Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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S100 proteins belong to the EF-hand Ca(2+ )-binding protein family and regulate a variety of cellular processes via interaction with different target proteins. Several diseases, including cancer and melanoma, are related to the abnormal expression of S100 proteins, which are expressed in cell- and tissue-specific manners. We investigated the expression of S100 family members in human uterine smooth muscle tumours. Expression of six members of the S100 protein family: S100A1, A4, A6, A7, A10 and A11, was found in human uterine leiomyoma and myometrium tissue, but expression of other members was not detected by RT-PCR. Real-time PCR showed that S100A11 expression was significantly increased in leiomyoma compared with myometrium. Suppression of S100A11 by small interfering RNA (siRNA) led to apoptosis, and the overexpression of S100A11 inhibited apoptosis in human uterine smooth muscle tumour cells. These findings suggest that S100A11 has an anti-apoptotic function and is related to the process of growth of human uterine leiomyoma.
Mol Hum Reprod 2004 Oct
PMID:Increased expression of calcium-binding protein S100 in human uterine smooth muscle tumours. 1532 23

Renal Cell Carcinoma (RCC) and uterine leiomyoma (often referred to as fibroids) are tumors arising from tubular epithelium and myometrial compartments of the kidney and uterus, respectively. These tumors have a very different clinical presentation, with RCC being one of the less common cancers, having a very poor prognosis, and occurring predominantly in men, whereas uterine leiomyoma are the most common tumor of women and are benign. Although they are distinct histologically, with RCC arising from epithelial cells and leiomyoma arising from smooth muscle cells, they share a common embryological origin. Renal tubular epithelial cells arise during nephrogenesis as a result of the mesenchymal-epithelial transition of condensed mesenchyme induced by the developing ureteric bud, and have a shared mesenchymal lineage with smooth muscle cells of the uterus. In addition to a common embryological origin, RCC and leiomyoma have been demonstrated to share a common genetic etiology. The Eker rat model was the first demonstration of a specific genetic linkage between RCC and uterine leiomyoma. Eker rats carry a germline defect in the rat homologue of the tuberous sclerosis complex 2 (TSC-2) tumor suppressor gene and develop spontaneous RCC and uterine leiomyoma with a high frequency. TSC patients are also at risk for RCC, and sporadic human uterine leiomyomas exhibit loss of function of the TSC-2 gene product, tuberin. Individuals with the inherited cancer syndrome hereditary leiomyomatosis and renal cell cancer (HLRCC) that have germline defects in the fumarate hydratase (FH) gene develop papillary RCC and uterine and skin leiomyomas. Benign cutaneous lesions and uterine leiomyoma also arise in German Shepherd dogs with germline mutations in the Birt-Hogg-Dube (BHD) gene, and these animals develop RCC and uterine leiomyoma with a high frequency. Identification of the tumor suppressor genes involved in these diseases, TSC, FH and BHD, and the elucidation of the function of their protein products, tuberin, fumarate hydratase and folliculin, respectively, opens new avenues for understanding the pathogenesis of both RCC and uterine leiomyoma.
Curr Mol Med 2004 Dec
PMID:The Eker rat: establishing a genetic paradigm linking renal cell carcinoma and uterine leiomyoma. 1557 28

Many studies have implicated numerous hormones, growth factors, cytokines and other signal transduction molecules in the pathogenesis of uterine leiomyoma. Estrogen and estrogen-related genes are thought to play a key role in the growth of uterine leiomyomas, but the molecular mechanisms are unclear. In an attempt to investigate various pathways that might be involved in estrogen-regulated uterine leiomyoma growth as well as to identify any novel effector genes, microarray studies comparing estrogen-treated uterine leiomyoma cells (UtLM) and normal myometrial cells to untreated cells were performed. Several genes were differentially expressed in estrogen treated UtLM cells, including insulin-like growth factor-I (IGF-I) and others potentially involved in the IGF-I signalling pathway, specifically genes for A-myb, a transcription factor which promotes cell cycle progression and for MKP-1, a dual specificity phosphatase that dephosphorylates mitogen-activated protein kinase. IGF-I and A-myb were up-regulated in estrogen-treated cells while MKP-1 was down-regulated. Two other cell cycle promoting genes, c-fos and myc, were also down-regulated in estrogen treated UtLM cells. These genes are typically up-regulated in response to estrogen in some cells, notably breast epithelial cells, yet consistently have lower expression levels in uterine leiomyoma tissue when compared to autologous myometrium. Our results demonstrate some novel genes that may play a role in the growth of uterine leiomyoma, strengthen the case for involvement of the IGF-I pathway in the response of UtLM to estrogen and corroborate evidence that uterine smooth muscle cells respond to estrogen with a different gene expression pattern than that seen in epithelial cells.
Mol Hum Reprod 2005 Jun
PMID:Estrogen-induced changes in IGF-I, Myb family and MAP kinase pathway genes in human uterine leiomyoma and normal uterine smooth muscle cell lines. 1587 65

Endometrial tissue from uterine disease-free women does not exhibit aromatase activity. In contrast, aromatase enzyme activity and mRNA levels are readily detectable in endometriosis. PGE2 stimulates both aromatase expression and activity in endometriotic stromal cells via promoter II region of the aromatase gene. This results in local production of estradiol, which induces PGE2 formation and establishes a positive feedback cycle. This mechanism seems to contribute to continuous production of estradiol and PGE2. Aromatase mRNA levels and enzyme activity are also present in uterine leiomyomata that are estrogen-dependent benign tumors of the myometrium. Successful treatment of endometriosis and uterine leiomyomata using aromatase inhibitors by recent pilot trials underscores the clinical significance of these molecular studies.
J Steroid Biochem Mol Biol 2005 May
PMID:Aromatase in endometriosis and uterine leiomyomata. 1602 48

Adenomyosis is a common gynaecological disorder characterized by the abnormal growth of endometrium into the myometrium and myometrial hypertrophy/hyperplasia. Uterine fibroids are benign neoplasms of the myometrium, and they represent a diagnostic pitfall for adenomyosis. In this study, we have used the genome-wide Affymetrix U133 Plus 2.0 microarray platform to compare the gene expression patterns of adenomyosis, uterine fibroids, normal endometrium and myometrium. Unsupervised principal component analysis (PCA) revealed that these four tissue types could be segregated from one another solely based on their gene expression profiles. Analysis of variance (ANOVA), followed by Tukey means separation test, significance analysis of microarrays (SAM) and 2-fold change threshold, identified 7415 probe sets as differentially expressed among the four groups of samples. Supervised cluster analysis based on these probe sets clustered adenomyosis most closely with endometrium and uterine fibroids with myometrium, consistent with the anatomic origin of these two diseases. The Tukey means separation post hoc testing found 2073 probe sets altered between adenomyosis and normal endometrium or myometrium, and 2327 probe sets altered in expression when comparing uterine fibroids with myometrium. Using Ingenuity Pathways Analysis (IPA), we found 9 highly significant functional networks in adenomyosis and 10 in uterine fibroids. Notably, the top network in both cases was associated with functions implicated in cancer and cell death. Finally, we compared the gene expression profiles of adenomyosis and uterine fibroids and identified 471 differentially expressed probe sets that may represent potential biomarkers for the differential diagnosis of these diseases.
Mol Hum Reprod 2006 Dec
PMID:Molecular characterization of human adenomyosis. 1702 Sep 5

Fibroids are benign neoplasms of myometrial smooth muscle cells (SMC). Despite being the most common tumor in humans, their etiology is poorly understood. Recent microarray studies have demonstrated that multiple members of the retinoid pathway are differentially expressed between myometrium and fibroids. The aim of this present study was to investigate gene expression of members of the retinoid pathway in matched myometrium and fibroids. We have demonstrated differential gene expression of two binding proteins [cellular retinol-binding proteins (CRBP) 1 and 2], three enzymes [alcohol dehydrogenase 1 (ADH1), aldehyde dehydrogenase (ALDH1) and retinol dehydrogenase (RODH)] and two receptors [retinoid X receptors (RXR) alpha and gamma] involved in the retinoid pathway by real-time PCR. There were no differences in gene expression for retinoid receptors RARalpha, beta, gamma and RXRbeta, and for the metabolizing enzyme cytochrome P450, family 26 subfamily A. We confirmed results for ADH1, ALDH1, CRBP1 and CRABP2 at the protein level by western blot. Using immunohistochemistry these proteins were mostly localized to myometrial and fibroid SMC. An exception to this was ALDH1 protein, which displayed strong staining localized to cells of the connective tissue, presumably fibroblasts, with a striking differential expression pattern between myometrium and fibroids. These results demonstrate that the retinoid pathway is altered in fibroids when compared with normal myometrium and specifically identify ALDH1 in fibroid fibroblasts. These alterations can lead to aberrant retinoic acid (RA) production and signaling, and alter the expression of RA target genes, which may be an important step in fibroid development.
Mol Hum Reprod 2007 Aug
PMID:Retinoic acid pathway genes show significantly altered expression in uterine fibroids when compared with normal myometrium. 1755 14

Uterine leiomyomata (UL), also known as fibroids, are the most common pelvic tumors in women of reproductive age and are the primary indication for hysterectomy in the USA. Many lines of evidence indicate a strong genetic component to the development of these tumors. In fact, approximately 40% of UL have non-random, tumor-specific chromosome abnormalities which have allowed classification into well-defined subgroups (deletion of portions of 7q, trisomy 12 or rearrangements of 12q15, 6p21 or 10q22) as well as identification of candidate genes for UL predisposition. Although benign, UL have been linked to malignancy through two genomic regions on chromosome 1. Mutation of fumarate hydratase (FH) at 1q43 is known to cause the Mendelian syndromes of multiple cutaneous and uterine leiomyomata (MCL) and hereditary leiomyomatosis and renal cell cancer (HLRCC), and recently, FH mutations have been detected in some non-syndromic UL. In addition, transcriptional profiling suggests that loss of the short arm of chromosome 1 in cellular leiomyomata, an uncommon histological variant of UL, may account in part for the presumed yet rare malignant transformation of UL to uterine leiomyosarcoma.
Hum Mol Genet 2007 Apr 15
PMID:Genetic heterogeneity among uterine leiomyomata: insights into malignant progression. 1761 50

The nuclear receptors PPARs (peroxisome proliferator-activated receptors) are transcription factors that play important roles in multiple disease conditions. The activation of PPARs by specific ligands is associated with growth suppression of several different types of human cancer, but the molecular mechanism responsible for this growth suppressive effect remains elusive. The aim of this study was to determine the distribution of PPARgamma protein/mRNA expression in uterine leiomyomas and to identify the PPARgamma induced signaling pathways responsible for the growth inhibition induced by treatment with ciglitizone, a synthetic ligand of PPARgamma, in view of identifying targets that could possibly affect the viability and proliferation of uterine leiomyoma cells. Dose-response studies on proliferation found that uterine leiomyoma was more sensitive to inhibition by ciglitizone treatments than normal myometrium. We also found that ciglitizone significantly stimulated gene expression driven by a PPAR-responsive element in cultured leiomyoma cells and reduced the survival of leiomyoma cells relative to the control cells. The reduced survival of ciglitizone treated leiomyoma cells resulted from a mechanism that involved the Fas receptor-mediated apoptosis signaling cascade. These results suggest that uterine leiomyomas growth and differentiation might be modulated through PPARgamma receptors and that PPARgamma ligands may be of potential use for uterine leiomyoma treatment.
Mol Hum Reprod 2007 Nov
PMID:Growth inhibition and apoptosis induced in human leiomyoma cells by treatment with the PPAR gamma ligand ciglitizone. 1789 92

Microarray studies have identified many genes that are down-regulated in uterine leiomyoma compared with myometrium, including early growth response gene-1 (EGR1). However, the mechanisms underlying coordinated down-regulation of this gene cohort remain unknown. To address the transcriptional role of EGR1 in leiomyoma, EGR1 binding to promoter sequences on target genes was assessed by chromatin immunoprecipitation (ChIP) assay in leiomyoma tissues and myometrium-derived KW cells. Computer analysis demonstrated that 50 out of 135 genes listed as down-regulated in array reports possessed potential binding sites for EGR1 within 1 kb promoter sequence. ChIP assay was performed for a random selection of 13 genes possessing potential binding sites for EGR1 (Group A), 3 genes known as EGR1 targets in other tissues (Group B), and 4 control genes. Decreased EGR1 bindings were significant for 11 out of 16 genes (Group A+B) in leiomyoma tissues compared with myometrium, and mRNA levels in tissue samples were actually decreased for 7 out of the 11 genes. ChIP analyses performed on KW cells showed induction of EGR1 binding to the promoter region of all genes except one Group A+B gene, but for none of the control genes. These results indicate that EGR1 is a key player in coordinated down-regulation of genes in leiomyoma. Application of ChIP-quantitative PCR assay with the aid of computer-assisted analysis of genome databases appears useful for the comprehensive interpretation of array data.
J Mol Endocrinol 2007 Nov
PMID:Early growth response gene-1 plays a pivotal role in down-regulation of a cohort of genes in uterine leiomyoma. 1797 60

Effects of progesterone receptor modulator CDB-2914 on the expression of the extracellular matrix (ECM) components were examined in cultured human uterine leiomyoma and myometrial cells. ECM metalloproteinase inducer (EMMPRIN), matrix metalloproteinases (MMPs), tissue inhibitors of MMP (TIMPs) and collagen levels were assessed by Western blot analysis, MMP activity assay and real-time RT-PCR. RNA interference (RNAi) of EMMPRIN was performed using small interfering mRNA. In cultured leiomyoma cells, CDB-2914 treatment at concentrations greater than or equal to 10(-8) M significantly increased EMMPRIN, MMP-1 and MMP-8 protein contents and MMP-1, MMP-2, MMP-3 and MMP-9 mRNA levels, and activity of MMP-1, MMP-2, MMP-3 and MMP-9 in the medium. TIMP-1 and TIMP-2 were significantly decreased at mRNA and protein levels by CDB-2914 treatment at concentrations > or =10(-7) M in these cells. CDB-2914 treatment decreased types I and III collagen protein contents. However, CDB-2914 treatment did not affect the ECM component expression in cultured myometrial cells. RNAi of EMMPRIN abrogated CDB-2914-mediated both induction of MMPs and reduction of TIMPs and collagens in cultured leiomyoma cells. These results suggest that CDB-2914 modulates the expression of EMMPRIN, MMPs, TIMPs and collagens in cultured leiomyoma cells without comparable effects on myometrial cells.
Mol Hum Reprod 2008 Mar
PMID:Progesterone receptor modulator CDB-2914 induces extracellular matrix metalloproteinase inducer in cultured human uterine leiomyoma cells. 1821 91


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