metastatic Breast Cancer". Press Release. Temple University Health System.

UpToDate Contents

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1. 止血の概要 overview of hemostasis
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4. 小児における志賀毒素産生性大腸菌（STEC）溶血性尿毒症症候群（HUS）の治療および予後 treatment and prognosis of shiga toxin producing escherichia coli stec hemolytic uremic syndrome hus in children
5. 2型糖尿病の病因 pathogenesis of type 2 diabetes mellitus

English Journal

Cyclopeptide RA-V inhibits cell adhesion and invasion in both estrogen receptor positive and negative breast cancer cells via PI3K/AKT and NF-κB signaling pathways.

Leung HW1, Wang Z2, Yue GG1, Zhao SM2, Lee JK1, Fung KP3, Leung PC1, Lau CB4, Tan NH5.
Biochimica et biophysica acta.Biochim Biophys Acta.2015 Aug;1850(8):1827-40. doi: 10.1016/j.bbamcr.2015.04.020. Epub 2015 May 4.
Cyclopeptide RA-V has potent anti-tumor and anti-angiogenic activities, but its potential anti-metastatic activity is unknown. Cancer cells acquire invasive ability to degrade and adhere to extracellular matrix (ECM), allowing them to migrate to adjacent tissues and ultimately metastasize. Hence, th
PMID 25953046

Extracellular ATP induces the rapid release of HIV-1 from virus containing compartments of human macrophages.

Graziano F1, Desdouits M2, Garzetti L3, Podini P3, Alfano M4, Rubartelli A5, Furlan R3, Benaroch P2, Poli G6.
Proceedings of the National Academy of Sciences of the United States of America.Proc Natl Acad Sci U S A.2015 Jun 23;112(25):E3265-73. doi: 10.1073/pnas.1500656112. Epub 2015 Jun 8.
HIV type 1 (HIV-1) infects CD4(+) T lymphocytes and tissue macrophages. Infected macrophages differ from T cells in terms of decreased to absent cytopathicity and for active accumulation of new progeny HIV-1 virions in virus-containing compartments (VCC). For these reasons, infected macrophages are
PMID 26056317

Urokinase receptor and CXCR4 are regulated by common microRNAs in leukaemia cells.

Alfano D1, Gorrasi A1, Li Santi A1, Ricci P2, Montuori N3, Selleri C4, Ragno P1.
Journal of cellular and molecular medicine.J Cell Mol Med.2015 Jun 16. doi: 10.1111/jcmm.12617. [Epub ahead of print]
The urokinase-type plasminogen activator (uPA) receptor (uPAR) focuses uPA proteolytic activity on the cell membrane, promoting localized degradation of extracellular matrix (ECM), and binds vitronectin (VN), mediating cell adhesion to the ECM. uPAR-bound uPA and VN induce proteolysis-independent in
PMID 26082201

Japanese Journal

Relationships of Systemic Oxidative Stress to Body Fat Distribution, Adipokines and Inflammatory Markers in Healthy Middle-aged Women

WU Bin,FUKUO Keisuke,SUZUKI Kazuhisa,YOSHINO Gen,KAZUMI Tsutomu
Endocrine Journal 56(6), 773-782, 2009
… Systemic oxidative stress was assessed by urinary creatinine-indexed 8-epi-prostaglandin F-<SUB>2α</SUB> … Lipid profile, adipokines and inflammatory markers including leptin, adiponectin, high sensitive C-reactive protein (hsCRP), plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor-α (TNF-α) were determined. …
NAID 130004443529

Morning Blood Pressure Predicts Hypertensive Organ Damage in Patients with Renal Diseases : Effect of Intensive Antihypertensive Therapy in Patients with Diabetic Nephropathy

Kuriyama Satoru,Otsuka Yasushi,Iida Rinako [他],MATSUMOTO Kei,TOKUDOME Goro,HOSOYA Tatsuo
Internal medicine 44(12), 1239-1246, 2005-12-01
… when evaluated on systolic OBP, both groups were comparable.3)Logistic regression analysis showed that the predictive variables to explain morning hypertension (more than 130 mmHg and increased systolic HBP) were age, amount of daily urinary protein excretion and left ventricular mass index (LVMI).4)Following conventional therapy, intensive antihypertensive therapy consisting of calcium channel blockers (CCB) and/or diuretics given in the morning, and angiotensin receptor blockers (ARB) given in the evening, together with α1-blockers given at …
NAID 10016917411

Identification of the Substrates for Plasma Hyaluronan Binding Protein

Choi-Miura Nam-Ho,Yoda Madoka,Saito Kiyomi [他],TAKAHASHI Katsuhiko,TOMITA Motowo
Biological & pharmaceutical bulletin 24(2), 140-143, 2001-02-01
… Plasma hyaluronan biding protein (PHBP) is a novel serine protease, which has an amino acid sequence homology to that of hepatocyte growth factor activator (HGFA), and has a similar domain structure to that of urinary plasminogen activator (u-PA), found in human plasma. …
NAID 110003638448

Related Pictures

★リンクテーブル★

リンク元	「ウロキナーゼ」「u-PA」「urokinase-type plasminogen activator」「尿プラスミノーゲン活性化酵素」
関連記事	「activator」「urinary」「plasminogen activator」

「ウロキナーゼ」

plasminogen activator, urokinase
Identifiers
Symbol	PLAU
Entrez	5328
HUGO	9052
OMIM	191840
RefSeq	NM_002658
UniProt	P00749
Other data
EC number	3.4.21.31
Locus	Chr. 10 q24

Urokinase
Clinical data
AHFS/Drugs.com	monograph
Identifiers
CAS Registry Number	9039-53-6
ATC code	B01AD04
DrugBank	DB00013
UNII	83G67E21XI
KEGG	D03341
ChEMBL	CHEMBL1201420
Chemical data
Formula	C1376H2145N383O406S18
Molecular mass	31126.5 g/mol
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