Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0338671 (Steroids)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Granulosa cells are the main producers of the female sex steroid hormones, progesterone and estradiol, which are responsible for the cyclicity in ovarian function. Programmed cell death in the ovary plays a crucial role in limiting the number of follicles that can ovulate and thus prevents the development of more embryos than can successfully complete pregnancy. Granulosa cell apoptosis is regulated by the concerted action of endocrine, paracrine, and autocrine factors. These factors lead to the developmental decision of whether the steroidogenic cell will luteinize and enter the pathway leading to programmed cell death, or whether the life span of the luteinized cell will be prolonged to continue secretion of progesterone, which is essential for the maintenance of pregnancy. At the level of the individual cell, we find that enhanced steroidogenesis can be maintained during the initial steps of apoptosis as long as the steroidogenic apparatus remains intact. This can be achieved by a unique mechanism of compartmentalization of steroidogenic organelles in the perinuclear region and migration of the multicatalytic proteinase, the proteasome, to the apoptotic blebs. Reorganization of the actin cytoskeleton during apoptosis may provide an efficient barrier between the proteolytic activity and the steroidogenic activity in the apoptotic cell. It is suggested that steroidogenesis can be maintained in the apoptotic cells as long as the steroidogenic organelles bearing the steroidogenic apparatus remain intact.
Steroids 1997 Jan
PMID:Apoptosis in steroidogenic cells: structure-function analysis. 902 38

Synthetic estrogen receptor ligands such as tamoxifen and raloxifene produce biologic responses which can be either estrogenic or anti-estrogenic, depending upon the tissue in which their action is examined. To reflect the fact that they are not 'pure' antagonists, such ligands have been more accurately termed selective estrogen receptor modulators (SERMs). Recent progress in our understanding of the molecular biology of estrogen receptor (ER) action has provided a great deal of evidence which promises to increase our understanding of the mechanism through which SERMs elicit their tissue-specific effects. The identification of numerous coactivators and corepressors which modulate receptor function and the realization of two subtypes of ER attest to the potential complexity through which SERMs produce diverse tissue-specific responses. Evidence from co-crystal structures of ER ligand-binding domains complexed with SERMs provides additional information as to how this class of ligands can elicit diverse biologic responses. SERMs also influence the stability of the ER protein, and recent information on the determinants of receptor stability and the role of proteasome-mediated protein degradation in ER-driven transcription also promises to give a fuller understanding of SERM biology. These aspects of the molecular biology of estrogen receptor action may help clarify the mechanism(s) of SERM biologic action and will be addressed in further detail in this review.
Steroids 2002 Jan
PMID:Molecular perspectives on selective estrogen receptor modulators (SERMs): progress in understanding their tissue-specific agonist and antagonist actions. 1172 17

Study of molecular actions of thyroid hormone receptor beta (TRbeta) mutants in vivo has been facilitated by creation of a mouse model (TRbetaPV mouse) that harbors a knockin mutant of TRbeta (denoted PV). PV, which was identified in a patient with resistance to thyroid hormone, has lost T3 binding activity and transcription capacity. The striking phenotype of thyroid cancer exhibited by TRbeta(PV/PV) mice has allowed the elucidation of novel oncogenic activity of a TRbeta mutant (PV) [PAS1] beyond nucleus-initiated transcription. PV was found to physically interact with the regulatory p85alpha subunit of phosphatidylinositol 3-kinase (PI3K) in both the nuclear and cytoplasmic compartments. This protein-protein interaction activates the PI3K signaling by increasing phosphorylation of AKT, mammalian target of rapamycin (mTOR), and p70(S6K). PV, via interaction with p85alpha, also activates the PI3K-integrin-linked kinase-matrix metalloproteinase-2 signaling pathway in the extra-nuclear compartment. The PV-mediated PI3K activation results in increased cell proliferation, motility, migration, and metastasis. In addition to affecting these membrane-initiated signaling events, PV affects the stability of the pituitary tumor-transforming gene (PTTG) product. PTTG (also known as securin), a critical mitotic checkpoint protein, is physically associated with TRbeta or PV in vivo. Concomitant with T3-induced degradation of TRbeta, PTTG is degraded by the proteasome machinery, but no such degradation occurs when PTTG is associated with PV. The degradation of PTTG/TRbeta is activated by the direct interaction of the T3-bound TRbeta with the steroid receptor coactivator-3 (SRC-3) that recruits a proteasome activator (PA28gamma). PV that does not bind T3 cannot interact directly with SRC-3/PA28gamma to activate proteasome degradation, and the absence of degradation results in an aberrant accumulation of PTTG. The PV-induced failure of timely degradation of PTTG results in mitotic abnormalities. PV, via novel protein-protein interaction and transcription regulation, acts to antagonize the functions of wild-type TRs and contributes to the oncogenic functions of this mutation.
Steroids 2007 Feb
PMID:Novel functions of thyroid hormone receptor mutants: beyond nucleus-initiated transcription. 1716 89

Glucocorticoid receptors (GRs) are members of a highly conserved family of ligand dependent transcription factors which following hormone binding undergo homologous down-regulation reducing the levels of receptor protein. This decline in human GR (hGR) is due in part to a decrease in protein receptor stability that may limit cellular responsiveness to ligand. To examine the role of the proteasome protein degradation pathway in steroid-dependent hGR responsiveness, we utilized the proteasomal inhibitors MG-132, beta-lactone, and epoxomicin. HeLa cells and COS cells were treated with proteasome inhibitors in the presence of the GR agonist dexamethasone (Dex), or were pretreated with proteasomal inhibitor and then Dex. Dexamethasone induced glucocorticoid responsive reporter activity significantly over untreated controls, whereas cells treated with proteasomal inhibitors and Dex together showed 2-3-fold increase in activity. Protein sequence analysis of the hGR protein identified several candidate protein degradation motifs including a PEST element. Mutagenesis of this element at lysine 419 was done and mutant K419A hGR failed to undergo ligand dependent down-regulation. Mutant K419A hGR displayed 2-3-fold greater glucocorticoid responsive reporter activity in the presence of Dex than wild type hGR. These differences in transcriptional activity were not due to altered subcellular localization, since when the mutant K419A hGR was fused with the green fluorescent protein (GFP) it was found to move in and out of the nucleus similarly to wild type hGR. Together these results suggest that the proteasome and the identified PEST degradation motif limit steroid-dependent human glucocorticoid receptor signaling.
Steroids 2010 Dec
PMID:Lysine 419 targets human glucocorticoid receptor for proteasomal degradation. 2061 82