Plasminogen activators are serine proteases that have been implicated in a wide variety of normal and abnormal processes. The experiments proposed address two broad questions concerning these enzymes: how is the synthesis of tissue plasminogen activator (tPA) controlled, and what are the respective roles for tPA and the urokinase-type plasminogen activator (uPA). Regulation of tPA synthesis will be studied in F9 teratocarcinoma cells, in which enzyme production can be conveniently controlled by manipulation of the culture conditions. The fact that tPA can feedback inhibit its own synthesis will also be examined in these cells by classical techniques and oligonucleotide-mediated mutagenesis followed by transfection and expression of specifically modified enzymes. The tumorigenic properties of F9 cells producing these modified tPAs will also be determined. In the rat ovary, granulosa cells produce tPA and thecal cells produce uPA. With both cells, enzyme synthesis is maximal at the time of ovulation and is induced by gonadotropins. This system will be used in vivo and in vitro to investigate the function of the two enzymes in the ovulatory process. The possibility that tPA is instrumental in degrading follicular proteoglycans, and that proteoglycans can stimulate the activity of tPA, will be examined.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD017875-06
Application #
3314894
Study Section
Molecular Cytology Study Section (CTY)
Project Start
1983-01-01
Project End
1990-12-31
Budget Start
1989-01-01
Budget End
1989-12-31
Support Year
6
Fiscal Year
1989
Total Cost
Indirect Cost
Name
State University New York Stony Brook
Department
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Wells, J M; Strickland, S (1997) Regulated localization confers multiple functions on the protease urokinase plasminogen activator. J Cell Physiol 171:217-25
Carroll, P M; Tsirka, S E; Richards, W G et al. (1994) The mouse tissue plasminogen activator gene 5' flanking region directs appropriate expression in development and a seizure-enhanced response in the CNS. Development 120:3173-83
Wells, J M; Strickland, S (1994) Aprotinin, a Kunitz-type protease inhibitor, stimulates skeletal muscle differentiation. Development 120:3639-47
Carroll, P M; Richards, W G; Darrow, A L et al. (1993) Preimplantation mouse embryos express a cell surface receptor for tissue-plasminogen activator. Development 119:191-8
Andrade-Gordon, P; Wang, S Y; Strickland, S (1992) Heparin-like activity in porcine follicular fluid and rat granulosa cells. Thromb Res 66:475-87
Huarte, J; Stutz, A; O'Connell, M L et al. (1992) Transient translational silencing by reversible mRNA deadenylation. Cell 69:1021-30
Salles, F J; Darrow, A L; O'Connell, M L et al. (1992) Isolation of novel murine maternal mRNAs regulated by cytoplasmic polyadenylation. Genes Dev 6:1202-12
Salles, F J; Schechter, N; Strickland, S (1990) A plasminogen activator is induced during goldfish optic nerve regeneration. EMBO J 9:2471-7
Andrade-Gordon, P; Strickland, S (1990) Fractionation of heparin by chromatography on a tissue plasminogen activator-Sepharose column. Proc Natl Acad Sci U S A 87:1865-9
Vassalli, J D; Huarte, J; Belin, D et al. (1989) Regulated polyadenylation controls mRNA translation during meiotic maturation of mouse oocytes. Genes Dev 3:2163-71

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