Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In an attempt to understand the mechanism by which estrogens stimulate cell proliferation and mammary carcinogenesis, metastatic human breast cancer cell lines (MCF7, ZR75-1) were found to secrete a 52,000 dalton (52K) protein under estrogen stimulation. Following its purification to homogeneity, the 52K protein was identified as a secreted procathepsin-D-like aspartyl protease bearing mannose-6-phosphate signals. This precursor displays an in vitro autocrine mitogenic activity on estrogen-deprived MCF7 cells and is able to degrade basement membrane and proteoglycans following its autoactivation. The total protease (52K + 48K and 34K) was detected and assayed by monoclonal antibodies and was found to be highly concentrated in proliferative and cystic mastopathies. In breast cancer, its cytosolic concentration appears to be correlated more to tumor invasiveness than to hormone responsiveness. The mRNA of the 52K protease accumulates rapidly following estradiol treatment, as was shown by Northern blot analysis with cloned cDNA. The 52K cathepsin-D-like protease is the first example of a lysosomal protease induced by estrogens in cancer cells. Results obtained using different approaches suggest that two cysteinyl cathepsins are also related to cell transformation and invasiveness. It has been proposed that cathepsin-B is involved in breast cancer and metastatic melanoma, and its regulation by estrogen has been shown in the rat uterus. Cathepsin-L corresponds to the major excreted protein (MEP) whose synthesis and secretion are markedly increased by transformation of NIH 3T3 cells with Ki ras and are regulated by several growth factors. In addition to secreted autocrine growth factors and to other proteases (plasminogen activator, collagenase), lysosomal cathepsins may therefore play an important role in the process of tumor growth and invasion as long as their precursor is secreted abundantly.
 ...
PMID:Estrogen-induced lysosomal proteases secreted by breast cancer cells: a role in carcinogenesis? 331 45

Plasminogen activator inhibitor-1 (PAI-1) is the most important inhibitor of tissue-type plasminogen activator (t-PA) in plasma and plays a major role in the regulation of fibrinolysis. Plasma t-PA/PAI-1 complexes are cleared via a receptor-dependent mechanism in hepatocytes, while the fate of complexes formed in the extracellular matrix and in thrombi is less well understood. In this study, the degradation of t-PA/PAI-1 complexes by monocytes was examined. THP-1 monocytoid cells and freshly isolated human monocytes internalize and degrade [125I]t-PA/PAI-1 complexes at rates of 11.4 +/- 5.9 (mean +/- S.D.) and 44.6 +/- 6.3 ng/10(6) cells/h, respectively. Degradation is blocked by receptor-associated protein (RAP), indicating a member of the low density lipoprotein (LDL) receptor family is involved in the uptake/degradation of t-PA/PAI-1 complexes by monocytes. Degradation of t-PA/PAI-1 complexes is also inhibited by chloroquine and by pepstatin A, suggesting that a lysosomal aspartyl protease is likely involved. SDS-PAGE and Western blotting demonstrated that the purified lysosomal aspartyl protease, cathepsin D, is capable of digesting t-PA (t1/2 15 min), active PAI-1 (t1/2 2 h), and t-PA/PAI-1 complex (t1/2 30 min). Cathepsin D sequentially cleaves PAI-1 after hydrophobic amino acids, yielding lower molecular weight fragments. PAI-1 conformation influences the degradative efficiency of cathepsin D, with vitronectin-bound PAI-1 and latent PAI-1 exhibiting resistance to proteolysis and > 10-fold prolongation in t1/2. These data provide evidence that t-PA/PAI-1 complexes are internalized by human monocytes via a member of the low density lipoprotein (LDL) receptor family, and identifies cathepsin D-like aspartyl protease activity as largely responsible for the degradation of these complexes. Furthermore, vitronectin-bound PAI-1 and latent PAI-1 are relatively resistant to degradation by cathepsin D, which may be of importance in complex physiological environments.
 ...
PMID:Cathepsin D-like aspartyl protease activity mediates the degradation of tissue-type plasminogen activator/plasminogen activator inhibitor-1 complexes in human monocytes. 766 1

Fibrin(ogen) is important for hemostasis and is cleared from sites of vascular injury primarily by the plasminogen activator system. However, there is emerging evidence in plasminogen activator-deficient transgenic mice that non-plasmin pathways may also be important for endogenous fibrinolysis. We have recently described an alternative, plasmin-independent fibrinolytic pathway in activated human monocytes that utilizes the integrin Mac-1 (CD11b/CD18), which directly binds and internalizes fibrin, resulting in its lysosomal degradation. The identity of the lysosomal fibrinolytic enzyme(s) responsible for monocyte/macrophage-mediated fibrinolytic is unknown. Protease inhibitor studies now suggest that an aspartyl protease is responsible for this fibrinolytic activity. We, therefore, examined the fibrinolytic properties of cathepsin D, a lysosomal aspartyl protease, and report that cathepsin D possesses both fibrinogenolytic and fibrinolytic activity. Cathepsin D cleavage of fibrinogen follows Michaelis-Menten kinetics with a Michaelis constant, Km, of 1.5 microM; catalytic rate constant, kcat, of 1.4 x 10(-3) s-1; and catalytic efficiency, kcat/Km, of 9.3 x 10(-4) microM-1 s-1. A pH-activity profile of fibrinogen digestion by cathepsin D demonstrates a pH optimum of 3.5 with 50% residual activity at pH 5.0. Fibrinolysis was assessed by fibrin plate and fibrin clot lysis assays. Cathepsin D possesses significant fibrinolytic activity over a dose range of 100 nM to 10 microM and is able to lyse fibrin, as well as albumin-enriched and albumin/red cell-enriched fibrin clots. Cathepsin D cleaves the alpha-, beta-, and gamma-chains of FGN, generating multiple low-molecular-weight fragments.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:The fibrin(ogen)olytic properties of cathepsin D. 820 91

The monocyte/macrophage plays a central role in fibrinolysis. Cell-surface of components of the plasminogen activator system leads to the elaboration of plasmin, which facilitates degradation of fibrin in the pericellular environment, as well as activation of matrixins, which promote degradation of matrix components. Fibrin degradation also occurs by way of a proteolytic system within the macrophage lysosome that does not involve plasmin. This alternate pathway involves first the binding of fibrin(ogen) to the surface integrin Mac-1 (CD11b/CD18) followed by internalization of the complex into the lysosome where the aspartyl protease cathepsin D degrades the protein. These molecular events underlie the many physiologic and pathophysiologic processes in which the monocyte/macrophage is involved, including adhesion, migration, matrix degradation and remodeling, wound healing, fibrinolysis, and atherosclerosis.
 ...
PMID:The macrophage and fibrinolysis. 912 15

Tumor cell invasion requires expression of degradative enzymes such as plasminogen activator, collagenase, and cathepsins. Cathepsin D, a lysosomal aspartic protease produced constitutively in human breast cancer cell lines, also has mitogenic activity in breast cancer cells. Additionally, high cathepsin D expression is associated with increased risk of metastasis in patients with node-negative breast cancer. Recently, a novel aspartic protease gene, ALP56 (aspartic-like protease 56kDa), has been identified. To examine possible interrelationships we quantitated ALP56 mRNA and cathepsin D mRNA in breast cancers using reverse transcription polymerase chain reaction. ALP56 mRNA expression was greater in cancers than in noncancerous tissues (p < 0.0001), as was expression of cathepsin D mRNA. ALP56 gene expression was dose-dependently down-regulated in T-47D breast cancer cells treated with estradiol, while cathepsin D was up-regulated. Expression of ALP56 mRNA in estrogen receptor (ER)-positive breast cancers was less than that in ER-negative cancers, and mRNA expression for ALP56 and cathepsin D did not correlate with one another. Thus ALP56 as well as cathepsin D may be a useful target molecule in breast cancer treatment.
 ...
PMID:A novel aspartic protease gene, ALP56, is up-regulated in human breast cancer independently from the cathepsin D gene. 1261 55

Two proteases cathepsin D (cath D) and urokinase plasminogen activator (uPA) are tissue markers associated with an increased risk of metastasis in breast cancer. We investigated whether cath D, the major aspartyl protease overexpressed by breast cancer cells can trigger a proteolytic cascade via activation of plasminogens at the extracellular pH measured in hypoxic tumors. The effects of the aspartyl protease inhibitor pepstatin on the plasminogen activator (PA) system were analysed by conditioning media of human MDA-MB231 breast cancer cells at pH 6.6 and pH 7.4. Zymography analysis of culture media showed that pepstatin inhibited the secreted activity of tissue-type plasminogen activator (tPA) but not that of uPA. tPA was identified on the basis of the molecular weight, the immunoreactivity with relevant antibodies and the resistance to amiloride, a specific uPA inhibitor. The secreted tPA activity measured by a chromogenic assay in the presence of amiloride was also inhibited by pepstatin at pH 6.6. Surprisingly, pepstatin did not affect secreted tPA protein concentration but markedly increased the amount of the secreted plasminogen activator inhibitor-1 (PAI-1). We conclude that cath D overexpressed by these cells, stimulates at pH 6.6, but not at neutral pH, the extracellular PA proteolytic activity indirectly via PAI-1 proteolysis. This suggests that cath D at acidic pH close to the hypoxic regions of solid tumors, contributes to trigger a proteolytic cascade facilitating cancer cell invasion and metastasis.
 ...
PMID:Cathepsin D stimulates the activities of secreted plasminogen activators in the breast cancer acidic environment. 2402 24