Recent Progress In Hormone Research[JOURNAL]
Sun
200 papers
Estrogen receptors: selective ligands, partners, and distinctive pharmacology.
Katzenellenbogen BS, Montano MM, Ediger TR … +8 more , Sun J, Ekena K, Lazennec G, Martini PG, McInerney EM, Delage-Mourroux R, Weis K, Katzenellenbogen JA
Recent Prog Horm Res · 2000 · PMID 11036937
The action of nuclear hormone receptors is tripartite, involving the receptor, its ligands, and its co-regulator proteins. The estrogen receptor (ER), a member of this superfamily, is a hormone-regulated transcription fa...
The action of nuclear hormone receptors is tripartite, involving the receptor, its ligands, and its co-regulator proteins. The estrogen receptor (ER), a member of this superfamily, is a hormone-regulated transcription factor that mediates the effects of estrogens and anti-estrogens (e.g., tamoxifen) in breast cancer and other estrogen target cells. This chapter presents our recent work on several aspects of estrogen action and the function of the ER: 1) elucidation of ER structure-function relationships and development of ligands that are selective for one of the two ER subtypes, ERalpha or ERbeta; 2) identification of ER-selective co-regulators that potentiate the inhibitory effectiveness of anti-estrogens and dominant-negative ERs and modulate the activity of estrogens; 3) characterization of genes that are regulated by the anti-estrogen-ER versus the estrogen-ER complex; and 4) elucidation of the intriguing pharmacology of these ER complexes at different gene regulatory sites. These findings indicate that different residues of the ER hormone-binding domain are involved in the recognition of structurally distinct estrogens and anti-estrogens and highlight the exquisite precision of the regulation of ER activities by ligands, with small changes in ligand structure resulting in major changes in receptor character. Studies also explore the biology and distinct pharmacology mediated by ERalpha and ERbeta complexed with different ligands through different target genes. The upregulation of the anti-oxidant detoxifying phase II enzyme, quinone reductase, by the anti-estrogen-occupied ER, mediated via the electrophile response element in the QR gene, may contribute to the beneficial antioxidant effects of anti-estrogens in breast cancer and illustrates the activation of some genes by ER via non-estrogen response element sequences. The intriguing biology of estrogen in its diverse target cells is thus determined by the structure of the ligand, the ER subtype involved, the nature of the hormone-responsive gene promoter, and the character and balance of co-activators and co-repressors that modulate the cellular response to the ER-ligand complex. The continuing development of novel ligands and the study of how they function as selective agonists or antagonists through ERalpha or ERbeta should allow optimized tissue selectivity of these agents for hormone replacement therapy and treatment and prevention of breast cancer.
Mechanism of capacitative Ca2+ entry (CCE): interaction between IP3 receptor and TRP links the internal calcium storage compartment to plasma membrane CCE channels.
Birnbaumer L, Boulay G, Brown D … +5 more , Jiang M, Dietrich A, Mikoshiba K, Zhu X, Qin N
Recent Prog Horm Res · 2000 · PMID 11036936
Activation of cells by agents that stimulate inositol trisphoshate (IP3) formation causes, via IP3 receptor (IP3R) activation, the release of Ca2+ from internal stores and also the entry of Ca2+ via plasma membrane catio...
Activation of cells by agents that stimulate inositol trisphoshate (IP3) formation causes, via IP3 receptor (IP3R) activation, the release of Ca2+ from internal stores and also the entry of Ca2+ via plasma membrane cation channels, referred to as capacitative Ca2+ entry or CCE channels. Trp proteins have been proposed to be the unitary subunits forming CCE channels; however, there is no definitive proof for this hypothesis. We have now identified amino acid sequences of a Trp and of an IP3R that interact to form stable complexes. These complexes appear to form in vivo, as evidenced by co-immunoprecipitation of Trp with IP3R and by the fact that expression of the respective interacting sequences modulates development of CCE brought about by store depletion. The finding that a Trp-interacting sequence of IP3R interferes with natural CCE leads us to conclude that Trp proteins are, indeed, structural members of CCE channels. We conclude further that direct coupling of IP3R to Trp is a physiological mechanism by which cells trigger CCE in response to signals that stimulate phosphoinositide hydrolysis and IP3 formation. Pros and cons of various CCE activation models are discussed.
Apolipoprotein B: from editosome to proteasome.
Chan L, Chang BH, Liao W … +2 more , Oka K, Lau PP
Recent Prog Horm Res · 2000 · PMID 11036935
Apolipoprotein (apo) B, the protein component of low-density lipoproteins (LDLs), has been under intense investigation for the last three decades. During the first decade after its initial description, most reports dealt...
Apolipoprotein (apo) B, the protein component of low-density lipoproteins (LDLs), has been under intense investigation for the last three decades. During the first decade after its initial description, most reports dealt with the physical-chemical characterization of apoB in its natural environment (i.e., intact LDL particles). A few studies dealing with attempts to elucidate the primary structure of apoB were published at this time (Deutsch et al., 1978; Bradley et al., 1980). However, most of these, in retrospect, represented heroic efforts that were doomed to failure because of the huge size and insoluble nature of apoB, once it is separated from its lipid environment. Indeed, during the 1970s, there was no universal agreement on the true molecular weight of the protein, which was not established until sometime into the second decade of apoB research (Yang et al., 1986b). The next 10 years were punctuated by breakthroughs on three different fronts in our understanding of apoB. The first exciting discovery was that apoB exists in two forms, apoB-100 and apoB-48 (Kane et al., 1980; Elovson et al., 1981). The next breakthrough was the elucidation of the primary structure of apoB-100 by a combination of cDNA cloning (Chen et al., 1986; Knott et al., 1986; Yang et al., 1986a) and direct peptide sequencing (Yang et al., 1986a, 1989). This decade of renaissance in apoB research was concluded by the elucidation of the structure of apoB-48. More important in terms of basic cellular molecular biology was the discovery of RNA editing, when apoB-48 was found to be the translation product of an edited apoB mRNA (Chen et al., 1987; Powell et al., 1987). RNA editing had just been described for a kinetoplastid protozoa the year before (Benne et al., 1986). ApoB mRNA editing was the first instance of RNA editing described in a higher eukaryote (Chan and Seeburg, 1995; Grosjean and Benne. 1998). The last decade, which brings us to the present, has been marked by studies that benefited from the breakthroughs of the 1980s. which enabled many different laboratories to examine various aspects of apoB structure, function, and expression. The function of apoB in vivo was analyzed in different animal models (e.g., transgenic animals that overexpress apoB) (Linton et al., 1993; Callow and Rubin, 1995; Veniant et al., 1997) and in knockout animals that have no functional apoB (Farese et al., 1995,1996; Huang et al., 1995,1996). Furthermore, the structure-function relationship of apoB has been investigated in mice that express site-specific apoB mutants (Callow and Rubin, 1995; Veniant et al., 1997: Borén et al., 1998). A breakthrough in a related area led to the identification and cloning of microsomal triglyceride transfer protein (MTP) (Wetterau and Zilversmitt, 1984: Wetterau et al., 1992; Sharp et al., 1993) and the demonstration that MTP is essential for apoB production (Gordon et al., 1994; Leiper et al., 1994). The absence of MTP was found to lead to the complete degradation of apoB, which harks back to an observation in 1987 that, even in the presence of MTP, a substantial proportion of newly synthesized apoB-100 undergoes intracellular degradation before secretion (Borchardt and Davis, 1987). Indeed, the intracellular degradation of apoB-100 is the major determinant of its production rate from the liver, since the transcription of apoB appears to be constitutive and not subject to much regulation (Pullinger et al., 1989). It was in 1996, almost a decade after the first description of apoB's destruction inside the cell, that the proteasome-ubiquitin pathway was found to be the major mechanism for the intracellular degradation of apoB-100 (Yeung et al., 1996). Another important development within the last decade was the cloning of APOBEC-1, the catalytic subunit of the apoB mRNA editing complex (editosome) (Teng et al., 1993). This chapter will review some of the major landmarks in apoB research in the last 10 to 15 years, concentrating mainl
Chronic hypersecretion of luteinizing hormone in transgenic mice disrupts both ovarian and pituitary function, with some effects modified by the genetic background.
Nilson JH, Abbud RA, Keri RA … +1 more , Quirk CC
Recent Prog Horm Res · 2000 · PMID 11036934
When the pituitary or hypothalamus becomes resistant to steroid negative feedback, a vicious cycle ensues, resulting in chronic hypersecretion of luteinizing hormone (LH) from the pituitary and steroids from the ovaries....
When the pituitary or hypothalamus becomes resistant to steroid negative feedback, a vicious cycle ensues, resulting in chronic hypersecretion of luteinizing hormone (LH) from the pituitary and steroids from the ovaries. In women, LH hypersecretion is implicated in infertility, miscarriages, and development of granulosa cell tumors. Progress in defining the underlying mechanisms of LH toxicity, however, has been limited by the lack of well-defined animal models. To that end, we have developed a new transgenic mouse model (alpha-LHbetaCTP) wherein LH hypersecretion occurs chronically and results in several dire pathological outcomes. Chronic hypersecretion of LH was achieved by introducing a transgene containing a bovine alpha subunit promoter fused to the coding region of a chimeric LHbeta subunit. The alpha subunit promoter directs transgene expression only to gonadotropes. The LHbeta chimera contains the carboxyl-terminal peptide (CTP) of the human chorionic gonadotropin beta subunit linked to the carboxyl terminus of bovine LHbeta. This carboxyl extension extends the half-life of LH heterodimers that contain the chimeric beta subunit. In intact alpha-LHbetaCTP females, serum LH is elevated five- to ten-fold in comparison to nontransgenic littermates. Levels of testosterone (T) and estradiol (E2) also are elevated, with an overall increase in the T-to-E2 ratio. These transgenic females enter puberty precociously but are anovulatory and display a prolonged luteal phase. Anovulation reflects the absence of gonadotropin-releasing hormone (GnRH) and the inability to produce a pre-ovulatory surge of LH. The ovaries are enlarged, with reduced numbers of primordial follicles and numerous, giant, hemorrhagic follicles. Despite the pathological appearance of the ovary, females can be superovulated and mated. Although pregnancy occurs, implantation is compromised due to defects in uterine receptivity. In addition, pregnancy fails at midgestation, reflecting a maternal defect presumably due to estrogen toxicity. When the transgene is in a CF-1 background, all females develop granulosa cell tumors and pituitary hyperplasia by five months of age. They die shortly thereafter due to bladder atony and subsequent kidney failure. When the transgene is placed in other strains of mice, their ovaries develop a luteoma rather than a granulosa cell tumor and the pituitary develops pituitary hyperplasia followed by adenoma. In summary, alpha-LHbetaCTP mice provide a direct association between abnormal secretion of LH and development of a number of ovarian and pituitary pathological responses.
Autocrine and paracrine Müllerian inhibiting substance hormone signaling in reproduction.
Ingraham HA, Hirokawa Y, Roberts LM … +4 more , Mellon SH, McGee E, Nachtigal MW, Visser JA
Recent Prog Horm Res · 2000 · PMID 11036933
Members of the transforming growth factor beta (TGFbeta) superfamily are polypeptide growth factors that exhibit diverse effects on normal cell growth, adhesion, mesenchymal-epithelial interactions, cell differentiation,...
Members of the transforming growth factor beta (TGFbeta) superfamily are polypeptide growth factors that exhibit diverse effects on normal cell growth, adhesion, mesenchymal-epithelial interactions, cell differentiation, and programmed cell death. This chapter will discuss the work of ourselves and others on one member of this large superfamily, Müllerian inhibiting substance (MIS, or anti-Müllerian hormone, AMH) and its role in reproductive tract development and the adult gonad. Using recombinant MIS protein, it is possible to begin unraveling the molecular mechanism of duct involution in the embryo. Our recent results suggest that MIS triggers cell death by altering mesenchymal-epithelial interactions. In addition to the developmental effects of MIS in secondary sexual differentiation, expression studies of the MIS ligand and the MIS type II receptor (MISIIR) suggest a potential regulatory role for MIS in adult germ cell maturation and gonadal function. Recent data from others suggest that MIS may act in a paracrine manner to block differentiation of interstitial cells of the adult gonad by repressing all or some steps of steroidogenesis. Our studies are highly suggestive of direct repression of steroidogenic enzyme gene expression by activation of the MIS signaling pathway. Thus, for the first time, an opportunity to define fully target genes and components of the MIS signaling pathway may be possible.
Placental prolactins and the physiology of pregnancy.
Lin J, Toft DJ, Bengtson NW … +1 more , Linzer DI
Recent Prog Horm Res · 2000 · PMID 11036932 · Publisher ↗
Mammalian pregnancy is characterized by a concerted and widespread series of changes in maternal physiology, many of which are direct responses to the binding of placental hormones to maternal targets. Among these placen...
Mammalian pregnancy is characterized by a concerted and widespread series of changes in maternal physiology, many of which are direct responses to the binding of placental hormones to maternal targets. Among these placental hormones are proteins closely related to prolactin. In rodents, a large number of these placental prolactin-related hormones are expressed that have a broad spectrum of activities, including activities on endothelial cells and blood cells.
Vascular endothelial growth factor and the regulation of angiogenesis.
Ferrara N
Recent Prog Horm Res · 2000 · PMID 11036931
The development of a vascular supply is essential not only for organ development and differentiation during embryogenesis but also for wound healing and reproductive functions in the adult Folkman, 1995). Angiogenesis is...
The development of a vascular supply is essential not only for organ development and differentiation during embryogenesis but also for wound healing and reproductive functions in the adult Folkman, 1995). Angiogenesis is also implicated in the pathogenesis of a variety of disorders: proliferative retinopathies, age-related macular degeneration, tumors, rheumatoid arthritis, and psoriasis (Folkman, 1995; Garner, 1994). Several potential regulators of angiogenesis have been identified, including fibroblast growth factor-a (aFGF), bFGF, transforming growth factor-alpha (TGF-alpha), TGF-beta, hepatocyte growth factor/scatter factor (HGF/SF), tumor necrosis factor-alpha (TNF-alpha), angiogenin, and interleukin-8 (IL-8) (Folkman and Shing, 1992; Risau, 1997). More recently, the angiopoietins, the ligands of the Tie-2 receptor (Suri et al., 1996; Maisonpierre et al., 1997), have been identified. Vascular endothelial growth factor (VEGF) is an endothelial-cell-specific mitogen. The finding that VEGF was potent and specific for vascular endothelial cells and, unlike bFGF, freely diffusible, led to the hypothesis that this molecule plays a unique role in the regulation of physiological and pathological angiogenesis (Ferrara and Henzel, 1989: Leung et al., 1989). Over the last few years, several additional members of the VEGF gene family have been identified, including placenta growth factor (PIGF) (Maglione et al., 1991,1993), VEGF-B (Olofsson et al., 1996), VEGF-C (Joukov et al., 1996; Lee et al., 1996), and VEGF-D (Orlandini et al., 1996. Achen et al., 1998). There is compelling evidence that VEGF plays an essential role in the development and differentiation of the cardiovascular system (Ferrara and Davis-Smyth, 1997).
Multistep signaling and transcriptional requirements for pituitary organogenesis in vivo.
Rosenfeld MG, Briata P, Dasen J … +7 more , Gleiberman AS, Kioussi C, Lin C, O'Connell SM, Ryan A, Szeto DP, Treier M
Recent Prog Horm Res · 2000 · PMID 11036930
During development of the mammalian pituitary gland, specific hormone-producing cell types, critical in maintaining homeostasis, emerge in a spatially and temporally specific fashion from an ectodermal primordium. We hav...
During development of the mammalian pituitary gland, specific hormone-producing cell types, critical in maintaining homeostasis, emerge in a spatially and temporally specific fashion from an ectodermal primordium. We have investigated the molecular basis of generating diverse cell phenotypes from a common precursor, providing in vivo and in vitro evidence that development of these cell types involves at least four sequential phases of signaling events and the action of a gradient at an ectodermal boundary. In the first phase, we hypothesize that this notochord induces invagination of Rathke's pouch from the oral ectoderm. This is followed by appearance of an ectodermal boundary, formed with exclusion of Shh from the nascent pouch. Next, signals from the ventral diencephalon--expressing BMP4, Wnt5a, FGF10, and FGF8--in concert with Shh represent critical in vivo signals for pituitary determination. Subsequently, a dorsal-ventral BMP2 signal gradient emanates from a ventral pituitary organizing center, forming at the boundary to oral ectoderm region from which Shh expression is selectively excluded. In concert with a dorsal FGF8 signal, this creates opposing gradients that generate overlapping patterns of specific transcription factors that underlie cell lineage specification events. The mechanisms by which these transient gradients of signaling molecules lead to the appearance of four ventral pituitary cell types appear to involve the reciprocal interactions of two transcription factors, Pit-1 and GATA-2, which are epistatic to the remainder of the cell type-specific transcription programs and serve as a molecular memory of the transient signaling events. Unexpectedly, this program includes a DNA-binding-independent function of Pit-1, suppressing the ventral GATA-2-dependent gonadotrope program by inhibiting GATA-2 binding to gonadotrope- but not thyrotrope-specific genes. This indicates that both DNA-binding-dependent and-independent actions of abundant determining factors contribute to generate distinct cell phenotypes. In the fourth phase, temporally specific loss of the BMP2 signal is required to allow terminal differentiation. The consequence of these sequential organ and cellular determination events is that each of the pituitary cell types--gonadotropes, thyrotropes, somatotropes, lactotropes, corticotropes, and melanotropes appears to be determined, in a ventral to dorsal gradient, respectively, apparently based on a combinatorial code of transcription factors induced by the gradient of specific signaling molecules.
Regulation of glycoprotein hormone alpha-subunit gene expression.
Maurer RA, Kim KE, Schoderbek WE … +2 more , Roberson MS, Glenn DJ
Recent Prog Horm Res · 1999 · PMID 10548887
The appropriate, regulated expression of the glycoprotein hormone subunit genes is required to enable the biosynthesis of luteinizing hormone, follicle-stimulating hormone, thyroid-stimulating hormone, and chorionic gona...
The appropriate, regulated expression of the glycoprotein hormone subunit genes is required to enable the biosynthesis of luteinizing hormone, follicle-stimulating hormone, thyroid-stimulating hormone, and chorionic gonadotropin. We have focused our attention on mechanisms mediating regulated transcription of the common alpha-subunit gene. Our studies have examined both the signaling mechanisms and the DNA elements and transcription factors that are important for alpha-subunit expression. Our initial efforts involved characterization of DNA elements of the alpha-subunit gene important for basal and GnRH-stimulated expression. Clustered point mutation analysis identified two different, unrelated sequences that play a role in alpha-subunit transcription. When tested as multiple copies on a minimal promoter, one of these elements was sufficient to permit a response to GnRH, while the other enhanced basal expression. Therefore, we designated these DNA elements as the GnRH-response element (GnRH-RE) and the pituitary glycoprotein hormone basal element (PGBE), respectively. The GnRH-RE contains a consensus binding site for the Ets family of transcription factors. As several Ets factors have been shown to mediate transcriptional responses to the mitogen-activated protein kinase (MAPK) pathway, we investigated the possibility that GnRH effects on alpha-subunit transcription may involve the MAPK cascade. We found that GnRH can indeed activate MAPK and that MAPK activation is sufficient and necessary for transcriptional activation of the alpha-subunit gene. Efforts to further characterize proteins that interact with the PGBE led to the cloning of a LIM-homeodomain transcription factor designated LH-2. Recombinant LH-2 selectively binds to the PGBE in vitro. Transfection experiments have shown that an expression vector for LH-2 can activate the alpha-subunit promoter in heterologous cells. LH-2 appears to be a component of the endogenous factors that bind to the PGBE. Thus, LH-2 appears to be an excellent candidate as a factor responsible for basal expression of the alpha-subunit gene. Overall, these studies have contributed to identification of molecular components important for regulated expression of the glycoprotein hormone alpha-subunit gene.
The role of PTEN, a phosphatase gene, in inherited and sporadic nonmedullary thyroid tumors.
Eng C
Recent Prog Horm Res · 1999 · PMID 10548886
PTEN/MMACI/TEP1, a tumor suppressor gene located on 10q23.3, encodes an almost ubiquitously expressed dual-specificity phosphatase. Germline mutations in PTEN have been found in the majority of cases of sporadic and fami...
PTEN/MMACI/TEP1, a tumor suppressor gene located on 10q23.3, encodes an almost ubiquitously expressed dual-specificity phosphatase. Germline mutations in PTEN have been found in the majority of cases of sporadic and familial Cowden syndrome (CS), an autosomal dominant inherited cancer syndrome characterised by multiple hamartomas and benign and malignant disease of the thyroid and breast. Interestingly, germline mutations in PTEN have also been found in about 50% of a related but distinct disorder, Bannayan-Ruvalcaba-Riley syndrome (BRR), which is characterised by neonatal-onset macrocephaly, mental retardation, Hashimoto's thyroiditis, lipomatosis, haemangiomas, hamartomatous polyps, and pigmented macules of the glans penis. Somatic PTEN mutation has been described to a greater or lesser extent in various benign and malignant tumor types. Somatic deletions have been described in follicular adenomas of the thyroid and papillary thyroid carcinomas.
Multiple endocrine neoplasia type 1: clinical and genetic features of the hereditary endocrine neoplasias.
Marx SJ, Agarwal SK, Kester MB … +20 more , Heppner C, Kim YS, Skarulis MC, James LA, Goldsmith PK, Saggar SK, Park SY, Spiegel AM, Burns AL, Debelenko LV, Zhuang Z, Lubensky IA, Liotta LA, Emmert-Buck MR, Guru SC, Manickam P, Crabtree J, Erdos MR, Collins FS, Chandrasekharappa SC
Recent Prog Horm Res · 1999 · PMID 10548885
MEN1 is a syndrome of parathyroid adenomas, gastrinomas, prolactinomas, and other endocrine tumors. Collagenomas and facial angiofibromas are newly recognized but common skin expressions. Many tumors in MEN1 are benign;...
MEN1 is a syndrome of parathyroid adenomas, gastrinomas, prolactinomas, and other endocrine tumors. Collagenomas and facial angiofibromas are newly recognized but common skin expressions. Many tumors in MEN1 are benign; however, many entero-pancreatic neuroendocrine tumors and foregut carcinoid tumors are malignant. MEN1 is thus the expression of a cancer gene but without available prevention or cure for malignancy. Hereditary (as compared to sporadic) endocrine tumors show early onset age and multiplicity, because each cell of the body has "one hit" by inheritance. Multiple neoplasia syndromes with endocrine tumor(s) all include nonendocrine components; their known defective genes seem mainly to disturb cell accumulation. Hereditary neoplasia/hyperplasia of one endocrine tissue reflects a defect that is tissue selective and directed at cell secretion. Though the hereditary endocrine neoplasias are rare, most of their identified genes also contribute to common sporadic endocrine neoplasms. Hereditary tumors may be caused by activation of an oncogene (e.g., RET) or, more often, by inactivation of a tumor suppressor gene (e.g., P53, MEN1). Recently, MEN1 was identified by positional cloning. This strategy included narrowing the gene candidate interval, identifying many or all genes in that interval, and testing the newly identified candidate genes for mutation in MEN1 cases. MEN1 was identified because it showed mutation in 14 of 15 MEN1 cases. NIH testing showed germline MEN1 mutations in 47 of 50 MEN1 index cases and in seven of eight cases with sporadic MEN1. Despite proven capacity to find germline MEN1 mutation, NIH testing found no MEN1 mutation among five families with isolated hyperparathyroidism, suggesting that this often arises from mutation of other gene(s). Analogous studies in Japan found that familial isolated pituitary tumors also did not show MEN1 germline mutation. MEN1 mutation testing can now be considered for cases of MEN1 and its phenocopies and for asymptomatic members of families with known MEN1 mutation. Germline MEN1 testing does not have the urgency of RET testing in MEN2a and 2b, as MEN1 testing does not commonly lead to an important intervention. Somatic MEN1 mutation was found in sporadic tumors: parathyroid adenoma (21%), gastrinoma (33%), insulinoma (17%), and bronchial carcinoid (36%). For each of these, MEN1 was the known gene most frequently mutated. MEN1 has a widely expressed mRNA that encodes a protein (menin) of 610 amino acids. The protein sequence is not informative about domains or functions. The protein was mainly nuclear. Menin binds to JunD, an AP-1 transcription factor, inhibiting JunD's activation of transcription. Most of the germline and somatic MEN1 mutations predict truncation of menin, a likely destructive change. Inactivating MEN1 mutations in germline and in sporadic neoplasms support prior predictions that MEN1 is a tumor suppressor gene. Germline MEN1 mutation underlies all or most cases of MEN1 (familial or sporadic). Somatic MEN1 mutation is the most common gene mutation in many sporadic endocrine tumor types.
The steroidogenic acute regulatory protein (StAR): a window into the complexities of intracellular cholesterol trafficking.
Strauss JF, Kallen CB, Christenson LK … +5 more , Watari H, Devoto L, Arakane F, Kiriakidou M, Sugawara T
Recent Prog Horm Res · 1999 · PMID 10548884
Stimulation of steroid-producing cells of the gonads and adrenals with tropic hormone results in a marked increase in steroid hormone synthesis within minutes. The rate-limiting step in this acute steroidogenic response...
Stimulation of steroid-producing cells of the gonads and adrenals with tropic hormone results in a marked increase in steroid hormone synthesis within minutes. The rate-limiting step in this acute steroidogenic response is the transport of cholesterol from the outer to the inner mitochondrial membrane, where the first committed step in steroid synthesis is performed by the side-chain cleavage enzyme system. This process of cholesterol translocation is blocked by inhibitors of protein synthesis, suggesting that the effect of trophic hormones, acting through the intermediacy of cAMP, most likely involves the de novo synthesis of a protein that is rapidly inactivated. The recently identified steroidogenic acute regulatory (StAR) protein appears to be the most likely candidate for the "labile" protein, based on the following observations: 1) Expression of StAR in COS-1 cells engineered to contain the cholesterol side-chain cleavage system substantially augments pregnenolone formation; 2) StAR protein is expressed almost exclusively in steroid-producing cells, except the trophoblast of the human placenta, and its presence is correlated with steroid hormone production; 3) StAR mRNA increases in response to cAMP; 4) StAR is a target for serine phosphorylation mediated by protein kinase A, a process that is essential for maximizing StAR activity; and 5) lack of functional StAR causes the autosomal recessive disease, congenital lipoid adrenal hyperplasia, characterized by markedly impaired gonadal and adrenal steroid hormone synthesis. Studies on the mechanism of action of StAR revealed that import into mitochondria is not essential to its steroidogenesis-enhancing activity and more likely represents a means of rapidly inactivating StAR. Truncation mutations and site-directed mutations established that the C-terminus of the StAR protein contains the functionally important domains. The demonstration of steroidogenic activity of recombinant StAR protein on isolated mitochondria from bovine corpus luteum using protein that lacks the mitochondrial targeting sequence confirmed that StAR import is not essential for its steroidogenic activity and suggested that StAR acts directly on the outer mitochondrial membrane in the absence of intermediary cytosolic factors. Evidence that StAR functions as a cholesterol transfer protein raises the possibility that StAR acts directly on lipids of the outer mitochondrial membrane, probably stimulating cholesterol desorption from the sterol-rich outer membrane and its movement to the relatively sterol-poor inner membrane.
The PPARs and PXRs: nuclear xenobiotic receptors that define novel hormone signaling pathways.
Kliewer SA, Lehmann JM, Milburn MV … +1 more , Willson TM
Recent Prog Horm Res · 1999 · PMID 10548883
Traditional pharmacologic approaches had identified several classes of xenobiotics that elicited characteristic biological effects in vivo but that lacked defined molecular mechanisms of action. Among these xenobiotics w...
Traditional pharmacologic approaches had identified several classes of xenobiotics that elicited characteristic biological effects in vivo but that lacked defined molecular mechanisms of action. Among these xenobiotics were the peroxisome proliferators, the thiazolidinediones (TZDs), and a set of compounds that induced the expression of cytochrome P450 (CYP) 3A genes and promoted the metabolism of other xenobiotics. All three classes of xenobiotics are now known to exert their actions through activation of orphan members of the nuclear receptor family of ligand-activated transcription factors. Peroxisome proliferators are a diverse group of amphipathic acids that include the fibrate class of triglyceride- and cholesterol-lowering drugs. TZDs sensitize tissues such as skeletal muscle, liver, and adipose to the actions of insulin and lower glucose and lipid levels in type 2 diabetics. The peroxisome proliferators and TZDs are now known to mediate their effects through the peroxisome proliferator-activated receptors (PPARs) alpha and gamma, respectively. The activities of these compounds established the PPARs as key regulators of glucose and lipid homeostasis. We and others have recently shown that various naturally occurring fatty acids and eicosanoids serve as PPAR ligands, suggesting a novel regulatory mechanism whereby dietary lipids and their metabolites can regulate gene transcription and impact overall energy balance. The third class of xenobiotics we have studied induces the expression of CYP3A genes, mono-oxygenases responsible for the metabolism of natural steroids as well as a variety of xenobiotics, including > 60% of all drugs. We have recently shown that compounds that induce CYP3A gene expression do so through activation of novel orphan receptors, termed the pregnane X receptors (PXRs). Many of the PXR activators are widely used drugs such as dexamethasone, lovastatin, and rifampicin, whose induction of CYP3A levels causes them to promote the metabolism of other drugs, often with adverse consequences. Thus, the finding that the PXRs regulate CYP3A gene expression provides a basis for the efficient identification and elimination of candidate drugs that will interact with other medicines. Searches for natural ligands have revealed that the PXRs are activated by C21 steroids, including pregnenolone and progesterone, suggesting that these orphan receptors define a novel steroid hormone signaling pathway. In sum, work from our laboratories and others has demonstrated that peroxisome proliferators, TZDs, and inducers of CYP3A gene expression exert their biological actions through the activation of orphan nuclear receptors. These findings provide insights into new endocrine signaling pathways and have important implications for the discovery of safer and more efficacious drugs for the treatment of a variety of diseases.
Enzymology and biology of CaaX protein prenylation.
Fu HW, Casey PJ
Recent Prog Horm Res · 1999 · PMID 10548882
Protein prenylation refers to a type of lipid modification in which either a 15-carbon farnesyl or 20-carbon geranylgeranyl isoprenoid is linked via a thioether bond to specific cysteine residues of proteins. The majorit...
Protein prenylation refers to a type of lipid modification in which either a 15-carbon farnesyl or 20-carbon geranylgeranyl isoprenoid is linked via a thioether bond to specific cysteine residues of proteins. The majority of prenylated proteins belong to a group termed "CaaX proteins" that are defined by a specific C-terminal motif that directs their modification by this process. The ménage of CaaX-type prenylated proteins encompasses a wide variety of molecules that are found primarily at the cytoplasmic face of cellular membranes. These include nuclear lamins, Ras and a multitude of GTP-binding proteins (G proteins), several protein kinases and phosphatases, as well as other important proteins. A tremendous number of cellular signaling processes and regulatory events are under the control of CaaX prenyl proteins. While the attached isoprenoid lipids, in general, support the membrane association of the modified proteins, some proteins also clearly participate directly in protein-protein interactions. This chapter will emphasize 1) the biochemistry of the two enzymes termed farnesyltransferase and geranylgeranyltransferase type I, responsible for CaaX protein prenylation, and 2) biological roles for these modifications. Throughout, we will attempt to highlight the significance of prenylation in specific cellular events. The critical importance of this class of lipid modifications is attested to by the emergence of farnesyltransferase as a target for the development of anti-cancer therapeutics.
The A and B isoforms of the human progesterone receptor: two functionally different transcription factors encoded by a single gene.
Giangrande PH, McDonnell DP
Recent Prog Horm Res · 1999 · PMID 10548881
In humans, the biological response to progesterone is mediated by two forms of the progesterone receptor (hPR-A; 94kDa and hPR-B; 114kDa). These two isoforms are transcribed from distinct, estrogen-inducible promoters wi...
In humans, the biological response to progesterone is mediated by two forms of the progesterone receptor (hPR-A; 94kDa and hPR-B; 114kDa). These two isoforms are transcribed from distinct, estrogen-inducible promoters within a single-copy progesterone receptor (PR) gene; the only difference between them is that the first 164 amino acids of hPR-B are absent in hPR-A. In most cell lines, hPR-A functions as a transcriptional repressor of progesterone-responsive promoters, whereas hPR-B functions as a transcriptional activator of the same genes. The observation, made in the early 1990s, that shorter isoforms of some transcriptional activators can act as transrepressors of the transcriptional activity of the larger isoforms, initiated a line of investigation that led to the discovery that hPR-A is a strong transrepressor of hPR-B activity. Interestingly, hPR-A also functions as a transdominant repressor of the transcriptional activity of the estrogen, glucocorticoid, androgen, and mineralocorticoid receptors. A specific inhibitory domain (ID) within hPR-A responsible for this activity has been mapped to the extreme amino terminus of the receptor. Interestingly, although this inhibitory domain is contained within both PR isoforms, its activity is manifest only in the context of hPR-A. The identification of a discrete inhibitory region within hPR-A, whose activity was masked in the context of hPR-B, suggests that these two receptor isoforms may interact with different proteins (transcription factors, co-activators, co-repressors) within the cell. In support of this hypothesis, we have recently observed that the co-repressor SMRT (silencing mediator of retinoid and thyroid receptors) interacts much more tightly with hPR-A than with hPR-B. This important finding led to the initial conclusion that the ability of hPR-A to repress hPR-B transcriptional activity could occur as a consequence of hPR-B/A heterodimerization, where the presence of SMRT in the complex could prevent transcriptional activation. The observation, however, that hPR-A also inhibits human estrogen receptor (hER) transcriptional activity, a receptor with which hPR-A is not able to heterodimerize, suggests that there must be additional complexity. This chapter outlines what is known about the mechanism of action of hPR-A and hPR-B and how this knowledge has enhanced our understanding of PR pharmacology.
Glycoprotein hormone structure-function and analog design.
Boime I, Ben-Menahem D
Recent Prog Horm Res · 1999 · PMID 10548880
Human chorionic gonadotropin (hCG), luteinizing hormone, follicle-stimulating hormone (FSH), and thyrotropin (TSH) are hormones that share a common alpha subunit but differ in their beta subunits. Recombinant DNA techniq...
Human chorionic gonadotropin (hCG), luteinizing hormone, follicle-stimulating hormone (FSH), and thyrotropin (TSH) are hormones that share a common alpha subunit but differ in their beta subunits. Recombinant DNA techniques, valuable tools for structure-function analyses, provide an approach for designing therapeutic analogs. FSH is used clinically to stimulate the ovarian follicles for in vitro fertilization and to initiate follicular maturation in women with infertility problems. The CG beta subunit contains a carboxy-terminal extension (CTP) with four serine O-linked oligosaccharides, which is important for the long half-life of hCG. A clinical problem of FSH is its relatively short half-life in circulation. Fusing CTP to the FSH beta coding sequence increased the in vivo potency of the resulting FSH dimer over three-fold. Analogs of the other hormones containing CTP also increase their biologic half-life. Subunit assembly is vital to the function of these hormones. To address whether alpha and beta subunits can be synthesized as one chain and also maintain biological activity, a chimera comprised of the hCG beta subunit genetically fused to the alpha subunit was constructed. The resulting polypeptide was efficiently secreted and displayed an increased biologic activity in vitro and in vivo. Similarly, the single-chain form of FSH also retained in vivo activity. Since subunit dissociation inactivates the activity of the heterodimer, single-chain analogs should have longer biological half-lives. These analogs represent suitable substrates for engineering potent and stable agonists and antagonists.
Apoptosis and cell death in the endocrine system.
Mountz JD, Zhang HG, Hsu HC … +4 more , Fleck M, Wu J, al-Maini MH, Zhou T
Recent Prog Horm Res · 1999 · PMID 10548879
Inflammatory diseases of the endocrine system--such as thyroiditis, diabetes, and Graves' disease--are considered to be autoimmune in origin. More recently, these and other autoimmune diseases have been associated with d...
Inflammatory diseases of the endocrine system--such as thyroiditis, diabetes, and Graves' disease--are considered to be autoimmune in origin. More recently, these and other autoimmune diseases have been associated with defects in Fas apoptosis. The mutation of the Fas or Fas ligand (FasL) has been observed in a minority of patients with autoimmune disease. However, dysfunction of the Fas apoptosis signaling pathway or production of soluble factors, including sFas and sFasL, may be more prevalent. Certain endocrine tissues, such as the testes, are immune privilege sites. Defects in Fas and FasL expression in immune privilege sites can trigger an inflammatory response. Other factors that trigger inflammatory diseases of the thyroid or islets may be loss of self tolerance, leading to an autoimmune response. An infectious trigger or other environmental agent can initiate organ damage, leading to release of new antigens that initiate the autoreactive process. We have developed a murine cytomegalovirus model of Sjögren's syndrome in which defects in the Fas/FasL pathway are necessary to enable chronic inflammation, even after the initial virus has been cleared. Another interaction between the endocrine system and apoptosis is by direct hormone interaction. This is exemplified by the orphan steroid receptor Nur77. Nur77 is important for T cell apoptosis after signaling through CD3. We have demonstrated that a dominant-negative Nur77 transgenic mouse exhibits a defect in thymic selection of T cells. Therefore, there are many potential mechanisms by which endocrine glands or hormones can affect the Fas apoptosis pathway, resulting in either cell death or a chronic inflammatory disease in the endocrine system, leading to hypothyroidism and diabetes. This inflammatory dysfunction can be reversed by a dominant-negative I kappa B that prevents nuclear translocation of NF-kappa B. We have developed antigen-specific, antigen-presenting cells that express high levels of FasL that can prevent tissue-specific inflammatory disease. Treatment with these cells prevents development of diabetes in NOD mice. Further understanding of the role and regulation of apoptosis in diseases of the endocrine system (e.g., diabetes, thyroiditis) should lead to better methods of treatment and prevention of these diseases.
Control of apoptosis signaling by Apo2 ligand.
Marsters SA, Pitti RA, Sheridan JP … +1 more , Ashkenazi A
Recent Prog Horm Res · 1999 · PMID 10548878
Apo2 ligand (Apo2L, also called TRAIL) is a member of the tumor necrosis factor (TNF) cytokine family. The closest homolog of Apo2L is CD95 (Fas/Apo1) ligand, to which it has 24% amino acid sequence identity. Similar to...
Apo2 ligand (Apo2L, also called TRAIL) is a member of the tumor necrosis factor (TNF) cytokine family. The closest homolog of Apo2L is CD95 (Fas/Apo1) ligand, to which it has 24% amino acid sequence identity. Similar to CD95L, Apo2L activates rapid apoptosis in many types of cancer cells; however, whereas CD95L mRNA expression is restricted mainly to activated T cells, natural killer cells, and immune-privileged sites, Apo2L mRNA occurs in a wide variety of tissues. Most normal cells appear to be resistant to Apo2L's cytotoxic action, suggesting the existence of mechanisms that can protect against apoptosis induction by Apo2L. The first receptor described for Apo2L, called death receptor 4 (DR4), contains a cytoplasmic "death domain"; DR4 transmits the apoptosis signal carried by Apo2L. We have identified three additional receptors that bind to Apo2L. One receptor, called DR5, contains a cytoplasmic death domain and signals apoptosis much like DR4. The DR4 and DR5 mRNAs are expressed in many normal tissues and tumor cell lines. The second receptor, designated decoy receptor 1 (DcR1), is a phospholipid-anchored cell-surface protein that lacks a cytoplasmic tail. The third receptor, called DcR2, is structurally similar to DR4 and DR5 but has a truncated cytoplasmic death domain and does not transmit a death signal. The mRNAs for DcR1 and DcR2 are expressed in multiple normal tissues but in few tumor cell lines. Transfection experiments indicate that DcR1 and DcR2 act as decoys that prevent Apo2L from inducing apoptosis through DR4 and DR5. These decoy receptors thus represent a novel mechanism for regulating sensitivity to a pro-apoptotic cytokine directly at the cell's surface. The preferential expression of these inhibitory receptors in normal tissues suggests that Apo2L may be useful as an anticancer agent that induces apoptosis in cancer cells while sparing normal cells.
Programmed cell death in the nematode C. elegans.
Hengartner MO
Recent Prog Horm Res · 1999 · PMID 10548877
Programmed cell death is a common feature during animal development. In the nematode C. elegans, more than 12 genes have been identified that function in the apoptotic killing and elimination of 131 of the 1090 cells tha...
Programmed cell death is a common feature during animal development. In the nematode C. elegans, more than 12 genes have been identified that function in the apoptotic killing and elimination of 131 of the 1090 cells that are generated during hermaphrodite development. These genes divide the process of programmed cell death into three distinct steps: execution of the death sentence; engulfment of dying cells; and degradation of dead, engulfed cells. Biochemical characterization of the genes in this pathway has led to the identification of an apoptotic machinery that mediates apoptotic death in this species. The proximal cause of apoptosis in C. elegans is the activation of the caspase homolog CED-3 from the inactive zymogen (proCED-3) into the mature protease. This activation is mediated by the Apaf-1 homolog CED-4. In cells that should survive, CED-3 and CED-4 pro-apoptotic activity is antagonized by the Bcl-2 family member CED-9. CED-9 has been proposed to prevent death by sequestering CED-4 and proCED-3 in an inactive ternary complex, the apoptosome. In cells fated to die, CED-9 is, in turn, inactivated by the pro-apoptotic BH3 domain-containing protein EGL-1, likely through a direct protein-protein interaction. The structural and functional conservation of cell death genes between nematodes and mammals strongly suggests that the apoptotic program is ancient in origin and that all metazoans share a common mechanism of apoptotic cell killing.
Phytoestrogens in health and disease.
Davis SR, Dalais FS, Simpson ER … +1 more , Murkies AL
Recent Prog Horm Res · 1999 · PMID 10548876
Phytoestrogens are compounds found in a wide variety of plant foods that historically are said to exhibit estrogen-like activity and, more recently, have been reported to display both estrogenic and anti-estrogenic effec...
Phytoestrogens are compounds found in a wide variety of plant foods that historically are said to exhibit estrogen-like activity and, more recently, have been reported to display both estrogenic and anti-estrogenic effects. Population-based studies have been interpreted to suggest that consumption of a phytoestrogen-rich diet is protective against breast, prostate, and bowel cancer and cardiovascular disease and ameliorates estrogen-deficiency symptoms in postmenopausal women. Consequently, there is a global movement towards increased consumption of phytoestrogen-rich foods and tabletized concentrated isoflavone extracts are being heavily promoted. Evaluating the effects and hence the potential benefits and risks of phytoestrogens is a complex task. The interindividual diversity and complexity in dietary phytoestrogen absorption and metabolism make the bioactivity of these compounds unpredictable. Epidemiological studies of relationships between phytoestrogens and cancer and cardiovascular disease that take into account confounding factors are scarce. Results of many of the in vitro and in vivo studies are conflicting and confusing. These compounds do not simply mimic the effects of human steroidal estrogen but rather demonstrate both similar and divergent actions. The ultimate actions of these compounds in specific cells are determined by many factors, including the relative levels of estrogen receptor (ER) alpha and ER beta and the diverse cocktail of co-activators and co-repressors present in any given cell type. Therefore, effects vary according to the phytoestrogen studied, cell line, tissue, species, and response being evaluated. Overall, it is naive to assume that exposure to these compounds is always good; inappropriate or excessive exposure may be detrimental. Extensive documentation of the specific intracellular effects of the various phytoestrogens in different tissues, the relationships between timing and duration of exposure and disease, and results from prospective randomized studies in humans of their clinical effects and potential side effects are essential. Only then can widespread recommendations regarding the dietary and pharmacological intake of these compounds be made.
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