Thesis (Ph. D.)--University of Wisconsin--Madison, 1982. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Graduation date: 2003

Thesis (Ph. D.)--University of Wisconsin--Madison, 1969. / Typescript. Vita. Includes bibliographical references.

Thesis (MSc)--Stellenbosch University, 2002. / ENGLISH ABSTRACT: The aim of this thesis was to define the interactions of the androgen receptor (AR) with an analog of a non-steroidal plant compound, Compound A (CpdA), as well as two synthetic progestins, medroxyprogesterone acetate (MPA) and norethindrone acetate (NET-A). The data presented indicates that CpdA has antiandrogenic properties, as it represses androgen-induced activation of both specific and non-specific androgen-responsive reporter constructs. It was found that CpdA exerts these effects by a mechanism other than competition with androgen for binding to the ligand-binding domain (LBD) of the receptor. On the other hand, it is demonstrated that both MPA and NET-A compete with androgen for binding to the AR and induce partial agonist activity via the receptor. Using mammalian two-hybrid assays it was revealed that CpdA, similar to anti-androgenic compounds that are able to compete with androgens for binding to the receptor, represses the androgen-induced interaction between the NH2- and COOH-terminals of the AR (N/C-interaction) without competing for binding to the LBD. Furthermore, it was shown that CpdA slightly represses the androgen-dependent recruitment of steroid receptor co-activator 1 (SRC1) to the activation function (AF2) domain of the AR. When the effects of MPA and NET-A on the N/C-interaction were studied, intriguing results were obtained. NET-A, as expected, induced this AR agonist-induced interaction. MPA, however, repressed this AR agonist-induced interaction, an effect previously associated with anti-androgenic activity, despite displaying partial agonist activity in transctivation experiments. On the other hand, both MPA and NET-A induced the interaction between SRC1 and the AF2 domain. In additional experiments with CpdA, it was found that CpdA did not affect the recruitment of SRC1 to the AF1 domain of the receptor; neither did it influence the constitutive activity of the NH2-terminal domain. The anti-androgenic activities of CpdA were confirmed by the toxic effect that this compound had on the androgen-dependent lymph node carcinoma of the prostate (LNCaP) cell-line as well as its ability to repress the androgen-induced expression of the prostate specific antigen (PSA) protein. Taken together, the results presented in this thesis, in combination with the knowledge available on AR function, contribute to an improved understanding of AR function. Furthermore, the importance of defining the precise mechanism by which individual compounds exert their effects is highlighted. In this regard it is demonstrated that two compounds (MPA and NET-A) that display partial agonist activity, can exert their effects via different mechanisms at the molecular level. Detecting such differences in the molecular mechanisms of action could facilitate the improved design of progestins as well as aid clinicians and their patients in selecting the best method of contraception. Lastly, the insights gained into the mechanisms of the anti-androgenic action of CpdA could be useful in therapeutic drug design for diseases, such as prostate cancer, that have an androgen-dependent etiology. / AFRIKAANSE OPSOMMING: Die doel van hierdie tesis was om die interaksies van die androgeen reseptor (AR) met ‘n analoog van ‘n nie-steroiediese plant verbinding, Verbinding A (VbgA), sowel as met twee sintetiese progestogene, medroksiprogesteroon asetaat (MPA) en noretiendroon asetaat (NET-A), te definieer. Die data verskaf dui daarop dat VbgA anti-androgeniese eienskappe besit deurdat dit androgeen-gei'nduseerde aktivering van beide spesifieke- en nie-spesifieke androgeen-responsiewe rapporteerderkonstrukte onderdruk. VbgA veroorsaak hierdie effekte deur ‘n meganisme wat nie kompetisie met androgeen vir binding aan die ligand-bindingsdomein (LBD) van die reseptor behels nie. In teenstelling hiermee word getoon dat beide MPA en NET-A kompeteer met androgeen vir binding aan die AR en gedeeltelike agonistiese aktiwiteit induseer via hierdie reseptor. Deur gebruik to maak van ‘n soogdier twee-hibried essai word getoon dat VbgA, soos ander anti-androgeniese verbindings wat kompeteer met androgeen vir binding aan die reseptor, die androgeen-gei'nduseerde interaksies tussen die NH2- en COOH-terminale van die AR (N/C-interaksie) onderdruk, sonder om te kompeteer vir binding aan die LBD. Daarby is dit bewys dat VbgA die androgeenafhanklike werwing van steroied reseptor ko-aktiveerde 1 (SRC1) na die aktiverings funksie (AF2) domein van die AR gedeeltelik onderdruk. Die studie van die effekte van MPA en NET-A op die N/C-interaksie het interessante resultate opgelewer. NETA, soos verwag, het hierdie AR agonis-gei'nduseerde interaksie geinduseer. MPA, aan die ander kant, het hierdie AR agonis-gei'nduseerde interaksie onderdruk, ‘n effek wat tevore met anti-androgeniese aktiwiteit geassosieer is, al het die transaktiveringseksperimente daarop gedui dat MPA ‘n AR agonis is. Aan die ander kant, het beide MPA en NET-A die interaksie tussen SRC1 en die AF2 domein geinduseer. In addisionele eksperimente met VbgA is gevind dat VbgA geen effek het op die werwing van SRC1 na die AF1 domein van die reseptor nie en ook geen invloed het op die konstitutiewe aktiwiteit van die NHh-terminaal domein nie. VbgA se antiandrogeniese eienskappe is bevestig deur die toksiese effekte op die androgeenafhanklike limfknoop karsinoom van die prostaat (LNCaP) sellyn sowel as deur sy vermoe om die androgen-gei'nduseerde uitdrukking van die prostaat spesifieke antigeen (PSA) protei'en te onderdruk. Die resultate aangebied in hierdie tesis, in kombinasie met die beskikbare kennis oor AR funksie, dra by tot ‘n verbeterde kennis van AR funksionering. Verder word die belang van die definiering van die meganisme waardeur individuele verbindings hulle effekte veroorsaak, getoon. In hierdie verband is getoon dat twee verbindings (MPA en NET-A), wat gedeeltelike agonistiese aktiwiteit besit, hulle effekte via verskillende meganismes op die molekulere vlak veroorsaak. Deur hierdie verskille in die molekulere meganismes van aksie uit te wys, kan beter progestogene ontwikkel word, en verder sal dit vir dokters en hul pasiente help om die beste voorbehoedmiddel te kies. Laastens, die insig wat verkry is ten opsigte van die meganismes van anti-androgeniese aktiwiteit van VbgA mag nuttig wees in die ontwerp van terapeutiese middels vir die behandeling van siektetoestande met androgeen-afhanklikke etiologie (bv. prostaatkanker).

Call number: LD2668 .T4 1986 K58 / Master of Science / Animal Sciences and Industry

"February 2004" / Bibliography: leaves 168-188. / xvii, 194 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, School of Molecular and Biomedical Science, Discipline of Physiology and Dept. of Obstetrics and Gynaecology, 2004?

Graduation date: 1999

Graduation date: 1993

Source: Masters Abstracts International, Volume: 46-05, page: 2669. Adviser: Margaret Caughy. Includes bibliographical references.

No description available.