The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation.

Publisher Summary This chapter discusses the role of plasminogen activators in various biological processes. In specific, it describes two types of plasminogen activators—namely, the urokinase-type plasminogen activator (u-PA) and the tissue-type plasminogen activator (t-PA), which are essentially different gene products. The amino acid sequences of these activators and nucleotide sequences of the corresponding cDNAs have largely been determined, and the cDNAs have been cloned using recombinant techniques. A variety of enzymatic as well as immunological assay and detection methods have also been developed that allows a precise quantification of the activators, a distinction between u-PA and t-PA, determination of whether an activator is present in its active or zymogen form, analysis of the kinetics of different steps of the cascade reaction, and immunocytochemical identification of u-PA and t-PA in tissue sections. Much of the studies on plasminogen activators and cancer has been guided by the hypothesis that proteolysis of the components of extracellular matrix, initiated by the release of plasminogen activator from the cancer cells, plays a decisive role for the degradation of normal tissue, and thereby for invasive growth and metastases.

Plasminogen activators, tissue degradation, and cancer.

https://www.cell.com/cell/pdf/0092-8674(90)90395-U.pdf

Antitumor promotion and antiinflammation: Down-modulation of AP-1 (Fos/Jun) activity by glucocorticoid hormone

Quinones represent a class of toxicological intermediates which can create a variety of hazardous effects in vivo, including acute cytotoxicity, immunotoxicity, and carcinogenesis. The mechanisms by which quinones cause these effects can be quite complex. Quinones are Michael acceptors, and cellular damage can occur through alkylation of crucial cellular proteins and/or DNA. Alternatively, quinones are highly redox active molecules which can redox cycle with their semiquinone radicals, leading to formation of reactive oxygen species (ROS), including superoxide, hydrogen peroxide, and ultimately the hydroxyl radical. Production of ROS can cause severe oxidative stress within cells through the formation of oxidized cellular macromolecules, including lipids, proteins, and DNA. Formation of oxidatively damaged bases such as 8-oxodeoxyguanosine has been associated with aging and carcinogenesis. Furthermore, ROS can activate a number of signaling pathways, including protein kinase C and RAS. This review explore...

Role of quinones in toxicology.

http://sun-lab.med.nyu.edu/files_private/sun-lab/attachments/1989.Cell.Cotsarelis-s.pdf

Existence of slow-cycling limbal epithelial basal cells that can be preferentially stimulated to proliferate: implications on epithelial stem cells.

The antiinflammatory steroids fluocinolone acetonide, fluocinonide, and fluclorolone acetonide were found to be very effective inhibitory agents of mouse skin tumor promotion. These steroids also drastically inhibited epidermal DNA synthesis and epidermal cellular proliferation induced by a phorbal ester tumor promoter. In addition, these compounds were potent inhibitors of plasminogen activator production in tumor cell cultures. The clinically used non-steroidal antiinflammatory agents oxyphenbutazone, indomethacin, and Seciazone also inhibited tumor promotion but were much less effective. Although these agents are useful against inflammatory disorders in general when given p.o., in our studies they had little effect on inflammation and epidermal cellular proliferation induced by a phorbol ester tumor promoter when given topically. The aforementioned nonsteroidal antiinflammatory agents also had little effect on epidermal DNA synthesis. Oxyphenbutazone and indomethacin were less potent inhibitors of plasminogen activator production in tumor cells than were the antiinflammatory steroids, and Seclazone produced a negligible inhibition. There is, therefore, a general correlation in the potencies of a series of steroidal antiinflammatory agents for inhibition of tumor promotion and their ability to inhibit plasminogen activator production by tumor cell cultures and epidermal DNA synthesis.

https://cancerres.aacrjournals.org/content/canres/37/5/1530.full.pdf

Effects of antiinflammatory agents on mouse skin tumor promotion, epidermal DNA synthesis, phorbol ester-induced cellular proliferation, and production of plasminogen activator.

Skin tumor initiating ability of benzo(a)pyrene 4,5- 7,8- and 7,8-diol-9,10-epoxides and 7,8-diol

Fluocinolone acetonide: a potent inhibitor of mouse skin tumor promotion and epidermal DNA synthesis.

Dose-response relationships on the abilities of several phorbol ester tumor promoters to promote skin tumors after 7,12-dimethylbenz[a]anthracene initiation and to bring about edema, inflammation, and epidermal hyperplasia were determined in female Charles River CD-1 mice. The promoting ability of the potent synthetic promoter, phorbol-12,13-dioctanoate (PdiC8), was determined over a dose range of 0.1-10 mug/application. Administration of PdiC8 two times weekly at dosages of 4, 6, 8, and 10 mug gave little variation in tumor response. A dose-dependent tumor response occurred at doses of 1-4 mug PdiC8. Only 1 papilloma was observed when PdiC8 was given twice weekly at a dose of 0.1 or 0.5 mug. A similar dose-response relation was observed for the ability of PdiC8 to stimulate epidermal hyperplasia. Investigations of other phorbol esters revealed an excellent correlation between their promoting ability and their ability to induce epidermal hyperplasia; however, that was not the case for compounds outside the phorbol ester series (i.e., acetic acid, cantharidin, and ethylphenylpropiolate).

Epidermal Cell Proliferation and Promoting Ability of Phorbol Esters

The ability of arene oxides and diol epoxides of benzo( a )pyrene to initiate skin tumors in mice was determined by using a two-stage system of tumorigenesis. (±)-7β,8α - Dihydroxy - 9α, 10α - epoxy- 7,8,9,10 - tetrahydrobenzo( a )pyrene was a more effective tumor initiator than was (±)-7β,8α-dihydroxy-9β,10β - epoxy-7,8,9,10-tetrahydrobenzo( a )pyrene when applied topically to CD-1 mice and then followed by twice-weekly applications of the promotor 12- O -tetradecanoylphorbol-13-acetate. (±)-7β,8α-Dihydroxy-9α,10α-epoxy-7,8,9,10-tetrahydrobenzo-( a )pyrene was approximately 20 to 30% as active as benzo( a )pyrene was as a tumor initiator. (±)-7β,8α-Dihydroxy-7β,8β-epoxy-7,8,9,10-tetrahydrobenzo( a )pyrene, benzo( a )pyrene, 9,10-oxide, and benzo( a )pyrene 11,12-oxide, possessed about 1, 2, and 10%, respectively, of the tumor-initiating activity of benzo( a )pyrene.

https://cancerres.aacrjournals.org/content/canres/37/11/4130.full.pdf

Aurora Viaje

Papers

Effects of antiinflammatory agents on mouse skin tumor promotion, epidermal DNA synthesis, phorbol ester-induced cellular proliferation, and production of plasminogen activator.

Skin tumor initiating ability of benzo(a)pyrene 4,5- 7,8- and 7,8-diol-9,10-epoxides and 7,8-diol

Fluocinolone acetonide: a potent inhibitor of mouse skin tumor promotion and epidermal DNA synthesis.

Epidermal Cell Proliferation and Promoting Ability of Phorbol Esters

Comparison of the tumor-initiating activities of benzo(a)pyrene arene oxides and diol-epoxides.