The receptor activator of nuclear factor-kB (RANK) and its ligand, RANKL has have been implicated as an important link between breast cancer and metastasis to bone because of their ability to activate intracellular signal cascades leading to altered cancer cell behaviour and bone breakdown. The JAK/STAT5a cell signaling pathway is also crucial to breast biology and is involved in transcriptional regulation of many genes. The objective of this study is to determine if RANKL mRNA expression is regulated through the JAK/STAT5a pathway by stimulating human breast cancer cell lines, MCF-7 and MDA-MB-231, with prolactin (PRL), epidermal growth factor (EGF) and heregulin-beta1 (HRG-1), all known to activate STAT5a and play a role in breast cancer progression. This study shows that RANKL expression is upregulated by PRL, EGF and HRG-1, and that PRL and HRG-1 regulate transcription through the JAK/STAT5a pathway. / UOIT

Endometrial glands are required for adult uterine function and develop post-natally in mammalian species. Therefore, studies were conducted using neonatal ewes as a model to determine: 1) the roles of estradiol-17-alpha and estrogen receptor-alpha (ER-beta) in endometrial gland development; 2) the role of ovaries in endometrial gland development; 3) the role of prolactin in endometrial gland development; and 4) factors regulating prolactin receptor expression in endometrial glands. Study one determined the effects of neonatal exposure of ewes to estradiol-17-alpha valerate (EV); EM-800, an ER-beta antagonist; or CGS-20267, an aromatase inhibitor on endometrial gland development. Results indicate E2-17-alpha does not regulate endometrial gland differentiation or development. Additionally, ER-beta does not regulate primary differentiation of glandular epithelium, but does influence coiling and branching morphogenesis of endometrial glands. Study two determined the effects of ovariectomy on endometrial gland morphogenesis. Results suggest that the ovary and, thus, an ovarian-derived factor(s) regulate, in part, the coiling and branching of endometrial glands. Expression of subunits of activin, follistatin, and inhibin in the neonatal ovine ovary in addition to modulation of the components of the activin/follistatin system in the uterus of ovariectomized ewes supports the hypothesis that the ovarian factors that influence endometrial adenogenesis in the neonatal ewe may be activin, follistatin, and/or inhibin. Studies three and four determined the role of prolactin in endometrial adenogenesis in the neonatal ewe. Studies in which either hypoprolactinemia or hyperprolactinemia were induced indicate that prolactin regulates ovine endometrial adenogenesis in the neonatal ewe. The aim of study five was to determine transcription factors that regulate the glandular epithelium specific expression of prolactin receptor. Prolactin receptor exon 2 was cloned and sequenced, but no identifiable exon 1 or promoter was found. Additionally, many bovine contigs containing portions of the prolactin receptor gene were identified suggesting the bovine genome will be a useful tool as it becomes more complete. These results indicate ER-beta, prolactin and prolactin receptor, along with an unidentified ovarian factor(s), influence endometrial gland development in the neonatal ewe; however, exposure of the neonatal ewe to exogenous estradiol-17-alpha prevents differentiation and development of endometrial glands.

The present investigation was designed to further our understanding of the interaction of pituitary (luteinizing hormone, LH) and placental (chorionic gonadotropin, CG) gonadotropins with the primate corpus luteum. Studies were performed (1) to characterize the LH/CG receptor population in the

Spinal muscle atrophy (SMA) is an autosomal recessive neurodegenerative disease which is characterized by the loss of α motor neurons from the anterior horn of the spinal cord, resulting in progressive muscle atrophy. The loss of functional Survival motor neuron (SMN) protein due to mutations or deletion in the SMN1 gene is the cause of SMA. A potential treatment strategy for SMA is to upregulate levels of the SMN protein originating from the copy gene SMN2 which can compensate in part for the absence of the functional SMN1 gene. I have shown a novel therapeutic strategy for SMA treatment through the activation of the p38 pathway by the bacterial antibiotic anisomycin which stabilizes and increases SMN mRNA levels in vitro. Activation of the p38 pathway by anisomycin leads to cytoplasmic accumulation of HuR protein which binds to the 3’UTR of SMN transcript resulting in increased SMN levels. This opens up a novel potential therapeutic strategy for SMA. I have also identified and demonstrated a significant induction of SMN protein levels in vitro and in vivo upon treatment with FDA approved drug celecoxib, which also activates the p38 pathway. Celecoxib mitigates disease severity along with increasing the lifespan of SMA mice. Sodium valproate, trichostatin A and aclarubicin, all agents which effectively enhance SMN2 expression, have been recently shown to activate STAT5 in SMA-like mouse embryonic fibroblasts and human SMN2-transfected NSC34 cells. Given that prolactin is also known to activate the STAT5 signalling pathway, can cross blood brain barrier and is FDA approved, we elected to assess its impact on SMN levels. In this manner, I have demonstrated a significant induction in SMN mRNA and protein levels in neuronal NT2 and MN-1 cells upon treatment with prolactin. I have also demonstrated that activation of the STAT5 pathway by prolactin is necessary for this transcriptional upregulation of the SMN gene. I have found that prolactin treatment induces SMN expression in brain and spinal cord samples and that it ameliorates the disease phenotype, improving motor neuron function and increasing survival in the SMA mouse model. Presently there is no cure for SMA. This study will help in the identification and characterization of potential therapeutic compounds for the treatment of SMA.

Thesis (Ph. D.)--University of Hong Kong, 2007. / Also available in print.

Diss. (sammanfattning) Linköping : Univ., 2002. / Härtill 6 uppsatser.

Thesis (Ph.D. in Cancer Biology) -- University of Colorado Denver, 2007. / Typescript. Includes bibliographical references (leaves 182-210). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;

Thesis (Ph. D.)--University of Missouri-Columbia, 1996. / Typescript. Vita. Includes bibliographical references (leaves 136-172). Also available on the Internet.

Thesis (Ph. D.)--University of Hong Kong, 2009. / Includes bibliographical references (leaves 207-262). Also available in print.

Thesis (Ph. D.)--University of Missouri-Columbia, 1996. / Typescript. Vita. Includes bibliographical references (leaves 136-172). Also available on the Internet.