Analysis of the human tissue-type plasminogen activator gene promoter activity during embryogenesis of transgenic mice and rats

Theuring, Franz; Aguzzi, Adriano; Kropp, C.; Wohn, Karl-Dieter; Hoffmann, Sigrid; Schleuning, W D

doi:10.1016/s0268-9499(95)80016-6

Cited by 12 publications

(17 citation statements)

References 56 publications

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“…Evaluation of 3 kb of upstream human t-PA gene sequence led to an expression pattern in transgenic mice of a linked reporter gene which did not fully resemble the pattern of endogenous t-PA-related antigen and mRNA expression (47). The presence of a far upstream enhancer in the human t-PA gene which is inducible by steroid hormones (except estrogen) and by RA is therefore proposed to be important for the expression of the t-PA gene in vivo.…”

Section: Discussionmentioning

confidence: 99%

Identification of a Multihormone Responsive Enhancer Far Upstream from the Human Tissue-type Plasminogen Activator Gene

Bulens

Merchiers²,

Ibañez–Tallon³

et al. 1997

Journal of Biological Chemistry

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A 2.4-kilobase (kb) DNA fragment, located 7.1 kb upstream from the human tissue-type plasminogen activator (t-PA) gene (t-PA2.4), acts as an enhancer which is activated by glucocorticoids, progesterone, androgens, and mineralocorticoids. Transient expression of t-PAchloramphenicol acetyltransferase reporter constructs in HT1080 human fibrosarcoma cells identified a glucocorticoid responsive unit with four functional binding sites for the glucocorticoid receptor, located between bp ؊7,501 and ؊7,974. The region from bp ؊7,145 to ؊9,578 (t-PA2.4) was found to confer a cooperative induction by dexamethasone and all-trans-retinoic acid (RA) to its homologous and a heterologous promoter, irrespective of its orientation. The minimal enhancer, defined by progressive deletion analysis, comprised the region from ؊7.1 to ؊8.0 kb (t-PA0.9) and encompassed the glucocorticoid responsive unit and the previously identified RA-responsive element located at ؊7. Vascular patency is the result of a dynamic equilibrium between blood coagulation and fibrinolysis. Injury of the vessel wall can initiate the blood clotting cascade resulting in the formation of a hemostatic clot. To counterbalance fibrin deposition, blood contains the fibrinolytic system, one main function of which is to dissolve blood clots in the circulation. It is composed of the inactive precursor plasminogen, which can be converted into the proteolytic enzyme plasmin by the plasminogen activators (PAs) 1 tissue-type and urokinase-type PA (t-PA and u-PA, respectively) leading to the degradation of fibrin. Fibrinolytic activity can be inhibited both at the level of the PAs and plasmin by PA inhibitors (PAI-1 and -2) and ␣ 2 -antiplasmin, respectively (for a review, see ref. 1). Phenotypic analysis of mice deficient for either t-PA, u-PA, or both suggested that t-PA and u-PA were complementary, not only in the prevention of uncontrolled fibrin deposition in vivo but also in distinct processes which require local extracellular proteolytic activity, such as wound healing and gonadotropin-induced ovulation, as reviewed elsewhere (2).Dexamethasone, a synthetic glucocorticoid, and androgens increase t-PA synthesis in vitro (3-5) and in vivo (6, 7). The level of t-PA expression in breast carcinoma cells correlates with the endogenous level of progesterone receptor (8), and progesterone induces t-PA-related antigen secretion in primary human endometrial cells (9). Vitamin A, retinoic acid (RA), and some of its (synthetic) analogues induce t-PA-related antigen secretion by human umbilical vein endothelial cells in vitro (10 -12) and in the plasma as well as in specific tissues of vitamin A-deficient rats in vivo (11,13,14), suggesting that circulating RA might regulate t-PA expression in the vessel wall. The induction of t-PA expression by glucocorticoids and RA can be reproduced in HT1080 human fibrosarcoma cells, and interestingly, both agents induce t-PA mRNA steady state levels and t-PA-related antigen secretion in a cooperative manner.2 Both steroid hormones and RA are t...

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Section: Discussionmentioning

confidence: 99%

Identification of a Multihormone Responsive Enhancer Far Upstream from the Human Tissue-type Plasminogen Activator Gene

Bulens

Merchiers²,

Ibañez–Tallon³

et al. 1997

Journal of Biological Chemistry

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“…Most of these functionsare independent of plasminogen(6), indicating the existenceo fa na s-yet-unidentifieds ubstrate for tPAi nt he CNS.Ithas become clear thattPA is important in both the developinga nd mature CNS.S tudiesa ddressing the transcriptional regulation of the tPAgene have describedcrucial regulatoryelementswithin the proximalregion and also at farupstreamlocations,therebyhighlighting the complex natureofthe tPApromoter. Transgenic miceexpressing 1.4 kb of the human tPApromoterfused to the LacZ reporter gene directedwidespread expression to the CNS during embryonic development (92). Transgenic mice bearing 1.4, 3.0 and 9.5 kb of the human tPAp romoterw ere used to studye xpression patterns directedb yt he human tPAp romoter in the adult CNS.…”

Section: Regulation Of Gene Transcriptionmentioning

confidence: 99%

Transcriptional and posttranscriptional regulation of the plasminogen activator system

Nagamine¹,

Medcalf²,

Muñoz‐Cánoves³

2005

Thromb Haemost

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SummaryThecoreprotein components of the plasminogenactivator (PA) system aret wo plasminogen activators, twop lasminogen activator inhibitorsand aurokinasetype plasminogenactivator-specific cell surfacer eceptor.Varioustypesofbiologicalr egulation areexerted through the interplayofthese components mutually and with extracellular matrix proteins and cell membrane proteins, with or without involving proteolytic activity.Reflecting these diverse biologicalroles, thelevel and activityofeach componento ft he PA system is under the control of av ariety of Keywords Review, plasminogen activator,generegulation,mRNA stability regulatorym echanisms. Thee xpression levelo fap rotein reflects the levelofthe corresponding mRNA, which is essentially the netresult of de novo synthesis,i.e.transcription, and degradation. Manyr ecents tudiesh aves hown thatt he regulation of mRNA stabilityisdynamic and cell specific.Accordingly, we are learning that the mRNAsofthe PA system arealsothe subject of diverse regulatorymechanisms. In this shortreview, we summarize current understanding of the transcriptionaland mRNAstabilityregulationofthe PA system.

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“…Following alkaline phosphatase treatment, the 4.0 kb fragment was inserted into the EcoRV site of the pBJ41 plasmid, resulting in the plasmid pBJ41BLGHERc (Archibald et al, 1990;Barash et al, 1994;McClenaghan et al, 1995;Yull et al, 1996). All expression constructs were prepared from plasmid DNA as described previously (Theuring et al, 1995).…”

Section: Dna Constructionmentioning

confidence: 99%

“…Outbred NMRI mice were used for microinjection. Transgenic mice were generated and identi®ed by previously described methods (Theuring et al, 1995).…”

Section: Generation and Identification Of Transgenic Micementioning

confidence: 99%

Mammary gland specific hEGF receptor transgene expression induces neoplasia and inhibits differentiation

et al. 2000

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Analysis of the human tissue-type plasminogen activator gene promoter activity during embryogenesis of transgenic mice and rats

Cited by 12 publications

References 56 publications

Identification of a Multihormone Responsive Enhancer Far Upstream from the Human Tissue-type Plasminogen Activator Gene

Identification of a Multihormone Responsive Enhancer Far Upstream from the Human Tissue-type Plasminogen Activator Gene

Transcriptional and posttranscriptional regulation of the plasminogen activator system

Mammary gland specific hEGF receptor transgene expression induces neoplasia and inhibits differentiation

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