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Title: Transducer of regulated CREB activity in ACTH-mediated Star transcription
Author: Smith, Lorna Ionie Freda
ISNI:       0000 0004 6057 8306
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2016
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The biosynthesis of glucocorticoids in the adrenal, the end product of the HPA axis, is regulated by the availability and activation of the labile protein StAR, which is subject to tight transcriptional regulation by ACTH. · Of the many factors involved in Star transcription, CREB and its co-activator Transducer of regulated CREB activity (TORC 1-3), have previously been established to be involved in mediating ACTH-induced transcriptional increases in adrenal zona fasciculata cells, through activation of the cAMP pathway. However, the vast majority of previous studies have been performed in vitro, using non-physiological conditions, including over expression of TORC isoforms and measuring responses to prolonged incubation periods, with supra-physiological levels of stimulation. Under basal conditions, glucocorticoids are dynamically released in response to rapid pulses of ACTH; therefore, I aimed to establish the roles of the individual TORC isoforms in mediating the equally dynamic Star transcriptional responses, and the role of TORC inhibitors, SIK1 and AMPKa, in response to a range of physiological conditions both in vitro and in vivo. My hypothesis is that the TORC/SIK system acts as an on/off switch for rapid activation and inactivation of Star transcription. By using murine adrenocortical cell lines, I initially established nuclear translocation of all three TORC isoforms in response to ACTH, mediated through PKA and calcineurin, and binding of pCREB, TORC 2 and TORC 3 to the Star promoter. I also showed that TORC 2 and TORC 3 knockdown only attenuated Star transcriptional increases, suggesting the involvement of other transcription factors in mediating ACTH signalling. By using an in vivo approach I have shown that the TORC/SIK pathway is differentially activated following an ultradian ACTH pulse and following an immune stress in the rat. My data further elucidate mechanisms regulating adrenal steroidogenic dynamics that are important for maintaining pulsatile pattern of glucocorticoid in health conditions.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available