Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sex steroids influence the growth of mammalian uterine tissues and the proto-oncogenes c-fos and c-jun have been implicated in the cascade of cellular events induced by the cyclic influence of oestrogen and progesterone. To investigate the role of these proto-oncogenes for fibroid growth their mRNA expression was measured in myometrium and fibroids under different hormonal conditions, using a solution hybridization method. Fibroids and myometrium were collected at surgery from premenopausal, postmenopausal and pregnant women as well as women treated with a gonadotrophin releasing hormone agonist (GnRHa; Goserelin). The phase of the menstrual cycle was determined in all the untreated, premenopausal, non-pregnant women. The mRNA expression of c-fos and c-jun in fibroids was significantly lower than in homologous myometrium. No significant differences in c-fos expression were observed in myometrium, or fibroids, due to menstrual cycle phase, GnRHa treatment, pregnancy or the menopause. The c-jun expression in myometrium from pregnant women without fibroid disease was significantly higher than the corresponding control myometrium from premenopausal, non-pregnant women. These results demonstrate a tissue difference in the expression of c-fos and c-jun between myometrium and fibroids.
Mol Hum Reprod 2000 Jan
PMID:Tissue differences but limited sex steroid responsiveness of c-fos and c-jun in human fibroids and myometrium. 1061 Dec 61

Uterine myomas often enlarge rapidly during pregnancy. This rapid increase in size may imply that human chorionic gonadotrophin (HCG) influences cell proliferation in uterine leiomyomata. To assess the direct effect of HCG on normal uterine smooth muscle and uterine leiomyomata, we investigated cell proliferation and the expression of cell cycle-related proteins in these cells. Reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed that HCG/LH receptor was present in both cultured myometrial and leiomyomal cells. Treatment with HCG significantly increased cell proliferation in both myometrial and leiomyomal cells (P < 0.03), especially at an early phase in the 9 day culture. The increase in the viable cell number induced by HCG treatment was significantly greater in leiomyoma cells than in myometrial cells on day 3 in culture (P < 0.03). In leiomyomal cells, the expression of proliferating cell nuclear antigen (PCNA), cyclin E and cdc2 was significantly increased by HCG treatment (P < 0.05) even at the lowest concentration used (3 nmol/l). In myometrial cells, the expression of cyclin E and cdc2 was significantly increased by HCG treatment (P < 0.05) only at the highest concentration used (30 nmol/l). These results suggest that HCG directly promotes the proliferation of myometrial and leiomyomal cells, with the latter showing the greater response of the two.
Mol Hum Reprod 2000 Jun
PMID:HCG promotes proliferation of uterine leiomyomal cells more strongly than that of myometrial smooth muscle cells in vitro. 1082 69

Uterine leiomyoma is a very common benign tumour with unclear pathophysiology in adult women. In the present study we have investigated the expression level of alpha(2)- and beta(2)-adrenoceptors, and the adenylyl cyclase and phosphodiesterase activity in leiomyoma tissue compared with adjacent myometrium. Our results show that the alpha(2)/beta(2)-adrenoceptor ratio is increased in leiomyoma, due to a significant decrease in beta(2)-adrenoceptor expression. These changes were not due to an increased innervation, as the tumour tissue was completely devoid of nerve fibres. Moreover, the adenylyl cyclase activity of leiomyoma membranes was found to be approximately 50% lower, whereas the phosphodiesterase activity was significantly increased (by approximately 100%). We found that stimulating an increase in intracellular cyclic AMP, by adenylyl cyclase activity through beta(2)-adrenoceptors (isoprenaline), by direct enzyme activation (forskolin), or by inhibition of phosphodiesterase activity (papaverine), potently blocked both protein and DNA synthesis in cultured leiomyoma smooth muscle cells. Our results imply the adrenoceptors might be involved in, or a consequence of, leiomyoma growth. The results also suggest a new interesting approach for leiomyoma pharmacotherapy.
Mol Hum Reprod 2000 Sep
PMID:Changes in beta(2)-adrenoceptor expression and in adenylyl cyclase and phosphodiesterase activity in human uterine leiomyomas. 1095 56

The objective of this study was to elucidate the role of annexin V, an endogenous inhibitor of protein kinase C (PKC), with regard to the antiproliferative effect of gonadotrophin-releasing hormone (GnRH) agonist (buserelin) on cultured human uterine leiomyoma cells. Uterine leiomyoma tissue was collected from the surgical specimens of patients and cells from 37 specimens (15 cases) were cultured. For up to 96 h after the addition of buserelin to the cultured cells, a time-dependent antiproliferative effect was noted in the group to which 10(-5) mol/l buserelin was added. Both the intracellular concentration of annexin V and the expression of annexin V mRNA increased time-dependently with the addition of buserelin. The intracellular concentration of annexin V increased with the addition of PKC activator (12-O:-tetradecanoylphorbor-13-acetate; TPA) much as it did with the addition of buserelin, and the rise in the concentration caused by the addition of buserelin was completely attenuated by pretreatment with PKC inhibitor (calphostin C). Our findings suggest that buserelin inhibits cell proliferation in cultured human uterine leiomyoma cells accompanied with an increase in the intracellular concentration of annexin V, mediated, at least in part, by the activation of PKC.
Mol Hum Reprod 2001 Feb
PMID:Involvement of annexin V in the antiproliferative effect of GnRH agonist on cultured human uterine leiomyoma cells. 1116 Aug 43

Uterine leiomyomas develop in reproductive-age women with high frequency and are dependent on the production of ovarian hormones. While it is generally accepted that these tumors are estrogen (E(2))-responsive, the role of progesterone (P(4)) in modulating tumor growth is less clear. In the present study, an in vivo/in vitro rat model was used to characterize progesterone receptor (PR) isoform expression in uterine leiomyoma and investigate PR signaling using progestins and antiprogestins in the leiomyoma-derived cell line ELT-3. PR-A was the predominant isoform expressed in normal myometrium, leiomyomas and ELT3 cells. In the normal myometrium, PR-A and PR-B levels varied during the estrous cycle with low ratios of PR-A relative to PR-B (PR-A/PR-B) coinciding with times of cell proliferation. Although PR ligands had no effect on basal levels of uterine leiomyoma cell proliferation in vitro, both progestins and antiprogestins inhibited E(2)-stimulated cell proliferation. In addition, E(2)-stimulated transactivation of an estrogen-response-element reporter gene as well as E(2)-induced upregulation of the PR were also inhibited by PR ligands. These data indicate that PR ligands can transdominantly suppress estrogen receptor signaling and stimulation of uterine leiomyoma cell growth.
Mol Cell Endocrinol 2002 Oct 31
PMID:Transdominant suppression of estrogen receptor signaling by progesterone receptor ligands in uterine leiomyoma cells. 1238 21

The objective of this study was to elucidate the biological significance of GnRH and antiprogestins and antiestrogen in leiomyoma and their interactions with ovarian steroid 'add-back' therapy. Leiomyoma and myometrial smooth muscle cells (LSMC and MSMC) were isolated and exposed to GnRH agonist (leuprolide acetate, LA), 17beta-estradiol (E2), medroxyprogesterone acetate (MPA), GnRH antagonist (Antide), estrogen antagonist, ICI182780 (Fulvestrant) and progesterone antagonists RU486 (Mifepristone) and ZK98299 (Onapristone) and combinations thereof. The rate of DNA synthesis, cell proliferation and transforming growth factor-beta (TGF-beta) expression were then determined. In both cell types, we found that in a dose-dependent manner, LA inhibited, whereas E2, MPA and the combination of E2 + MPA stimulated, the rate of DNA synthesis in these cells. Antide reversed the inhibitory effect of LA, while LA partly inhibited the stimulatory effect of the steroids. In addition, RU486, ICI182780 and ZK98299 at 0.1 micro mol/l or higher doses inhibited the rate of DNA synthesis and partly reversed the effects of E2 and/or MPA. We also found that LSMC expressed elevated levels of TGF-beta1 compared with MSMC. In both cell types, the effects of LA, E2, MPA, RU, ZK and ICI and combinations thereof on TGF-beta1 production were reflective of their effects on DNA synthesis. In line with this, TGF-beta1 was found to stimulate DNA synthesis and the E2-, TGF-beta1- or E2 + TGF-beta1-induced DNA synthesis was found to be inhibited by TGF-beta1 neutralizing antibodies and/or LA. In conclusion, the results provide further evidence that GnRH agonist- and RU486-induced leiomyoma regression is mediated in part through an interactive mechanism that results in altered cell growth and suppression of TGF-beta production.
Mol Hum Reprod 2002 Dec
PMID:Effects of GnRH analogues, 'add-back' steroid therapy, antiestrogen and antiprogestins on leiomyoma and myometrial smooth muscle cell growth and transforming growth factor-beta expression. 1246 39

The aetiology of uterine fibroids remains unknown, despite causing significant gynaecological morbidity. Fibroids have a reduced microvascular density when compared with adjacent myometrial tissue. The aim of this study was to identify genes with differential expression between fibroid and adjacent normal myometrium, particularly genes with a role in angiogenesis. Total RNA was extracted from fibroid/myometrium pairs from 12 hysterectomy specimens, and used to perform 24 cDNA microarrays. There were 10,500 genes screened on each microarray for differential expression. Analysis of expression data was carried out using multiple t-tests, as well as a novel class prediction algorithm (GeneRaVE). The differential gene expression of selected genes was confirmed by quantitative 'real time' RT-PCR. Selected genes with a role in angiogenesis were further analysed for expression in isolated cell populations of endothelial cells (fibroid and myometrium) and smooth muscle cells (fibroid and myometrium), to see if their expression was confined to particular cell types. Twenty-five genes with differential gene expression between fibroid and myometrium were identified. Insulin-like growth factor-2, endothelin A receptor, connective tissue growth factor (CTGF), cysteine-rich angiogenic inducer 61 (CYR61) and collagen 4alpha2 (COL4A2) were confirmed by RT-PCR. CTGF and CYR61, both angiogenesis promoters, were reduced in expression relative to myometrium. COL4A2, the precursor for an angiogenesis inhibitor, canstatin, was increased relative to myometrium. These three genes display an anti-angiogenic expression profile in fibroids relative to myometrium. These findings may explain the reduced microvascular density seen in fibroids relative to myometrium.
Mol Hum Reprod 2003 Sep
PMID:Fibroids display an anti-angiogenic gene expression profile when compared with adjacent myometrium. 1290 May 13

The expression of Gas6, the protein product of the growth arrest-specific gene 6 (gas6), a member of the vitamin K-dependent protein family, and the receptor tyrosine kinases Axl and Sky and their mRNAs in uterine leiomyoma and normal uterine myometrium tissues were investigated by competitive RT-PCR-Southern blot analysis using recombinant RNA and immuno histochemical analysis respectively. There was no significant difference between the histoscores and levels of Sky mRNA in uterine leiomyoma and normal uterine myometrium, although the levels of Gas6 and Axl mRNAs in uterine leiomyoma were significantly higher than in normal uterine myometrium in each case. It is suggested that Gas6 and Axl signal transduction is aberrantly stimulated in uterine leiomyoma, possibly related to its growth.
Mol Hum Reprod 2003 Nov
PMID:Clinical implications of coexpression of growth arrest-specific gene 6 and receptor tyrosine kinases Axl and Sky in human uterine leiomyoma. 1456 12

GnRH agonist therapy is known to reduce uterine leiomyoma volume, although the molecular mechanisms responsible for this effect remain poorly understood. In this study, we have investigated the molecular mechanisms involved in the anti-proliferative effect of a GnRH agonist, leuprolide acetate (LA), in uterine leiomyomas obtained from six patients treated with LA for 3 months before surgery (group B), compared with tumours from six untreated patients (group A). To this end, we have evaluated the expression and the activity of molecules involved in the regulation of cell survival and proliferation. In group B, the total activity of PI3K was reduced by 60% compared with control samples. Furthermore, LA caused a reduction of PKB activation of approximately 50%, measured as serine 473 phosphorylation. In parallel with PKB reduction in LA samples, we observed a 60% reduction in the phosphorylation of its substrate BAD. While Bcl-xL/BAD association was not significantly modified in LA-treated leiomyomas, BAD/14.3.3 interaction was reduced, due to a 50% decreased 14.3.3 expression. In addition, LA was able to reduce the expression of the antiapoptotic proteins FLIP and PED/PEA15 by 70 and 50% respectively, compared with control samples. We next evaluated the activation of MAP kinases in leiomyomas. Activation of p42 and p44 MAP kinase isoforms was increased by 30% in group B. However, the phosphorylation of the transcription factor Elk1 was not increased in a similar fashion in LA-treated leiomyomas compared with group A. Thus, these data suggest that LA reduction of leiomyoma volume is mediated at least in part by a decreased activation of the PI3K/PKB survival pathway and by the suppression of antiapoptotic factors.
Mol Hum Reprod 2004 Jan
PMID:Molecular mechanisms involved in GnRH analogue-related apoptosis for uterine leiomyomas. 1466 5

Uterine fibroids (leiomyomas) are a major women's health problem. Currently, the standard for treatment remains hysterectomy, since no other treatment modalities can reduce both symptoms and recurrence. As leiomyomas are benign neoplasias of smooth muscle cells, we sought to understand the regulation of uterine smooth muscle cell mitogenesis by CCN5, a growth arrest-specific gene in vascular smooth muscle cells which is induced and maintained by heparin treatment. Using autologous human myometrial and leiomyoma smooth muscle cells, we demonstrate that the proliferation and motility of both cell types are inhibited by the overexpression of CCN5. Surprisingly, we show that even though CCN5 is induced by heparin in vascular smooth muscle cells, treatment with heparin does not induce CCN5 expression in human uterine smooth muscle cells. Furthermore, we examine CCN5 mRNA expression in 10 autologous pairs of human myometrial and leiomyoma tissues and determine that CCN5 is down-regulated in 100% of the leiomyoma tissues analysed when compared to their normal myometrial counterparts. Thus, our data strongly suggest that CCN5 may exert an important function in maintaining the normal uterine phenotype and that loss of the anti-proliferative protein CCN5 from normal myometrium may account, at least in part, for tumorigenesis.
Mol Hum Reprod 2004 Mar
PMID:The growth arrest-specific gene CCN5 is deficient in human leiomyomas and inhibits the proliferation and motility of cultured human uterine smooth muscle cells. 1498 Nov 45


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