Browsing by Subject "Receptors, Steroid"
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Item Addison's disease(1982-08-19) Kokko, Juha P.Item Gonadotropin-induced Steroidogenesis and Downstream Signals Leading to Oocyte Maturation(2009-01-09) Evaul, Kristen Elizabeth; Hammes, Stephen R.The Hammes laboratory is interested in understanding the process of steroid-mediated oocyte maturation. This includes examining both steroid production and steroid signaling. In these studies, gonadotropin-induced steroid production was examined in the gonads using mouse models, as well as steroid-induced oocyte maturation in frog models. cAMP signaling is known to be important for steroid production, but further downstream pathways were not well characterized. These studies illuminate other downstream signaling pathways triggered by luteinizing hormone (LH) that regulate steroid production in the testes using Leydig cells, which are the primary steroidogenic cells in the testes. A novel downstream pathway was found involving epidermal growth factor receptor (EGFR) transactivation, downstream mitogen-activated protein kinase (MAPK) and steroidogenic acute regulatory protein (StAR) activation that was essential for short, but not long-term LH-induced steroidogenesis in MLTC-1 and primary mouse leydig cells. Despite this discrepancy in vitro, EGFR signaling was required in vivo for testicular testosterone production. To study the effects of steroids on oocyte maturation, the Xenopus laevis frog model was used. It has been shown that G-beta gamma, as well as other signals, keep the oocyte in meiotic arrest. Steroids block this constitutive signal, leading to oocyte maturation. To directly measure rapid changes in G-beta gamma signaling in oocytes, G-beta gamma sensitive-inward rectifying potassium channel currents (GIRKS) were exogenously expressed in Xenopus oocytes. Adding testosterone, the physiologic mediator of oocyte maturation in Xenopus, decreased the G-beta gamma mediated signal. This happened rapidly supporting the well known idea that maturation is a transcription-independent process. It was also seen that the classical androgen receptor (AR) was being used for this process. When the AR was knocked down, testosterone could only decrease GIRK signal at higher concentrations. This showed that testosterone is working, at least partially, through the AR. These studies may help elucidate novel targets for polycystic ovary syndrome (PCOS), which is characterized by excess androgen due to improper steroid production.Item The Role of EGFR Signaling in Gonadotropin-Induced Steroidogenesis(2010-11-02) Carbajal, Liliana; Hammes, Stephen R.Recent evidence has demonstrated that cross talk between G protein-coupled receptors and Epidermal Growth Factor Receptor (EGFR) is critical for steroidogenesis in all three major steroid-producing tissues. We have recently characterized the intracellular signals regulating Luteinizing Hormone (LH) -induced steroid production in Leydig cells, demonstrating a linear pathway whereby LH receptor activation stimulates cAMP production and PKA signaling. Protein Kinase A (PKA) signaling then triggers EGF receptor activation, which activates the Mitogen Activated Protein Kinase (MAPK) cascade to promote steroidogenic acute regulatory (StAR) phosphorylation and translocation to the mitochondria. Interesting, PKA-mediated transactivation of the EGF receptor occurs via both intracellular, ligand-independent signaling, as well as extracellular, ligand-dependent activation that requires Matrix Metalloproteinase (MMP)-mediated release of membrane-bound EGF receptor ligands. However, only intracellular signaling is required for LH-induced steroid production. Furthermore, the LH-EGFR pathway appears to be important only for early steroidogenesis in Leydig cells, as LHinduced steroidogenesis beyond 60 minutes no longer requires EGFR or MAPK signaling. Here we characterize the LH-induced signals that regulate steroidogenesis in the ovary. We demonstrate that, similar to Leydig cells, activation of the EGF receptor is important for gonadotropin-induced steroid production in the ovary. Trans-activation of the EGFR is mediated by an increase of cAMP and PKA signaling. However, steroidogenesis in the ovary is dependent on an extracellular ligandindependent mechanism, as MMPs were shown to be crucial for the cleavage and activation of membrane bound EGFR upon LH stimulation. EGFR signaling was shown to activate the MAPK cascade and lead to subsequent phosphorylation of the steroidogenic acute regulatory protein (StAR). Interestingly, EGFR and MAPK signaling, unlike that in Leydig cells, as necessary for short and long term gonadotropininduced steroid production in the ovary. In vivo studies further demonstrate the importance of EGFR signaling since serum progesterone levels were significantly reduced when EGFR was inhibited. These findings demonstrate physiologic importance and potential treatment options since women with endocrine disorder such as PCOS can be treated with EGFR antagonist to reduce excess steroid production in the ovary.