Scientists have long hypothesized the existence of tissue-specific (somatic) stem cells and have searched for their location in different organs. The theory that adrenocortical organ homeostasis is maintained by undifferentiated stem or progenitor cells can be traced back nearly a century. Similar to other organ systems, it is widely believed that these rare cells of the adrenal cortex remain relatively undifferentiated and quiescent until needed to replenish the organ, at which time they undergo proliferation and terminal differentiation. Historical studies examining cell cycle activation by label retention assays and regenerative potential by organ transplantation experiments suggested that the adrenocortical progenitors reside in the outer periphery of the adrenal gland. Over the past decade, the Hammer laboratory, building on this hypothesis and these observations, has endeavored to understand the mechanisms of adrenocortical development and organ maintenance. In this review, we summarize the current knowledge of adrenal organogenesis. We present evidence for the existence and location of adrenocortical stem/progenitor cells and their potential contribution to adrenocortical carcinomas. Data described herein come primarily from studies conducted in the Hammer laboratory with incorporation of important related studies from other investigators. Together, the work provides a framework for the emerging somatic stem cell field as it relates to the adrenal gland.
BackgroundMembers of the microRNA (miR)-200 family, which are involved in tumor metastasis, have potential as cancer biomarkers, but their regulatory mechanisms remain elusive.MethodsWe investigated FOXP3-inducible breast cancer cells, Foxp3 heterozygous Scurfy mutant (Foxp3 sf/+) female mice, and patients with breast cancer for characterization of the formation and regulation of the miR-200 family in breast cancer cells and circulation. Participants (259), including patients with breast cancer or benign breast tumors, members of breast cancer families, and healthy controls, were assessed for tumor and circulating levels of the miR-200 family.ResultsFirst, we identified a FOXP3-KAT2B-miR-200c/141 axis in breast cancer cells. Second, aging Foxp3 sf/+ female mice developed spontaneous breast cancers and lung metastases. Levels of miR-200c and miR-141 were lower in Foxp3 sf/+ tumor cells than in normal breast epithelial cells, but plasma levels of miR-200c and miR-141 in the Foxp3 sf/+ mice increased during tumor progression and metastasis. Third, in patients with breast cancer, the levels of miR-200c and 141 were lower in FOXP3 low relative to those with FOXP3 high breast cancer cells, especially in late-stage and metastatic cancer cells. The levels of miR-200c and miR-141 were higher in plasma from patients with metastatic breast cancer than in plasma from those with localized breast cancer, with benign breast tumors, with a family history of breast cancer, or from healthy controls. Finally, in Foxp3 sf/+ mice, plasma miR-200c and miR-141 appeared to be released from tumor cells.ConclusionsmiR-200c and miR-141 are regulated by a FOXP3-KAT2B axis in breast cancer cells, and circulating levels of miR-200c and miR-141 are potential biomarkers for early detection of breast cancer metastases.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-017-0858-x) contains supplementary material, which is available to authorized users.
Nuclear hormone receptors (NRs) mediate the transcriptional responses to a wide variety of physiological stimuli and thus function as important regulators of development, metabolism, and reproduction. By binding to specific DNA sequences, NRs serve as platforms for the recruitment of various coregulatory factors that effect gene regulation. Transcriptional coactivators often function either through their enzymatic activities (as in the examples of acetyl and methyl transferases) or through the formation of productive complexes with the basal transcription machinery. In contrast, corepressors often have enzymatic activities opposite those of coactivators, such as those of deactylases and demethylases. Thus, coregulators, by functioning as coactivators or corepressors of NR activity, play pivotal roles in mediating hormone action (reviewed in references 13 and 42).The best-characterized coactivators are the p160 family proteins SRC-1 (NCoA1), TIF2 (GRIP1/NCoA2/SRC-2), and AIB1 (pCIP/ACTR/NCoA3/SRC-3) (3, 51, 62, 66). These coactivators harbor autonomous activation domains and NR interaction domains (28,65). Recently, the steroid receptor RNA activator (SRA) has been characterized as the only known coregulator that can function as an RNA (36). SRA was shown to coactivate glucocorticoid receptors without direct physical interaction, as part of a ribonucleoprotein complex with p160 coactivators. In addition, SRA coactivates retinoic acid receptors, and this function is dependent upon SRA pseudouridinylation (78). SRA also functions as a thyroid hormone receptor (TR) coactivator by direct physical interaction (72). The TR SRA binding domain is a 41-amino-acid region located between the second zinc finger and the ligand binding domain. Although SRA-protein interactions play important roles in NR activity, the molecular mechanisms and biological functions of these interactions remain largely unknown.Steroidogenic factor 1 (SF-1/NR5A1/Ad4BP) belongs to the NR5A subfamily of orphan NRs that bind DNA with high affinity as monomers. SF-1 plays critical roles in the regulation of sex determination, adrenal and gonadal development, reproductive function, and steroidogenesis (16,40,41,52,63). SF-1 interacts with several transcriptional coactivators, such as SRC-1 (11, 25), TIF2 (17), and p300 (9), resulting in the induction of a large number of genes including those for the adrenocorticotropin hormone (ACTH) receptor/melanocortin 2 receptor (Mc2R) and steroidogenic acute regulatory protein (StAR) (58, 70). We and others have shown that sumoylation inhibits and phosphorylation activates SF-1 (73), while recent structural analyses have revealed that phospholipids can serve as activating SF-1 ligands (33, 37).Dax-1 (dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on X chromosome gene 1; NR0B1) is an unusual member of the nuclear receptor superfamily. Although the carboxyl-terminal region of Dax-1 is homologous to
Steroids can induce both transcription-dependent (genomic) and independent (nongenomic) signaling. Here, several classical androgen receptor ligands were tested for their ability to modulate genomic and nongenomic responses, focusing on the role of the oocyte-expressed Xenopus classical androgen receptor (XeAR) in mediating these processes. Cellular fractionation and immunohistochemistry revealed that the XeAR was located throughout oocytes, including within the plasma membrane. RNA interference and oocyte maturation studies suggested that androgen-induced maturation was mediated in part by the XeAR in a transcription-independent fashion, perhaps by altering G protein-mediated signaling. While inducing minimal transcription in oocytes, all AR ligands promoted significant XeAR-mediated transcription in CV1 cells. In contrast, only testosterone and androstenedione potently induced oocyte maturation, whereas dihydrotestosterone and R1881 actually inhibited testosterone and human chorionic gonadotropin-induced maturation and signaling. These results suggest that the nature of a steroid-induced signal (genomic vs. nongenomic) may depend on the type of target cell, the receptor location within cells, as well as the ligand itself. The identification of molecules capable of selectively altering genomic vs. nongenomic signaling may be useful in delineating the roles of these pathways in mediating androgen responses and might lead to the development of novel compounds that specifically modulate these signals in vivo.
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