Progesterone-RankL paracrine signaling has been proposed as a driver of stem cell expansion in the mammary gland, and Elf5 is essential for differentiation epithelial progenitor cells. We demonstrate that expression induced by progesterone cooperate to promote alveolar development. The receptor are expressed mutually exclusive pattern, we identify RankL mediator effects on CD61+ cells their consequent differentiation. Blockade action prevented progesterone-induced side branching Elf5(+)...

Early embryo miscarriage is linked to inadequate endometrial decidualization, a cellular transformation process that enables deep blastocyst invasion into the maternal compartment. Although much of events underpin stromal cell (ESC) decidualization are well recognized, individual gene(s) and molecular pathways drive initiation progression this remain elusive. Using genetic mouse model primary human ESC culture model, we demonstrate steroid receptor coactivator-2 (SRC-2) indispensable for...

Progesterone, via the progesterone receptor (PGR), is essential for endometrial stromal cell decidualization, a cellular transformation event in which fibroblasts differentiate into decidual cells. Uterine decidualization supports embryo implantation and placentation as well subsequent events, together ensure successful pregnancy. Accordingly, impaired results not only failure or early fetal miscarriage, but also may lead to potential adverse outcomes all three pregnancy trimesters....

Is Growth Regulation by Estrogen in Breast Cancer 1 (GREB1) required for progesterone-driven endometrial stromal cell decidualization? GREB1 is a novel progesterone-responsive gene human (HESC) decidualization. Successful establishment of pregnancy requires HESCs to transform from fibroblastic epithelioid cells process called This depends on the hormone progesterone, but molecular mechanisms which it occurs have not been determined. Primary and transformed expression was knocked down were...

Abstract The p53 transcription factor is a master regulator of cellular responses to stress that commonly inactivated in diverse cancer types. Despite decades research, the mechanisms by which impedes tumorigenesis across vastly different contexts requires further investigation. bulk research has been completed using vitro studies cell lines or vivo mouse models, but much less known about action non-transformed human tissues. Here, we investigated how states modify transcriptional program...

Understanding how androgen receptor (AR) function is modulated by exposure to steroids, growth factors or small molecules can have important mechanistic implications for AR-related disease therapies (e.g., prostate cancer, insensitivity syndrome, AIS), and in the analysis of environmental endocrine disruptors.We report development a high throughput (HT) image-based assay that quantifies AR subcellular subnuclear distribution, transcriptional reporter gene activity on cell-by-cell basis....

Infertility and early embryo miscarriage is linked to inadequate endometrial decidualization. Although transcriptional reprogramming known drive decidualization in response progesterone, the key signaling effectors that directly mediate this hormone are not fully known. This knowledge gap clinically significant because identifying signals progesterone-driven will address some of current limitations diagnosing therapeutically treating patients at most risk for pregnancy loss. We recently...

Aberrant expression of DNA polymerase β, a key enzyme involved in base excision repair, leads to genetic instability and carcinogenesis. Pol β has been previously shown be regulated at the level transcription, but there is also evidence post-transcriptional regulation, since rat transcripts undergo alternative polyadenylation, resulting 3′UTR contain least one regulatory element. Data presented here indicate that RNA short folds form strong secondary structure (hairpin). Its role was...

HAX-1 is a multi-functional protein that involved in the regulation of apoptosis, cell motility and calcium homeostasis. It also reported to bind RNA: it associates with structural motifs present 3' untranslated regions at least two transcripts, but functional significance this binding remains unknown. Although has been detected various cellular compartments, predominantly cytoplasmic. Our detailed localization studies isoforms revealed partial nuclear localization, extent which depends on...

Recent data from human and mouse studies strongly support an indispensable role for steroid receptor coactivator-2 (SRC-2)-a member of the p160/SRC family coregulators-in progesterone-dependent endometrial stromal cell decidualization, essential cellular transformation process that regulates invasion developing embryo into maternal compartment. To identify key progesterone-induced transcriptional changes are dependent on SRC-2 required we performed comparative genome-wide profiling tissue...

Abstract Despite the success of medical strategies to reduce androgen levels in treatment prostate cancer, this disease invariably relapses a castrate-resistant state that is generally fatal. Although it had been thought androgen-insensitive cancers no longer relied on receptor (AR) for growth and survival, now clear not case. Because are known occur by many mechanisms keep AR functionally active, block accumulation nucleus may be therapeutically useful. Here, we report discovery selective...

As pleiotropic coregulators, members of the p160/steroid receptor coactivator (SRC) family control a broad spectrum transcriptional responses that underpin diverse array physiological and pathophysiological processes. Because their potent coregulator properties, strict controls on SRC expression levels are required to maintain normal tissue functionality. Accordingly, an unwarranted increase in cellular has been causally linked initiation and/or progression number clinical disorders....

Androgen insensitivity syndrome (AIS) is a rare disease associated with inactivating mutations of AR that disrupt male sexual differentiation, and cause spectrum phenotypic abnormalities having as common denominator loss reproductive viability. No established treatment exists for these conditions, however there are sporadic reports patients (or recapitulated in cell lines) respond to administration supraphysiologic doses pulses) testosterone or synthetic ligands. Here, we utilize novel high...

Steroid receptor coactivator-3 (SRC-3; also known as NCOA3 or AIB1) is a member of the multifunctional p160/SRC family coactivators, which includes SRC-1 and SRC-2. Clinical cell-based studies well investigations on mice have demonstrated pivotal roles for each SRC in numerous physiological pathophysiological contexts, underscoring their functional pleiotropy. We previously critical involvement SRC-2 murine embryo implantation human endometrial stromal cell (HESC) decidualization, cellular...

Inactivation of the p53 tumor suppressor, either by mutations or through hyperactivation repressors such as MDM2 and MDM4, is a hallmark cancer. Although many inhibitors p53-MDM2/4 interaction have been developed, Nutlin, their therapeutic value limited highly heterogeneous cellular responses. We report here multi-omics investigation response to MDM2/4 inhibitors, leading identification FAM193A widespread regulator function. CRISPR screening identified necessary for Nutlin. expression...

Establishment of a successful pregnancy requires not only implantation healthy embryo into receptive uterus but also progesterone receptor (PGR)-dependent transformation endometrial stromal cells (ESCs) specialized decidual cells. Decidual support the developing and are critical for placentation. We have previously shown that known transcriptional coregulator PGR, steroid coactivator-2 (SRC-2), is driver decidualization in both human mouse endometrium. However, full spectrum genes...

Although a benign gynecological disorder, endometriosis displays some pathogenic features of malignancy, such as cell proliferation, migration, invasion, and adaptation to hypoxia. Current treatments include pharmacotherapy and/or surgery, which are limited efficacy often associated with adverse side-effects. Therefore, develop more effective therapies treat this disease, broader understanding the underlying molecular mechanisms that underpin needs be attained. Using immortalized human...

Summary The promyelocytic leukemia zinc finger (PLZF) transcription factor mediates a wide‐range of biological processes. Accordingly, perturbation PLZF function results in myriad physiologic defects, the most conspicuous which is abnormal skeletal patterning. Although whole body knockout Plzf mouse ( KO ) has significantly expanded our understanding vivo, conditional model that enables tissue or cell‐type specific ablation not been developed. Therefore, we used CRISPR/Cas 9 gene editing to...

Unlike cancers of related exocrine tissues such as the mammary and prostate gland, diagnosis treatment aggressive salivary gland malignancies have not markedly advanced in decades. Effective clinical management malignant is undercut by our limited knowledge concerning key molecular signals that underpin etiopathogenesis this rare heterogeneous head neck cancer. Without critical drive tumorigenesis, tumor vulnerabilities cannot be exploited allow for targeted therapies. This insufficiency...

Speckle-type poz protein (SPOP) is an E3-ubiquitin ligase adaptor for turnover of a diverse number proteins involved in key cellular processes such as chromatin remodeling, transcriptional regulation, and cell signaling. Genomic analysis revealed that SPOP somatic mutations are found subset endometrial cancers, suggesting these act oncogenic drivers this gynecologic malignancy. These studies also raise the question to role wild-type normal uterine function. To address question, we generated...

Abstract Steroid receptor coactivator-2 (SRC-2) is a transcriptional coregulator that modulates the activity of many transcription factors. Levels SRC-2 are elevated in endometrial biopsies from polycystic ovary syndrome patients, population predisposed to cancer (EC). Increased expression also detected neoplastic endometrium suggesting causal link between and emergence disorders can lead cancer. Here, we reveal knockdown reduces EC cell proliferation anchorage-independence. Additionally,...