Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Uterine leiomyoma is the most common benign smooth muscle cell tumor of the myometrium. Although Bcl-2 protein is known to be an apoptosis-inhibiting gene product and to prevent apoptotic cell death in a variety of cells, there are no published data regarding whether human leiomyomas express Bcl-2 protein. In the present study, we examined the expression of Bcl-2 protein in leiomyomas in comparison with that in the normal myometrium using an immunohistochemical method and immunoblot analysis with a monoclonal antibody to human Bcl-2 protein. Furthermore, we investigated whether sex steroid hormones could influence the levels of Bcl-2 protein expression in leiomyoma cells cultured in vitro under serum-free, phenol red-free conditions. Immunohistochemical staining for Bcl-2 protein was prominent in leiomyoma cells, but was scarcely present in normal myometrial smooth muscle cells. The expression of Bcl-2 protein in leiomyoma cells was most abundant in the secretory, progesterone-dominated, phase of the menstrual cycle, but was less abundant in the proliferative phase of the menstrual cycle. Western blot analyses of leiomyoma and myometrium tissue extracts revealed that Bcl-2 protein, with a molecular mass estimated at approximately 26 kDa, was abundantly present in leiomyoma tissue extracts, but was undetectable in normal myometrial tissue extracts. In monolayer cultures of uterine leiomyoma cells under a serum-free condition, the addition of progesterone (100 ng/mL) resulted in a striking increase in Bcl-2 protein expression in the cultured leiomyoma cells relative to that in control cultures, whereas the addition of 17 beta-estradiol (10 ng/mL) resulted in a reduction in Bcl-2 protein expression in the cells. The concentrations of sex steroids used were within the physiological tissue concentrations found in leiomyomas and myometrium. The present results suggest that the abundant expression of Bcl-2 protein may have a molecular basis characteristic of leiomyomas in the human uterus and that progesterone may play a vital role in the enhanced expression of Bcl-2 protein in human uterine leiomyoma cells.
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PMID:Increased expression of Bcl-2 protein in human uterine leiomyoma and its up-regulation by progesterone. 898 76

Uterine leiomyoma is the most common smooth muscle cell tumor of the myometrium. Estrogen and progesterone (P4) are believed to be physiological regulators of leiomyoma growth. We recently showed that Bcl-2 protein, an apoptosis-inhibiting gene product, was abundantly expressed in leiomyoma relative to its expression in the normal myometrium and that Bcl-2 protein expression in cultured leiomyoma cells was up-regulated by P4, but down-regulated by 17 beta-estradiol (E2). To further characterize the molecular mechanism of sex steroidal regulation of leiomyoma growth, we examined the effect of menstrual phase on proliferating cell nuclear antigen (PCNA) expression in leiomyoma and investigated whether sex steroids could influence PCNA expression in leiomyoma cells cultured under serum-free conditions by immunoblot and immunohistochemical analyses. As epidermal growth factor (EGF) has been shown to mediate estrogen action and to play a crucial role in regulating leiomyoma growth, we also investigated the effects of sex steroids on the expression of EGF and EGF receptor (EGF-R) in cultured leiomyoma cells. The PCNA labeling index in leiomyomas was much greater in the secretory, P4-dominated, phase than in the proliferative phase of the menstrual cycle and was significantly higher than that in the adjacent normal myometrium throughout the menstrual cycle. In monolayer cultures of leiomyoma cells, the addition of either E2 (10 ng/mL) or P4 (100 ng/mL) resulted in an increase in PCNA expression in the cells compared to that in control cultures, whereas in monolayer cultures of myometrial cells, the addition of E2 augmented PCNA expression in the cells, but P4 did not. Immunoblot analysis of proteins extracted from cultured leiomyoma cells revealed that leiomyoma cells contained immunoreactive EGF with a molecular mass of 133 kDa and that the addition of P4 resulted in a remarkable increase in the expression of 133- and 71-kDa immunoreactive EGF in the cells compared to that in control cultures, whereas the addition of E2 resulted in a somewhat lower expression of immunoreactive EGF in the cells. Furthermore, immunocytochemical analysis with a monoclonal antibody to human EGF-R demonstrated that the treatment with E2 augmented EGF-R expression in the cells compared to that in untreated cells, but P4 did not. The concentrations of sex steroids used were within the physiological tissue concentrations found in leiomyomas and myometria. These results indicate that P4 up-regulates the expression of PCNA and immunoreactive EGF in leiomyoma cells, whereas E2 up-regulates the expression of PCNA and EGF-R in those cells. As it is evident that EGF plays a crucial role as a local factor in regulating leiomyoma growth, the P4-induced increase in PCNA expression in leiomyoma cells may be mediated by P4-induced enhanced expression of EGF-like proteins in the cells, whereas the E2-induced increase in PCNA expression in leiomyoma cells may be mediated by E2-induced enhanced expression of EGF-R in those cells. It is, therefore, conceivable that P4 and E2 act in combination to stimulate the proliferative potential of leiomyoma cells through the induction of EGF-like proteins and EGF-R expression in uterine leiomyoma.
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PMID:Up-regulation by progesterone of proliferating cell nuclear antigen and epidermal growth factor expression in human uterine leiomyoma. 962 59

Bcl-2 is one of the many proteins that regulate programmed cell death and is overexpressed in B-cell lymphomas. The expression of bcl-2 in mesenchymal cells and soft tissue tumours was the subject of this study. Normal mesenchymal tissue and representative cases of soft tissue tumours of different types (n>200) were investigated immunohistochemically for bcl-2 expression. Although bcl-2 expression was normally relatively restricted to some smooth muscle cells and neural cells, bcl-2 immunoreactivity was widespread in different types of soft tissue neoplasms, both benign and malignant. Consistently positive tumours included solitary fibrous tumour, haemangiopericytoma, schwannoma and synovial sarcoma. The few soft tissue tumours that were consistently negative for bcl-2 included nodular fasciitis and desmoid tumour. Leiomyomas and leiomyosarcomas were heterogeneous; all uterine leiomyomas were bcl-2 positive, but all oesophageal leiomyomas were negative, paralleling the reactivity observed in the smooth muscle at those sites. Gastrointestinal stromal tumours showed bcl-2 reactivity; this was less consistent in malignant tumours. Along the malignancy gradient, there was no consistent trend in the bcl-2 reactivity. Dermatofibrosarcomas showed increase of bcl-2 expression with fibrosarcomatous transformation, whereas smooth muscle sarcomas and malignant peripheral nerve sheath sarcomas were less consistently positive than the corresponding benign neoplasms. We conclude that bcl-2 expression is widespread in soft tissue tumours, but shows constitutional expression patterns that are often parallel to the normal tissue counterparts. Compared with benign soft tissue tumours, bcl-2 expression is often reduced in sarcomas, but it cannot be used as a prognostic marker without correlation of the data to its phenotypic expression patterns.
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PMID:Cell-type- and tumour-type-related patterns of bcl-2 reactivity in mesenchymal cells and soft tissue tumours. 976 29

Uterine leiomyomas appear during the reproductive years and regress after menopause, indicating the ovarian steroid-dependent growth potential. In order to characterize the molecular mechanism of sex steroidal regulation of leiomyoma growth, we examined whether sex steroids could influence the proliferation of leiomyoma cells. As epidermal growth factor (EGF) has been shown to mediate estrogen action and play a crucial role in regulating leiomyoma growth, we also investigated the effects of sex steroids on EGF and EGF receptor (EGF-R) expression in leiomyoma cells. In cultures of leiomyoma cells, the addition of either estradiol (E(2); 10 ng/ml) or progesterone (P(4); 100 ng/ml) resulted in an increase in proliferating cell nuclear antigen (PCNA) expression in the cells, whereas in cultures of normal myometrial cells, the addition of E(2) augmented PCNA expression in the cells, but P(4) did not. Immunoblot analysis revealed that leiomyoma cells contained immunoreactive EGF and that P(4) treatment resulted in an increase in EGF expression in the cells, whereas E(2) treatment resulted in a lower EGF expression in the cells. By contrast, E(2) treatment augmented EGF-R expression in cultured leiomyoma cells, but P(4) did not. These results indicate that P(4) upregulates the expression of PCNA and EGF in leiomyoma cells, whereas E(2) upregulates the expression of PCNA and EGF-R in those cells. It is, therefore, conceivable that P(4) and E(2) act in combination to stimulate the proliferative potential of leiomyoma cells through the induction of EGF and EGF-R expression. We also found that Bcl-2 protein, an apoptosis-inhibiting gene product, was abundantly expressed in leiomyoma relative to that in normal myometrium and that Bcl-2 protein expression in leiomyoma cells was upregulated by P(4), but downregulated by E(2). It seems, therefore, likely that P(4) may also participate in leiomyoma growth through the induction of Bcl-2 protein in leiomyoma cells. The abundant expression of Bcl-2 protein in leiomyoma cells may be one of the molecular bases for the enhanced growth of a leiomyoma relative to that of normal myometrium in the uterus.
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PMID:Molecular bases for the actions of ovarian sex steroids in the regulation of proliferation and apoptosis of human uterine leiomyoma. 1054 3

Uterine leiomyomas appear during the reproductive years and regress after menopause, indicating the ovarian steroid-dependent growth potential. Recently we have found that the use of levonorgestrel-releasing intrauterine system (IUS) is effective in the long-term contraception and management of menorrhagic women with uterine myomas because of a striking reduction in menorrhagia. These clinical experiences prompted us to characterize the effects of progestin on the proliferation and apoptosis of leiomyoma cells cultured in vitro. As epidermal growth factor (EGF) has been shown to mediate estrogen action and play a crucial role in regulating leiomyoma growth, we also investigated the effects of sex steroids on EGF and EGF receptor (EGF-R) expression in leiomyoma cells. In cultures of leiomyoma cells, the addition of either E(2) (10 ng/ml) or P(4) (100 ng/ml) resulted in an increase in proliferating cell nuclear antigen (PCNA) expression in the cells; whereas in cultures of normal myometrial cells, the addition of E(2) augmented PCNA expression in the cells, but P(4) did not. Immunoblot analysis revealed that leiomyoma cells contained immunoreactive EGF and that P(4) treatment resulted in an increase in EGF expression in the cells. In contrast, E(2) treatment augmented EGF-R expression in cultured leiomyoma cells, but P(4) did not. These results indicate that P(4) up-regulates the expression of PCNA and EGF in leiomyoma cells, whereas E(2) up-regulates the expression of PCNA and EGF-R in those cells. It is, therefore, conceivable that P(4) and E(2) act in combination to stimulate the proliferative potential of leiomyoma cells through the induction of EGF and EGF-R expression. We also found that Bcl-2 protein, an apoptosis-inhibiting gene product, was abundantly expressed in leiomyoma relative to that in normal myometrium, suggesting that the abundant expression of Bcl-2 protein in leiomyoma cells may be one of the molecular bases for the enhanced growth of leiomyoma relative to that of normal myometrium in the uterus. Furthermore, Bcl-2 protein expression in leiomyoma cells was up-regulated by P(4), but down-regulated by E(2). Therefore, it seems likely that P(4) may also participate in leiomyoma growth through the induction of Bcl-2 protein in leiomyoma cells.
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PMID:Effects of progesterone on uterine leiomyoma growth and apoptosis. 1110 63

Angiogenesis is essential for tumor growth and metastasis. Some angiogenic factors, such as vascular endothelial growth factor (VEGF), platelet-derived endothelial cell growth factor (PD-ECGF), transforming growth factor-alpha (TGF-alpha) and basic fibroblast growth factor (bFGF) are involved in increased angiogenic activity and disease progression in many carcinomas. However, there is little information regarding the association between angiogenic factors and leiomyosarcoma. Although there are abundant vessels in the sarcoma which enable it to easily receive nutrition and medicinal components, chemotherapy cannot effectively treat leiomyosarcoma. This means the resistance to anticancer drugs in leiomyosarcoma is very strong. However, the resistant mechanism is still unclear. In this study, expressions of VEGF, PD-ECGF, TGF-alpha, bFGF, intratumoral microvessel density (IMVD), and p53, Bcl-2 and Bax were examined by immunohistochemistry in 30 patients with leiomyosarcoma and 21 patients with leiomyoma. With regard to angiogenesis, PD-ECGF and TGF-alpha were closely associated with an increase in IMVD (p=0.012, 0.0196, respectively), and VEGF and PD-ECGF were significantly expressed in leiomyosarcoma compared with leiomyoma (p=0.041, 0.041, respectively). Although p53 expression in leiomyosarcoma was significantly higher than in leiomyoma (p=0.016), the frequency of p53 positivity was not so high (47%). On the other hand, the ratio of Bcl-2/Bax in leiomyosarcoma was significantly higher than that in leiomyoma (p=0.033). The findings of this study suggest that in leiomyosarcoma, angiogenic factors, such as PD-ECGF, VEGF and TGF-alpha expression may be involved in tumor angiogenesis, and the frequently high ratio of Bcl-2/Bax and expression of p53 gene mutation might be related to chemoresistance mechanism.
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PMID:Expression of angiogenic factors and apoptotic factors in leiomyosarcoma and leiomyoma. 1144 64

IGF-I has been reported to play a role in regulating proliferation of human leiomyoma cells. There is, however, little evidence to suggest that IGF-I inhibits apoptosis in the leiomyoma cells. The present study was conducted to elucidate whether IGF-I affects apoptosis and Bcl-2 protein expression, an apoptosis-inhibiting gene product, in cultured leiomyoma cells. In addition, we examined the effect of IGF-I on proliferating cell nuclear antigen (PCNA) expression in cultured leiomyoma cells. Isolated human leiomyoma cells were subcultured in phenol red-free DMEM supplemented with 10% FBS for 120 h and then stepped down to serum-free conditions for an additional 72 h in the absence or presence of graded concentrations of IGF-I (1.0, 10, and 100 ng/ml). The effects of IGF-I on Bcl-2 protein and PCNA expression in cultured leiomyoma cells were assessed by Western immunoblot analysis and immunocytochemical staining, whereas the effects of IGF-I on the cell viability and apoptosis of the cultured cells were determined by 3-(4,5-dimethylatriazol-2-yl)-2,5diphenyltetrasodium bromide (MTT) assay and terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end labeling assay, respectively. Immunocytochemical staining demonstrated that IGF-I treatment resulted in the increase in PCNA labeling index in cultured leiomyoma cells in a dose-dependent manner. Immunoblot analysis of proteins extracted from the cultured leiomyoma cells revealed that the addition of IGF-I (10 and 100 ng/ml) significantly increased the expression of 35-kDa immunoreactive PCNA and 26-kDa Bcl-2 protein, compared with those in control cultures. Cell survival and proliferation of cultured leiomyoma cells, assessed by MTT assay, was significantly augmented by IGF-I treatment, compared with those of control cultures. Terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end labeling assay showed that the apoptosis-positive rate of leiomyoma cells treated with IGF-I was significantly decreased, compared with that in control cultures. The present results suggest that IGF-I plays crucial roles in leiomyoma cell growth, not only in promoting the proliferative potential by up-regulation of PCNA expression but also in down-regulating apoptosis by up-regulation of Bcl-2 protein expression in leiomyoma cells.
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PMID:Up-regulation by IGF-I of proliferating cell nuclear antigen and Bcl-2 protein expression in human uterine leiomyoma cells. 1170 40

To determine the role of cell proliferation and apoptosis in uterine leiomyoma growth, we studied protein expression of two major regulatory proteins of apoptosis -- Bcl-2 (anti-apoptotic) and Bax (pro-apoptotic) -- and two endogenous markers of cell replication - proliferating cell nuclear antigen (PCNA) and Ki-67 - in tumors and matched myometrium from premenopausal women. Conventional mitotic indices also were determined, and all proliferation data were correlated to tumor size. In situ end-labeling of fragmented DNA and routine histology were used to assess apoptosis. Our results showed that the apoptosis-regulating proteins (Bcl-2 and Bax) were expressed in the cytoplasm of the leiomyoma and myometrial smooth muscle cells throughout the menstrual cycle. Bax expression differed from Bcl-2 in that it also was found in the cytoplasm of vascular smooth muscle cells of the myometria and tumors. Both tumors and myometrial samples expressed 26-kDa and 21-kDa proteins that reacted with antibodies directed towards Bcl-2 and Bax, respectively. Apoptosis was not a prominent feature of uterine leiomyomas or myometrium. PCNA- and Ki-67-labeling and mitotic counts were significantly ( P<0.05) higher in leiomyomas than in matched myometrial samples. Proliferative activity was variable for individual tumors of the same patient and independent of tumor size. Our results suggest that altered apoptosis by overexpression of Bcl-2 or by decreased expression of Bax does not appear to be a major factor in uterine leiomyoma growth. We conclude that increased cell proliferation is the most significant contributor to growth and that the proliferative state is autonomous for each tumor in a given patient and is independent of tumor size.
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PMID:Cell proliferation and apoptosis in human uterine leiomyomas and myometria. 1211 Dec 1

GnRH agonist (GnRH-a) therapy is known to shrink uterine leiomyoma, although the molecular mechanisms responsible for this effect remain poorly understood. Conflicting results exist as to whether GnRH-a treatment increases apoptosis in leiomyoma cells. The aim of this study is to investigate the effects of GnRH-a on uterine leiomyomas by profiling the expression levels of apoptosis-related molecules such as Fas/Fas ligand (FasL), caspases 3, 6, 7, 8, 9, and 10, and Bcl-2 from specimens of 20 patients receiving Leuplin Depot (LA), a long-acting GnRH-a, of 3 doses before myomectomy, as well as 24 controls. We found that uterine leiomyomas had up-regulated expressions of FasL and caspase 3 as compared with their homologous normal myometrium control. Both leiomyomas and myometria from LA-treated patients, however, presented a significant decrease in the expressions of FasL and caspase 3 as compared with those from LA-naive control patients. In addition, it was at the posttranscription level that the tumorigenesis of leiomyoma modulated the expressions of FasL and caspase 3 higher, whereas LA suppressed them at gene transcription. Unlike the case of FasL and caspase 3 mentioned above, no significant difference was found between leiomyomas and homologous myometria in the expressions of Fas and caspases 6, 7, 8, 9, and 10. The LA effect made drug-treated leiomyomas produce less Fas and caspases 7, 9, and 10 as compared with nontreated leiomyomas. Immunohistochemical analysis showed that both Fas and FasL were localized predominantly in cytosol. Moreover, leiomyomas had an up-regulated Bcl-2 level, which remained high even in the LA-treated cells. Our findings provide molecular evidence to support our previous observations that GnRH-a therapy fails to increase apoptosis in uterine leiomyomas.
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PMID:Fas and its ligand, caspases, and bcl-2 expression in gonadotropin-releasing hormone agonist-treated uterine leiomyoma. 1236 38

It is now evident that the use of levonorgestrel-releasing intrauterine system (LNg-IUS) is effective for long-term management of menorrhagic women with uterine myomas because of a striking reduction in menorrhagia. This prompted us to characterize the effects of progesterone (P4) on the growth and apoptosis of uterine leiomyoma cells. On the other hand, we have recently noted that epidermal growth factor (EGF) and IGF-I play a crucial role in prompting uterine leiomyoma growth through stimulating the proliferative potential and inhibiting apoptosis of cultured human leiomyoma cells. In the present review, attention was paid to evaluate the effects of P4 on the expression of growth factors (EGF, IGF-I) and apoptosis-related factors (TNFalpha, Bcl-2 protein) in cultured uterine leiomyoma cells. Treatment with P4 augmented EGF and Bcl-2 protein expression, but inhibited IGF-I and TNFalpha expression in cultured leiomyoma cells. It is known that TNFalpha induces apoptosis in a variety of cell types and Bcl-2 protein is an apoptosis-inhibiting gene product. Thus, the results obtained suggest that P4 has dual actions on uterine leiomyoma growth: one is to stimulate leiomyoma cell growth and survival through up-regulating EGF and Bcl-2 protein expression as well as down-regulating TNFalpha expression in those cells, and the other is to inhibit leiomyoma cell growth through down-regulating IGF-I expression in those cells. This may explain why the size of uterine myomas during use of LNg-IUS increases in some but decreases in other instances. This may also explain why the size of uterine myomas during pregnancy does not increase despite the overwhelming increase in circulating concentrations of sex steroid hormones.
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PMID:Effects of progesterone on growth factor expression in human uterine leiomyoma. 1466 73


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