RESUMO
Dysregulation of the fibroblast growth factors/fibroblast growth factor receptor (FGF/FGFR) pathway has been implicated in a wide range of human disorders and several members have been localized in the nuclear compartment. Hormone-activated steroid receptors or ligand independent activated receptors form nuclear complexes that activate gene transcription. This review aims to highlight the interplay between the steroid receptor and the FGF/FGFR pathways and focuses on the current knowledge on nuclear action of FGF members in endocrine-related tissues and cancer. The nuclear trafficking and targets of FGF/FGFR members and the available evidence on the interplay with steroid hormones and receptors is described. Finally, the data on aberrant FGF/FGFR signaling is summarized and the nuclear action of FGF members on endocrine resistant breast cancer is highlighted. Identifying the mechanisms underlying FGF-induced endocrine resistance will be important to understand how to efficiently target endocrine-related diseases and even enhance or restore endocrine sensitivity in hormone receptor positive tumors.
Assuntos
Núcleo Celular/metabolismo , Sistema Endócrino/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Neoplasias/metabolismo , Receptores de Esteroides/metabolismo , Animais , Fatores de Crescimento de Fibroblastos/genética , HumanosRESUMO
In this chapter, we summarize the birth of the field of nuclear receptors. These receptors exhibit a multitude of roles in cell biology and hence have attracted a great deal of interest in the drug discovery field. It is not certain whether these receptors evolved independently or an ancestral protein acquired various functions upon binding to preexisting small molecules, ligands. Currently, members of this receptor superfamily are categorized in six groups, including "orphan receptors." Research in the area has resulted in several clinically used drugs and continues to reveal further previously unknown roles for these receptors paving the road toward more valuable discoveries in the future.
Assuntos
Receptores Nucleares Órfãos/metabolismo , Receptores de Esteroides/metabolismo , Transdução de Sinais , Animais , Humanos , Ligantes , Receptores Nucleares Órfãos/fisiologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/fisiologia , Receptores de Esteroides/fisiologiaRESUMO
Steroid receptors are members of a subfamily of the nuclear receptor superfamily. They play a dual role of steroid hormone receptors and transcription factors. Actually, these receptors are steroid-activated transcription factors. Classical soluble receptors exist as oligomeric complexes with the Hsp90-based chaperone machinery. The steroid receptor field was born and developed along with the molecular chaperone field. Chaperones are not exclusive partners associated to these receptors, but also comprise a large variety of heterocomplexes with other proteins involved in signal transduction. By using the glucocorticoid receptor (GR) as a standard model for most Hsp90-client proteins, in this chapter we describe the functional GR·Hsp90 heterocomplex assembly system from reticulocyte lysate or purified proteins.
Assuntos
Proteínas de Choque Térmico HSP90/metabolismo , Técnicas In Vitro/métodos , Multimerização Proteica , Receptores de Glucocorticoides/metabolismo , Animais , Estrutura Quaternária de Proteína , Coelhos , Receptores de Glucocorticoides/química , Reticulócitos/metabolismoRESUMO
In this article we summarize the birth of the field of nuclear receptors, the discovery of untransformed and transformed isoforms of ligand-binding macromolecules, the discovery of the three-domain structure of the receptors, and the properties of the Hsp90-based heterocomplex responsible for the overall structure of the oligomeric receptor and many aspects of the biological effects. The discovery and properties of the subfamily of receptors called orphan receptors is also outlined. Novel molecular aspects of the mechanism of action of nuclear receptors and challenges to resolve in the near future are discussed.
RESUMO
The cervix is a dynamic structure that undergoes dramatic changes during the estrous cycle, pregnancy and parturition. It is well established that hormonal changes, including estrogens, progestogens and prostaglandins, regulate the expression of key proteins involved in cervical function. The arachidonic acid cascade is important in the remodeling and relaxation of the cervix in the days preceding parturition. Despite the complexity of this mechanism, regulation of cervical function has received little study in the mare. Therefore, the objective of this study was to compare the expression of estrogen receptor α (ESR1) and ß (ESR2), progesterone receptor (PGR), prostaglandin E2 type 2 (PTGER2) and type 4 (PTGER4) receptors as well as cyclooxygenase-1 (PTGS1) and -2 (PTGS2) in the equine cervical mucosa and stroma during estrus, diestrus and late pregnancy using qPCR. Immunohistochemistry was used to localize ESR1, ESR2, PGR, PTGER2 and PTGER4 receptors in these regions of the cervix. Relative mRNA expression of ESR1 and PGR was greater during estrus and diestrus than in late pregnancy in both the mucosa and stroma of the cervix. Expression of PTGER2 was highest in the cervical stroma during late pregnancy compared to either estrus or diestrus. Moreover, PTGS1 expression in mucosa and PTGS2 in stroma was greater during late pregnancy compared with estrus, but not diestrus. Immunostaining for ESR1, ESR2, PGR, PTGER2 and PTGER4 was consistently detected in the nucleus and cytoplasm of epithelium of the endocervix as well as the smooth muscle cytoplasm of the cervix in all stages evaluated. Immunolabeling in smooth muscle nuclei was detected for ESR1 and PGR in estrus, diestrus and late pregnancy, and for ESR2 in estrus and late pregnancy stages. The changes noted in late gestation likely reflect preparation of the equine cervix for subsequent parturition.
Assuntos
Colo do Útero/metabolismo , Regulação da Expressão Gênica , Cavalos/fisiologia , Prostaglandina-Endoperóxido Sintases/genética , Receptores de Prostaglandina E/genética , Receptores de Esteroides/genética , Animais , Diestro , Estro , Feminino , Gravidez , Prostaglandina-Endoperóxido Sintases/metabolismo , Receptores de Prostaglandina E/metabolismo , Receptores de Esteroides/metabolismoRESUMO
Immunophilins are a family of intracellular receptors for immunosuppressive drugs. Those immunophilins that are related to immunosuppression are the smallest proteins of the family, i.e., FKBP12 and CyPA, whereas the other members of the family have higher molecular weight because the show additional domains to the drug-binding site. Among these extra domains, the TPR-domain is perhaps the most relevant because it permits the interaction of high molecular weight immunophilins with the 90-kDa heat-shock protein, Hsp90. This essential molecular chaperone regulates the biological function of several protein-kinases, oncogenes, protein phosphatases, transcription factors and cofactors . Hsp90-binding immunophilins where first characterized due to their association with steroid receptors. They regulate the cytoplasmic transport and the subcellular localization of these and other Hsp90 client proteins, as well as transcriptional activity, cell proliferation, cell differentiation and apoptosis. Hsp90-binding immunophilins are frequently overexpressed in several types of cancers and play a key role in cell survival. In this article we analyze the most important biological actions of the best characterized Hsp90-binding immunophilins in both steroid receptor function and cancer development and discuss the potential use of these immunophilins for therapeutic purposes as potential targets of specific small molecules.
Assuntos
Proteínas de Choque Térmico HSP90/metabolismo , Imunofilinas/metabolismo , Neoplasias/metabolismo , Animais , HumanosRESUMO
The objective of this study was to compare expression of estrogen receptor alpha (ER-α), ß (ER-ß), progesterone receptor (PR), as well as prostaglandin E2 type 2 (EP2) and 4 (EP4) receptors in the equine myometrium and endometrium during estrus, diestrus and early pregnancy. Tissues were collected during estrus, diestrus, and early pregnancy. Transcripts for ER-α (ESR1), ER-ß (ESR2), PR (PGR), EP2 (PTGER2) and EP4 (PTGER4) were quantified by qPCR. Immunohistochemistry was used to localize ER-α, ER-ß, PR, EP2 and EP4. Differences in transcript in endometrium and myometrium were compared by the ΔΔCT method. Expression for ESR1 (P<0.05) tended to be higher during estrus than diestrus in the endometrium (P=0.1) and myometrium (P=0.06). In addition, ESR1 expression was greater during estrus than pregnancy (P<0.05) in the endometrium and tended to be higher in estrus compared to pregnancy in the myometrium (P=0.1). Expression for PGR was greater (P<0.05) in the endometrium during estrus and diestrus than during pregnancy. In the myometrium, PGR expression was greater in estrus than pregnancy (P=0.05) and tended to be higher during diestrus in relation to pregnancy (P=0.07). There were no differences among reproductive stages in ESR2, PTGER2 and PTGER4 mRNA expression (P>0.05). Immunolabeling in the endometrium appeared to be more intense for ER-α during estrus than diestrus and pregnancy. In addition, immunostaining for PR during pregnancy appeared to be more intense in the stroma and less intense in glands and epithelium compared to estrus and diestrus. EP2 immunoreactivity appeared to be more intense during early pregnancy in both endometrium and myometrium, whereas weak immunolabeling for EP4 was noted across reproductive stages. This study demonstrates differential regulation of estrogen receptor (ER) and PR in the myometrium and endometrium during the reproductive cycle and pregnancy as well as abundant protein expression of EP2 in the endometrium and myometrium during early pregnancy in mares.