Apmis

Rygaard, Jørgen

doi: 10.1111/j.1699-0463.1999.tb01519.xpmid: N/A

BODE, WOLFRAM; FERNANDEZ‐CATALAN, CARLOS; NAGASE, HIDEAKI; MASKOS, KLAUS

doi: 10.1111/j.1699-0463.1999.tb01520.xpmid: 10190274

Nature uses protein inhibitors as important tools to regulate the proteolytic activity of their target proteinases. Most of these inhibitors for which 3D structures are available are directed towards serine proteinases, interacting with their active‐sites in a substrate‐like “canonical” manner via an exposed reactive‐site loop of conserved conformation. More recently, some non‐canonically binding serine proteinase inhibitors, two cysteine proteinase inhibitors, and three zinc endopeptidase inhibitors have been characterized in the free and complexed state, displaying novel mechanisms of inhibition with their target proteinases. These different interaction modes are briefly discussed, with particular emphasis on the interaction between matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors of metalloproteinases (TIMPs).

WERB, ZENA; VU, THIENNU H.; RINKENBERGER, JULIE L.; COUSSENS, LISA M.

doi: 10.1111/j.1699-0463.1999.tb01521.xpmid: 10190275

Embryonic development and tumor progression both require the exquisite coordination of programs for extracellular matrix (ECM) formation and remodeling, and those for angiogenesis and vascular development. Without a vascular supply the normal tissue or tumor is limited in size and organization. Without ECM remodeling the alteration of tissue and tumor boundaries and cellular migrations are limited. Recent insights into the molecular mechanisms regulating the extracellular environment of the growing embryonic tissue or tumors have implicated proteases, the matrix metalloproteinases (MMPs) in particular, in both the process of ECM remodeling and angiogenesis, and in a potential causal relationship between these processes. This review focuses on the roles that MMPs play in regulating three processes in which both proteolysis and vascular development are tightly coordinated: embryo implantation, bone development and tumor progression.

MATTERS, GAIL L.; BOND, JUDITH S.

doi: 10.1111/j.1699-0463.1999.tb01522.xpmid: 10190276

A novel mRNA isoform encoding the cell surface metalloproteinase meprin β is expressed in mouse teratocarcinoma cells and in a variety of cultured human cancer cells. In both mouse and human cells, the cancer cell‐specific mRNA isoform, referred to as β', has an extended 5′ UTR as compared to the meprin β mRNA isoform expressed in normal kidney and intestinal epithelium. The work herein aimed to determine the molecular mechanisms for the expression of meprin β and β' in normal and cancer cells, respectively. Analysis of the 5′ end of the mouse meprin β gene revealed that the unique sequences in the β and β' mRNA isoforms are encoded by separate exons that are alternately spliced, and transcribed from independent promoters. By contrast, the human meprin β and β' mRNAs have identical sequences except for 87 additional bases in the 5′ UTR sequence of β', indicating that a single, mixed usage promoter directs expression of the isoforms. The region upstream of the human meprin β' transcription start site contained elements with homology to the promoters of intestine‐specific genes, interspersed with AP‐1 and PEA3 elements; the latter were essential to meprin β' promoter activity in cancer cells. Phorbol myristal acetate increased meprin β' mRNA levels in cultured human colon cancer cells, providing further evidence that AP‐1/PEA3 sites are actively involved in meprin β' expression.

FROSCH, BARBARA A.; BERQUIN, ISABELLE; EMMERT‐BUCK, MICHAEL R.; MOIN, KAMIAR; SLOANE, BONNIE F.

doi: 10.1111/j.1699-0463.1999.tb01523.xpmid: 10190277

Upregulation, membrane association and secretion of cathepsin B have been shown to occur in many types of tumors and to correlate positively with their invasive and metastatic capabilities. To further understand changes in cathepsin B activity and localization, we have been examining its regulation at many levels including transcription and trafficking. Our studies indicate that there may be three promoter regions in the cathepsin B gene. Of these, continued examination of the promoter upstream of exon I has indicated possible control by several regulatory factors including E‐box and Sp‐1 binding elements. Upregulation of cathepsin B at this level may account for some of the secretion of cathepsin B found in tumors. We have also gathered evidence that endo‐and exocytosis of cathepsin B may be regulated by ras and ras‐related proteins in addition to previously described trafficking systems. There is also evidence that several populations of lysosomes may exist and that trafficking to different populations may determine whether cathepsin B is secreted from the tumor cell or remains intracellular. Our results indicate that membrane association and secretion of cathepsin B is not a random process in the tumor cell, but rather part of a tightly controlled system.

MURPHY, GILLIAN; STANTON, HEATHER; COWELL, SUSAN; BUTLER, GEORGINA; KNÄUPER, VERA; ATKINSON, SUSAN; GAVRILOVIC, JELENA

doi: 10.1111/j.1699-0463.1999.tb01524.xpmid: 10190278

The activation of pro matrix metalloproteinases (MMPs) by sequential proteolysis of the propeptide blocking the active site cleft is regarded as one of the key levels of regulation of these proteinases. Potential physiological mechanisms including cell‐associated plasmin generation by urokinase‐like plasminogen activator, or the action of cell surface MT1‐MMPs appear to be involved in the initiation of cascades of pro MMP activation. Gelatinase A, collagenase 3 and gelatinase B may be activated by MT‐MMP based mechanisms, as evidenced by both biochemical and cell based studies. Hence the regulation of MT‐MMPs themselves becomes critical to the determination of MMP activity. This includes activation, assembly at the cell surfaces as TIMP‐2 complexes and subsequent inactivation by proteolysis or TIMP inhibition.

BALBÍN, MILAGROS; PENDÁS, ALBERTO M.; URÍA, JOSÉ A.; JIMÉNEZ, MARIA G.; FREIJE, JOSÉ P.; LÓPEZ‐OTÍN, CARLOS

doi: 10.1111/j.1699-0463.1999.tb01525.xpmid: 10190279

Human collagenase‐3 (MMP‐13) is a matrix metalloproteinase originally identified in breast carcinomas. Recent studies have revealed that this enzyme is also produced by a variety of malignant tumors including head and neck carcinomas, chondrosarcomas and basal cell carcinomas of the skin. In all cases, the expression of collagenase‐3 is associated with aggressive tumors. Different cytokines, growth factors and tumor promoters are able to up‐regulate collagenase‐3 expression in tumor cells or in stromal cells surrounding epithelial tumor cells. Functional analysis of the collagenase‐3 gene promoter has allowed the identification of AP‐1 and OSE‐2 elements mediating, at least in part, its expression in both normal and pathological conditions.

LOSKUTOFF, DAVID J.; CURRIDEN, SCOTT A.; HU, GENG; DENG, GANG

doi: 10.1111/j.1699-0463.1999.tb01526.xpmid: 10190280

Type I plasminogen activator inhibitor (PAI‐1) is the primary inhibitor of tissue‐and urokinase‐type plasminogen activators. It circulates in plasma complexed with vitronectin (VN), the primary PAI‐1 binding protein. The somatomedin B (SMB) domain of VN contains both the high affinity PAI‐1 binding site and the specific site for urokinase plasminogen activator receptor (uPAR). PAI‐1 is able to regulate uPAR‐mediated cell adhesion by competing with uPAR for VN binding. Binding of PAI‐1 to SMD may also affect integrin‐mediated cell adhesion to VN by hindering integrin binding to the RGD sequence adjacent to the uPAR binding site.

MINGERS, ANNE‐MARIE; PHILAPITSCH, ANTON; ZEITLER, PETRA; SCHUSTER, VOLKER; SCHWARZ, HANS PETER; KRETH, HANS WOLFGANG

doi: 10.1111/j.1699-0463.1999.tb01527.xpmid: 10190281

On the basis of a questionnaire sent to the ophthalmology departments of hospitals throughout Germany, 10 patients with ligneous conjunctivitis or pseudomembranous disease, ranging in age from 1 to 71 years were identified. All 10 patients had severely reduced plasminogen levels. Genetic analysis revealed homozygous type I plasminogen deficiency (which had not previously been described in humans) in 7 patients and compound heterozygous plasminogen deficiency in 1 patient. Clear differentiation was not possible in 2 patients. Most of the parents had heterozygous plasminogen deficiency. None of the patients had experienced any episodes of thrombosis. Additionally, the following observations were made: 1) Levels of polymorphonuclear (PMN)‐elastase protein were markedly elevated in 6 of 6 patients and 10 of 11 parents tested, and levels were higher in homozygotes than in heterozygotes. 2) Hereditary factor XII deficiency was found in 3 of 6 patients tested. 3) Cl‐inhibitor was elevated in 2 of 4 patients, prekallikrein was elevated in 1 of 4 patients, and plasminogen activator inhibitor type 1 was elevated in 1 of 4 patients. Infusions of lys‐plasminogen concentrate induced pronounced fibrinolytic activity as indicated by high levels of D‐dimer, increases in plasmin‐antiplasmin complex and decreases in polymorphonuclear elastase. Cl‐inhibitor, prekallikrein and PAI‐1 normalized after repeated infusions of lys‐plasminogen. In contrast to dysplasminogenemia, severe type I plasminogen deficiency might be seen as a problem of extravascular space, in particular of the mucous membranes, possibly triggered by mechanically induced or inflammatory lesions of the vessels supplying the tissue.

SALVESEN, GUY S.

doi: 10.1111/j.1699-0463.1999.tb01528.xpmid: 10190282

Members of a family of cysteine proteases known as caspases orchestrate the intracellular biochemical events that enable animal cells to kill themselves by apoptosis. To counteract the apoptotic response to infection, some viruses have adapted and evolved proteins that specifically block caspases. More recently, it has been demonstrated that endogenous proteins belonging to the IAP family can regulate apoptosis by directly inactivating some of the caspases involved in initiating and executing programmed cell death.