KLK4T2 Is a Hormonally Regulated Transcript from the KLK4 Locus.
Ontology highlight
ABSTRACT:
SUBMITTER: Lundwall A
PROVIDER: S-EPMC8657796 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:The Kallikrein-related peptidase, KLK4, has been shown to be significantly overexpressed in prostate tumours in numerous studies and is suggested to be a potential biomarker for prostate cancer. KLK4 may also play a role in prostate cancer progression through its involvement in epithelial-mesenchymal transition, a more aggressive phenotype, and metastases to bone. It is well known that genetic variation has the potential to affect gene expression and/or various protein characteristics and hence we sought to investigate the possible role of single nucleotide polymorphisms (SNPs) in the KLK4 gene in prostate cancer. Assessment of 61 SNPs in the KLK4 locus (± 10 kb) in approximately 1300 prostate cancer cases and 1300 male controls for associations with prostate cancer risk and/or prostate tumour aggressiveness (Gleason score <7 versus ? 7) revealed 7 SNPs to be associated with a decreased risk of prostate cancer at the P(trend)<0.05 significance level. Three of these SNPs, rs268923, rs56112930 and the HapMap tagSNP rs7248321, are located several kb upstream of KLK4; rs1654551 encodes a non-synonymous serine to alanine substitution at position 22 of the long isoform of the KLK4 protein, and the remaining 3 risk-associated SNPs, rs1701927, rs1090649 and rs806019, are located downstream of KLK4 and are in high linkage disequilibrium with each other (r(2) ? 0.98). Our findings provide suggestive evidence of a role for genetic variation in the KLK4 locus in prostate cancer predisposition.
| S-EPMC3435290 | biostudies-literature
Project description:HUNK is a protein kinase that is implicated in HER2-positive (HER2+) breast cancer progression and resistance to HER2 inhibitors. Though prior studies suggest there is therapeutic potential for targeting HUNK in HER2+ breast cancer, pharmacological agents that target HUNK are yet to be identified. A recent study showed that the broad-spectrum kinase inhibitor staurosporine binds to the HUNK catalytic domain, but the effect of staurosporine on HUNK enzymatic activity was not tested. We now show that staurosporine inhibits the kinase activity of a full length HUNK protein. Our findings further suggest that inhibiting HUNK with staurosporine has a strong effect on suppressing cell viability of HER2/neu mammary and breast cancer cells, which express high levels of HUNK protein and are dependent on HUNK for survival. Significantly, we use in vitro and in vivo methods to show that staurosporine synergizes with the HER2 inhibitor lapatinib to restore sensitivity toward HER2 inhibition in a HER2 inhibitor resistant breast cancer model. Collectively, these studies indicate that pharmacological inhibition of HUNK kinase activity has therapeutic potential for HER2+ breast cancers, including HER2+ breast cancers that have developed drug resistance.
| S-EPMC6267597 | biostudies-literature
Project description:Dominance hierarchies are ubiquitous in invertebrates and vertebrates, but little is known on how genes influence dominance rank. Our gaps in knowledge are specifically significant concerning female hierarchies, particularly in insects. To start filling these gaps, we studied the social bumble bee Bombus terrestris, in which social hierarchies among females are common and functionally significant. Dominance rank in this bee is influenced by multiple factors, including juvenile hormone (JH) that is a major gonadotropin in this species. We tested the hypothesis that the JH responsive transcription factor Krüppel homologue 1 (Kr-h1) mediates hormonal influences on dominance behavior. We first developed and validated a perfluorocarbon nanoparticles-based RNA interference protocol for knocking down Kr-h1 expression. We then used this procedure to show that Kr-h1 mediates the influence of JH, not only on oogenesis and wax production, but also on aggression and dominance rank. To the best of our knowledge, this is the first study causally linking a gene to dominance rank in social insects, and one of only a few such studies on insects or on female hierarchies. These findings are important for determining whether there are general molecular principles governing dominance rank across gender and taxa.
| S-EPMC8614866 | biostudies-literature
Project description:Estrogen tightly regulates the levels of circulating gonadotropins, but a direct effect of estrogen receptor alpha (ERalpha) on the mammalian LHbeta gene has remained poorly defined. We demonstrate here that ERalpha can associate with the LHbeta promoter through interactions with Sf-1 and Pitx1 without requiring an estrogen response element (ERE). We show that gonadotropin-releasing hormone (GnRH) promotes ERalpha ubiquitylation and also degradation while stimulating expression of ubc4. GnRH also increases the association and lengthens the cycling time of ERalpha on the LHbeta promoter. The ERalpha association and transactivation of the LHbeta gene, as well as ERalpha degradation, are increased following ubc4 overexpression, while the effects of GnRH are abated following ubc4 knockdown. Our results indicate that ERalpha ubiquitylation and subsequent transactivation of the LHbeta gene can be induced by increasing the levels of the E2 enzyme as a result of signaling by an extracellular hormone, thus providing a new form of cross talk in hormonally stimulated regulation of gene expression.
| S-EPMC1190261 | biostudies-literature
Project description:A previously unidentified gonadotropin-regulated long chain acyl-CoA synthetase (GR-LACS) was cloned and characterized as a 79-kDa cytoplasmic protein expressed in Leydig cells of the rat testis. GR-LACS shares sequence identity with two conserved regions of the LACS and luciferase families, including the ATP/AMP binding domain and the 25-aa fatty acyl-CoA synthetase signature motif, but displays low overall amino acid similarities (23-28%). GR-LACS mRNA is expressed abundantly in Leydig cells of the adult testis and to a lesser degree in the seminiferous tubules in spermatogonia and Sertoli cells. It is also observed in ovary and brain. Immunoreactive protein expression was observed mainly in Leydig cells and minimally in the tubules but was not detected in other tissues. In vivo, treatment with a desensitizing dose of human chorionic gonadotropin caused transcriptional down-regulation of GR-LACS expression in Leydig cells. The expressed protein present in the cytoplasm of transfected cells displayed acyl-CoA synthetase activity for long chain fatty acid substrates. GR-LACS may contribute to the provision of energy requirements and to the biosynthesis of steroid precursors and could participate through acyl-CoA's multiple functions in the regulation of the male gonad.
| S-EPMC34396 | biostudies-literature
Project description:Here we report that low concentrations of alcohol (1-3 mM) increased Cl(-) currents gated by a recombinant GABA(A) receptor, alpha(4)beta(2)delta, by 40-50% in Xenopus laevis oocytes. We also found greater hippocampal expression of receptors containing alpha(4) and delta subunits, using a rat model of premenstrual syndrome (PMS) in which 1-3 mM alcohol preferentially enhanced GABA-gated currents, and low doses of alcohol attenuated anxiety and behavioral reactivity. The alcohol sensitivity of delta-containing receptors may underlie the reinforcing effects of alcohol during PMS, when eye saccade responses to low doses of alcohol are increased.
| S-EPMC2887346 | biostudies-literature
Project description:Cancer-induced skeletal muscle defects show sex-specific differences in severity with men performing poorly compared to women. Hormones and sex chromosomal differences are suggested to mediate these differences, but the functional skeletal muscle markers to document these differences are unknown. We show that the myogenic microRNA miR-486 is a marker of sex-specific differences in cancer-induced skeletal muscle defects. Cancer-induced loss of circulating miR-486 was more severe in men with bladder, lung, and pancreatic cancers compared to women with the same cancer types. In a syngeneic model of pancreatic cancer, circulating and skeletal muscle loss of miR-486 was more severe in male mice compared to female mice. Estradiol (E2) and the clinically used selective estrogen receptor modulator toremifene increased miR-486 in undifferentiated and differentiated myoblast cell line C2C12 and E2-inducible expression correlated with direct binding of estrogen receptor alpha (ERα) to the regulatory region of the miR-486 gene. E2 and toremifene reduced the actions of cytokines such as myostatin, transforming growth factor β, and tumor necrosis factor α, which mediate cancer-induced skeletal muscle wasting. E2- and toremifene-treated C2C12 myoblast/myotube cells contained elevated levels of active protein kinase B (AKT) with a corresponding decrease in the levels of its negative regulator PTEN, which is a target of miR-486. We propose an ERα:E2-miR-486-AKT signaling axis, which reduces the deleterious effects of cancer-induced cytokines/chemokines on skeletal muscle mass and/or function.
| S-EPMC8335968 | biostudies-literature
Project description:Study questionIs human endometrial leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) gene expression limited to the postulated epithelial stem cell niche, stratum basalis glands, and is it hormonally regulated?Summary answerLGR5 expressing cells are not limited to the postulated stem cell niche but LGR5 expression is hormonally regulated.What is known alreadyThe human endometrium is a highly regenerative tissue; however, endometrial epithelial stem cell markers are yet to be confirmed. LGR5 is a marker of stem cells in various epithelia.Study design, size, durationThe study was conducted at a University Research Institute. Endometrial samples from 50 healthy women undergoing benign gynaecological surgery with no endometrial pathology at the Liverpool Women's hospital were included and analysed in the following six sub-categories; proliferative, secretory phases of menstrual cycle, postmenopausal, those using oral and local progestagens and samples for in vitro explant culture.Participants/materials, setting, methodsIn this study, we used the gold standard method, in situ hybridisation (ISH) along with qPCR and a systems biology approach to study the location of LGR5 gene expression in full thickness human endometrium and Fallopian tubes. The progesterone regulation of endometrial LGR5 was examined in vivo and in short-term cultured endometrial tissue explants in vitro. LGR5 expression was correlated with epithelial proliferation (Ki67), and expression of previously reported epithelia progenitor markers (SOX9 and SSEA-1) immunohistochemistry (IHC).Main results and the role of chanceLGR5 gene expression was significantly higher in the endometrial luminal epithelium than in all other epithelial compartments in the healthy human endometrium, including the endometrial stratum basalis (P < 0.05). The strongest SSEA-1 and SOX9 staining was observed in the stratum basalis glands, but the general trend of SOX9 and SSEA-1 expression followed the same cyclical pattern of expression as LGR5. Stratum functionalis epithelial Ki67-LI and LGR5 expression levels correlated significantly (r = 0.74, P = 0.01), however, they did not correlate in luminal and stratum basalis epithelium (r = 0.5 and 0.13, respectively). Endometrial LGR5 demonstrates a dynamic spatiotemporal expression pattern, suggesting hormonal regulation. Oral and local progestogens significantly reduced endometrial LGR5 mRNA levels compared with women not on hormonal treatment (P < 0.01). Our data were in agreement with in silico analysis of published endometrial microarrays.Large scale dataWe did not generate our own large scale data but interrogated publically available large scale data sets.Limitations, reasons for cautionIn the absence of reliable antibodies for human LGR5 protein and validated lineage markers for the various epithelial populations that potentially exist within the endometrium, our study does not formally characterise or examine the functional ability of the resident LGR5+ cells as multipotent.Wider implications of the findingsThese data will facilitate future lineage tracing studies in the human endometrial epithelium; to identify the location of stem cells and further complement the in vitro functional studies, to confirm if the LGR5 expressing epithelial cells indeed represent the epithelial stem cell population.Study funding/competing interest(s)This work was supported by funding from the Wellbeing of Women project grant (RTF510) and Cancer Research UK (A14895). None of the authors have any conflicts of interest to disclose.
| S-EPMC5972618 | biostudies-literature
Project description:1. The incorporation of [35S]methionine into protein was investigated in tissue minces from different regions of the rabbit epididymis incubated in vitro. Rates of synthesis were in the order: epididymal regions 2-5 greater than region 7 greater than region 6 greater than region 1 greater than region 8 greater than ductus deferens greater than ductuli efferentes. 2. Separation of labelled proteins on polyacrylamide gels containing sodium dodecyl sulphate followed by fluorography revealed that one protein (mol.wt. approx. 90 000) was characteristic of region 1, four proteins (one of mol.wt. 54 000 and three of mol.wt. 20 000) were synthesized principally in regions 2-5, and one protein (mol.wt. 22 500) was produced mainly in regions 6, 7 and 8. 3. Castration for 14 days decreased incorporation of [35S]methionine into total protein to less than 10% of that in controls in all regions of the epididymis. However, testosterone treatment for a further period of 14 days restored protein synthesis to normal values in regions 6, 7 and 8, but not in region 1 or regions 2-5. In regions 2-5 the synthesis of three proteins of mol.wt. 20 000 declined after castration, but was not stimulated by exogenous testosterone. Since the 20 000-mol.wt. proteins were major tissue proteins, accounting for 16-25% of the total synthesized, they were used as markers for investigating hormone action in the epididymis. 4. Castration followed immediately by testosterone treatment or ligation of the ductuli efferentes resulted in a decrease in their synthesis, suggesting that they are partially dependent on factors in testicular fluid. Purification and characterization showed them to be acidic glycoproteins with a number of biochemical and immunological properties in common. 5. It is suggested that there is a synergistic action between blood androgens and factors in testicular fluid in regulating protein synthesis in the proximal regions of the rabbit epididymis.
| S-EPMC1162973 | biostudies-other
Project description:Matrix metalloproteinase 20 (MMP20) and kallikrein-related peptidase 4 (KLK4) are secreted proteinases that are essential for proper dental enamel formation. We characterized and compared enamel formed in wild-type, Mmp20 (-/-), Klk4 (-/-), Mmp20 (+/-) Klk4 (+/-), and Mmp20 (-/-) Klk4 (-/-) mice using dissecting and light microscopy, backscattered scanning electron microscopy (bSEM), SEM, microcomputed tomography (?CT), and energy-dispersive X-ray analysis (EDX). Following eruption, fractures were observed on Mmp20 (-/-), Klk4 (-/-), Mmp20 (+/-) Klk4 (+/-), and Mmp20 (-/-) Klk4 (-/-) molars. Failure of the enamel in the Mmp20 (+/-) Klk4 (+/-) molars was unexpected and suggested that digenic effects could contribute to the etiology of amelogenesis imperfecta in humans. Micro-CT analyses of hemimandibles demonstrated significantly reduced high-density enamel volume in the Mmp20 (-/-) and Klk4 (-/-) mice relative to the wild-type, which was further reduced in Mmp20 (-/-) Klk4 (-/-) mice. bSEM images of 7-week Mmp20 (-/-) and Mmp20 (-/-) Klk4 (-/-) mandibular incisors showed rough, pitted enamel surfaces with numerous indentations and protruding nodules. The Mmp20 (+/-) and Mmp20 (+/-) Klk4 (+/-) incisors showed prominent, evenly spaced, horizontal ridges that were more distinct in Mmp20 (+/-) Klk4 (+/-) incisors relative to Mmp20 (+/-) incisors due to the darkening of the valleys between the ridges. In cross sections, the Mmp20 (-/-) and Mmp20 (-/-) Klk4 (-/-) exhibited three distinct layers. The outer layer exhibited a disturbed elemental composition and an irregular enamel surface covered with nodules. The Mmp20 null enamel was apparently unable to withstand the sheer forces associated with eruption and separated from dentin during development. Cells invaded the cracks and interposed between the dentin and enamel layers. MMP20 and KLK4 serve overlapping and complementary functions to harden enamel by removing protein, but MMP20 potentially serves multiple additional functions necessary for the adherence of enamel to dentin, the release of intercellular protein stores into the enamel matrix, the retreat of ameloblasts to facilitate thickening of the enamel layer, and the timely transition of ameloblasts to maturation.
| S-EPMC4799876 | biostudies-literature