Endocrine Abstracts

Cumulative genetic abnormalities within an oncogenic pathway may contribute to earlier onset or increased aggressiveness of cancers. An example in human and murine cancer is the dysregulation of Wnt signalling by inactivation of the adenomatous polyposis coli (APC) gene that results in accumulation of nuclear β-catenin and earlier onset of renal cell carcinoma, which can be accelerated by p53-deficiency. We therefore investigated the effects of such cumulative genetic abn...

The pathogenesis of pituitary adenomas is poorly understood. One of the first genetic abnormalities identified in association with pituitary adenomas occurs in patients with multiple endocrine neoplasia type-1 (MEN-1), due to mutations in the MEN1 gene, encoding menin. A tumor suppressor, menin associates with histone methyltransferase complexes to change the expression of cyclin-dependent kinase (CDK) inhibitor genes, which may serve as an underlying epigenetic mecha...

Aberrant development of the pituitary gland can result in the clinical manifestation of hypopituitarism. The Wnt/β-catenin pathway has been shown to be involved in normal organogenesis, terminal differentiation and the aetiology of pituitary tumours. However, the specific developmental roles during hypothalamic–pituitary development of some of the Wnt/β-catenin effectors, such as Tcf3, have been hampered due to the early lethality of null embryos for th...

The pulsatile release of GnRH regulates the synthesis and secretion of pituitary FSH and LH. Two transcription factors, the cAMP response element binding protein (CREB) and inducible cAMP early repressor (ICER), have been implicated in the regulation of rat FSHβ gene expression. We hypothesized that CREB and ICER are activated by distinct signaling pathways in response to pulsatile GnRH to modulate FSHβ gene expression, which is preferentially stimulated at low (ever...

Mammalian genes display pulsatile transcription dynamics with bursts of expression occurring with variable duration and frequency. Using the human prolactin gene as a model of tissue specific gene regulation, we have characterised the transcription dynamics of this gene in cell lines, primary cells and pituitary tissue slices. Our data indicate that the tissue environment may have an important influence on cellular transcription activity. Cultures of cells from enzymatically d...

Background: Acromegaly is associated with increased morbidity and mortality, however currect medical treatment controls the disease in <60% of patients. Pegvisomant, a pegylated GH antagonist, controls the disease in over 95% of cases, but is not cost effective as it requires high dose daily injections and has side-effects. We have developed a technology for generating a long acting potent GH antagonist.Hypothesis: That a GH antagonist fused to GH bi...