ER-α 36在子宫内膜癌中的功能及Icaritin诱导的细胞凋亡的研究
|
摘要
雌激素受体(estrogen receptor, ER)是固醇类核受体超家族成员之一。广泛存在于各种组织中,在正常的组织发育和肿瘤发生中起重要作用。雌激素受体分为ER-α和ER-β两种亚型。ER-α36是最近发现的新的α亚型,基因定位于6号染色体q24.2-25.3,cDNA全长5.4kb,编码分子量约为36kDa的蛋白。ER-a36 mRNA的转录起始点位于ER-α66基因的第一个内含子中。与ER-α66不同,ER-α36缺少氨基端转录激活域AF-1和羧基端转录激活域AF-2,但保留了DNA结构域和部分配体结合域。在ER-α36羧基末端有27个特有的氨基酸残基,代替了ER-α66基因第7和第8个外显子编码的位于氨基末端的138个氨基酸残基。
本研究的主要目的是探讨ER-α36在子宫内膜癌细胞系Ishikawa中的功能及其调节细胞增殖的机制。激光共聚焦的结果表明,ER-α36主要定位于人子宫内膜癌细胞系Ishikawa的细胞膜上和细胞质中,而ER-α66主要定位于人子宫内膜癌细胞系Ishikawa的细胞核中。PKC信号通路是细胞中常见的激酶信号通路,参与各种细胞功能,包括细胞增殖,分化,衰老,凋亡以及肿瘤的形成。子宫内膜癌是常见的妇科恶性肿瘤之一,近年来发病率明显增高。实验和流行病学研究发现PKC在子宫内膜癌的发生中起着重要的作用,但具体的机制并不是十分清楚。虽然,在先前的研究中,PKCδ的主要功能是参与细胞凋亡的过程,然而,有不少研究表明,在一部分细胞系中PKCδ起着促进细胞增殖的作用。本实验中,我们发现用雌激素(E2)和偶联BSA的雌激素(E2-BSA)处理子宫内膜癌细胞系Ishikawa后都能激活PKCδ. RNA干扰ER-α36后能废除E2激活的PKCδ,这些结果表明,雌激素通过ER-α36调节的膜起始信号通路迅速激活PKCδ。通常情况下,PKCα活性的提高与肿瘤细胞的迁移和增殖相关。此外,PKCα表现出抑制或减轻肿瘤细胞的细胞凋亡特征。本实验中,我们发现雌激素不能激活PKCα,表明PKCα并不参与雌激素依赖的子宫内膜癌增殖。cAMP是一个第二信使,在各种刺激的情况下起信号传导的作用,在真核细胞中cAMP的主要功能是激活cAMP依赖性蛋白激酶(PKA)。本实验中,只有E2能激活PKA,E2-BSA并不能激活PKA。表明膜受体并不参与雌激素依赖的PKA激活。E2和E2-BSA能激活ERK1/2,并且这个过程需要ER-α36和PKCδ的参与。同时我们的结果表明,ER-α36介导了膜起始的E2诱导的cyclin D1/cdk4的表达水平的提高。以上结果表明ER-a36通过调节膜起始的PKCS/ERK通路参与雌激素调节的子宫内膜癌的增殖。
水合淫羊藿素(Icaritin)是一种中药淫羊藿的提取物,研究表明其具有选择性雌激素受体调节活性和抗肿瘤效应。Icaritin具有多种生物学活性,如刺激神经元和心脏细胞分化,提高成骨细胞和抑制破骨细胞的分化,预防激素相关的骨坏死以及通过ERK1/2信号通路诱导前列腺癌细胞细胞凋亡。先前的报道表明Icairitin在低浓度处理雌激素受体阳性的乳腺癌细胞MCF-7时表现出雌激素样活性。然而,在微摩尔浓度时抑制前列腺癌细胞PC-3的增殖。这些结果表明Icaritin在不同浓度时表现出雌激素样和抗雌激素样活性并且作为一种选择性雌激素受体调节剂调剂细胞的增殖。但目前国内外并没有Icaritin在子宫内膜癌细胞中研究的报道。
丝裂原活化蛋白激酶(MAPK)参与多种细胞功能,如细胞增殖、分化、迁移和死亡。MAPK主要包括三个亚族,ERK1/2, JNK和p38蛋白激酶。JNK和p38激活后主要参与细胞凋亡和分化。先前的研究表明短暂的激活ERK1/2在细胞增殖中起作用,但持续激活ERK1/2诱导细胞周期阻滞和分化。
在本研究中,我们检测了Icaritin对子宫内膜癌细胞HeclA增殖的影响,研究发现Icaritin能有效抑制HeclA细胞的生长,并同时抑制细胞周期蛋白cyclin D1和细胞周期蛋白依赖性激酶cdk4的表达,上调细胞周期抑制蛋白WAF1/p21和KIP1/p27的蛋白表达。接下来,研究发现Icaritin能诱导Hec1 A细胞凋亡,这个过程伴随着caspase 9和caspase 3的激活,PARP的裂解和细胞色素c的释放。如果我们提前加入广谱的caspase抑制剂z-VAD-fmk,则会抑制Icaritin诱导的细胞凋亡。Icaritin处理Hec1 A细胞后,抗凋亡蛋白Bcl-2蛋白表达水平下降,同时促凋亡蛋白Bax的表达水平上升。我们进一步的研究表明,在子宫内膜癌细胞系Hecl A中Icaritin能持续激活ERK1/2,并且ERK1/2的抑制剂U0126能抑制Icaritin激活ERK1/2,同时抑制了Icaritin诱导的Hecl A细胞的生长抑制和细胞凋亡。以上结果表明,Icaritin能通过线粒体途径诱导子宫内膜癌Hecl A细胞凋亡,并且持续激活ERK1/2在此凋亡过程中起着非常重要的作用,从而表明Icaritin有可能成为治疗子宫内膜癌的有效药物。
Estrogen receptor (ER) belongs to the steroid hormone family of the nuclear receptor superfamily and expressed in various tissues.ER plays an important role in tissue development and tumor occurrence.ER consists of ER-a and ER-(3. Previously, we identified and cloned a novel variant of ER-a. ER-a36.ER-a36 gene is localized on chromososme 6q24.2-25.3 and contains a 5.4 kb cDNA, which encode a 310 amino acid open-deading frame and a a protein with a molecular weight of 36 kDa that is transcribed from previously unidentified promoter located in the first intron of the original 66 kDa ER-a (ER-a66) gene.ER-a36 lacks both transcriptional activation domains of ER-a66 (AF-1 and AF-2).but it retains the DNA-binding domain and partial ligand-binding domain. It possesses a unique 27 amino acid domain that replaces the last 138 amino acids encoded by exons 7 and 8 of the ER-a66 gene.
The purpose of this study was to investigate the function and the underlying mechanisms of ER-a36 in growth regulation of endometrial Ishikawa cancer cells. The cellular localization of ER-a36 and ER-a66 were determined by immunofluorescence in the Ishikawa cells.Immunofluorescence staining of Ishikawa cells demonstrated that ER-a36 was expressed mainly on the plasma membrane and in the cytoplasm, while ER-a66 was predominantly localized in the cell nucleus. PKC isoforms are involved in a variety of cellular functions, including growth, differentiation, tumor promotion, aging, and apoptosis.Although early studies of the effect of PKC8 on cell proliferation suggested that PKC8 suppresses proliferation. However, several reports have demonstrated that PKC5 could act as a positive regulator of cell proliferation. Here, we found that both E2 and E2-BSA stimulated the activation of PKC5 signaling pathway in Ishikawa cells, and knockdown of ER-a36 expression with the shRNA abrogated E2-induced PKC5 phosphorylation. These indicated that ER-a36 mediates membrane-initiated PKC8 pathway induced by E2. In general, increased PKCαactivity is associated with increased motility and proliferation of cancer cells. In addition, PKCαhas been shown to inhibit or facilitate apoptosis of cancer cells. Here, we found that E2 was unable to induce PKCa phosphorylation. cAMP is a second messenger that plays a role in intracellular signal transduction of various stimuli. A major function of cAMP in eukaryotes is activation of cAMP-dependent protein kinase (PKA). In the present study, only E2 was able to induce cAMP-dependent protein kinase A (PKA) phosphorylation. E2-and E2-BSA-induced ERK phosphorylation required ER-α36 and PKCδ. Furthermore, E2 enhances cyclin D1/cdk4 expression via ER-α36.
Our results demonstrated that E2 activates the PKCδ/ERK pathway and enhances cyclin D1/cdk4 expression via the membrane-initiated signaling pathways mediated by ER-α36, suggesting a possible involvement of ER-α36 in E2-dependent growth-promoting effects in endometrial cancer cells.
Icaritin, a compound from Epimedium Genus, Icaritin exhibits many pharmacological and biological activities, such as stimulation of neuronal and cardiac differentiation, enhancement of osteoblastic and suppressed osteoclastic differentiation and activity, prevention of steroid-associated osteonecrosis, induction of human prostatic smooth muscle cells apoptosis via ERK1/2 pathway. Previously, it was reported that icaritin exhibits estrogen-like activity in estrogen receptor-positive breast cancer MCF-7 cells at sub-micromolar concentrations. At micromolar range, however, icaritin inhibited growth of prostate cancer PC-3 cells. These results indicated that icaritin has both agonist and antagonist activities depending on concentrations and may function as an estrogen receptor modulator to regulate cell growth. However, there are no reports on activity of Icaritin against endometrial cancer.
Mitogen-activated protein (MAP) kinases participate in diverse cellular functions such as cell proliferation, cell differentiation, cell motility, and cell death. There are three major MAPK family subgroups:extracellular signal-regulated kinase1/2 (ERK1/2),c-Jun N-terminal of stress-activated protein kinasesl/2 (JNK1/2) and the p38 protein kinases. The signaling cascades involving JNK and p38, activated by extracellular stress signals, are involved in cell differentiation and apoptosis. Previous studies have demonstrated that transient activation of ERK1/2 plays a pivotal role in cell proliferation and that sustained ERK1/2 activation induces cell cycle arrest and differentiation.
Here,we examined Icaritin effect on cell growth of human endometrial cancer Hecl A cells and found that Icaritin potently inhibited proliferation of Hecl A cells. Icaritin-inhibited cell growth was associated with increased levels of p21 and p27 expression and reduced cyclinDl and cdk 4 expression. Icaritin also induced cell apoptosis accompanied by activation of caspases as evidenced by the cleavage of endogenous substrate Poly (ADP-ribose) polymerase (PARP) and cytochrome c release, which was abrogated by pretreatment with the pan-caspase inhibitor z-VAD-fmk. Icaritin treatment also induced expression of pro-apoptotic protein Bax with a concomitant decrease of Bcl-2 expression. Furthermore, Icaritin induced sustained phosphorylation of extracellular signal-regulated kinase 1/2 (the MAPK/ERK1/2) in Hecl A cells and U0126, a specific MAP kinase kinase (MEK1/2) inhibitor, blocked the ERK activation by Icaritin and abolished the Icaritin-induced growth inhibition and apoptosis. Our results demonstrated that Icaritin induced sustained ERK activation and inhibited growth of endometrial cancer Hecl A cells, and provided a rational for preclinical and clinical evaluation of Icaritin for endometrial cancer therapy.
本研究的主要目的是探讨ER-α36在子宫内膜癌细胞系Ishikawa中的功能及其调节细胞增殖的机制。激光共聚焦的结果表明,ER-α36主要定位于人子宫内膜癌细胞系Ishikawa的细胞膜上和细胞质中,而ER-α66主要定位于人子宫内膜癌细胞系Ishikawa的细胞核中。PKC信号通路是细胞中常见的激酶信号通路,参与各种细胞功能,包括细胞增殖,分化,衰老,凋亡以及肿瘤的形成。子宫内膜癌是常见的妇科恶性肿瘤之一,近年来发病率明显增高。实验和流行病学研究发现PKC在子宫内膜癌的发生中起着重要的作用,但具体的机制并不是十分清楚。虽然,在先前的研究中,PKCδ的主要功能是参与细胞凋亡的过程,然而,有不少研究表明,在一部分细胞系中PKCδ起着促进细胞增殖的作用。本实验中,我们发现用雌激素(E2)和偶联BSA的雌激素(E2-BSA)处理子宫内膜癌细胞系Ishikawa后都能激活PKCδ. RNA干扰ER-α36后能废除E2激活的PKCδ,这些结果表明,雌激素通过ER-α36调节的膜起始信号通路迅速激活PKCδ。通常情况下,PKCα活性的提高与肿瘤细胞的迁移和增殖相关。此外,PKCα表现出抑制或减轻肿瘤细胞的细胞凋亡特征。本实验中,我们发现雌激素不能激活PKCα,表明PKCα并不参与雌激素依赖的子宫内膜癌增殖。cAMP是一个第二信使,在各种刺激的情况下起信号传导的作用,在真核细胞中cAMP的主要功能是激活cAMP依赖性蛋白激酶(PKA)。本实验中,只有E2能激活PKA,E2-BSA并不能激活PKA。表明膜受体并不参与雌激素依赖的PKA激活。E2和E2-BSA能激活ERK1/2,并且这个过程需要ER-α36和PKCδ的参与。同时我们的结果表明,ER-α36介导了膜起始的E2诱导的cyclin D1/cdk4的表达水平的提高。以上结果表明ER-a36通过调节膜起始的PKCS/ERK通路参与雌激素调节的子宫内膜癌的增殖。
水合淫羊藿素(Icaritin)是一种中药淫羊藿的提取物,研究表明其具有选择性雌激素受体调节活性和抗肿瘤效应。Icaritin具有多种生物学活性,如刺激神经元和心脏细胞分化,提高成骨细胞和抑制破骨细胞的分化,预防激素相关的骨坏死以及通过ERK1/2信号通路诱导前列腺癌细胞细胞凋亡。先前的报道表明Icairitin在低浓度处理雌激素受体阳性的乳腺癌细胞MCF-7时表现出雌激素样活性。然而,在微摩尔浓度时抑制前列腺癌细胞PC-3的增殖。这些结果表明Icaritin在不同浓度时表现出雌激素样和抗雌激素样活性并且作为一种选择性雌激素受体调节剂调剂细胞的增殖。但目前国内外并没有Icaritin在子宫内膜癌细胞中研究的报道。
丝裂原活化蛋白激酶(MAPK)参与多种细胞功能,如细胞增殖、分化、迁移和死亡。MAPK主要包括三个亚族,ERK1/2, JNK和p38蛋白激酶。JNK和p38激活后主要参与细胞凋亡和分化。先前的研究表明短暂的激活ERK1/2在细胞增殖中起作用,但持续激活ERK1/2诱导细胞周期阻滞和分化。
在本研究中,我们检测了Icaritin对子宫内膜癌细胞HeclA增殖的影响,研究发现Icaritin能有效抑制HeclA细胞的生长,并同时抑制细胞周期蛋白cyclin D1和细胞周期蛋白依赖性激酶cdk4的表达,上调细胞周期抑制蛋白WAF1/p21和KIP1/p27的蛋白表达。接下来,研究发现Icaritin能诱导Hec1 A细胞凋亡,这个过程伴随着caspase 9和caspase 3的激活,PARP的裂解和细胞色素c的释放。如果我们提前加入广谱的caspase抑制剂z-VAD-fmk,则会抑制Icaritin诱导的细胞凋亡。Icaritin处理Hec1 A细胞后,抗凋亡蛋白Bcl-2蛋白表达水平下降,同时促凋亡蛋白Bax的表达水平上升。我们进一步的研究表明,在子宫内膜癌细胞系Hecl A中Icaritin能持续激活ERK1/2,并且ERK1/2的抑制剂U0126能抑制Icaritin激活ERK1/2,同时抑制了Icaritin诱导的Hecl A细胞的生长抑制和细胞凋亡。以上结果表明,Icaritin能通过线粒体途径诱导子宫内膜癌Hecl A细胞凋亡,并且持续激活ERK1/2在此凋亡过程中起着非常重要的作用,从而表明Icaritin有可能成为治疗子宫内膜癌的有效药物。
Estrogen receptor (ER) belongs to the steroid hormone family of the nuclear receptor superfamily and expressed in various tissues.ER plays an important role in tissue development and tumor occurrence.ER consists of ER-a and ER-(3. Previously, we identified and cloned a novel variant of ER-a. ER-a36.ER-a36 gene is localized on chromososme 6q24.2-25.3 and contains a 5.4 kb cDNA, which encode a 310 amino acid open-deading frame and a a protein with a molecular weight of 36 kDa that is transcribed from previously unidentified promoter located in the first intron of the original 66 kDa ER-a (ER-a66) gene.ER-a36 lacks both transcriptional activation domains of ER-a66 (AF-1 and AF-2).but it retains the DNA-binding domain and partial ligand-binding domain. It possesses a unique 27 amino acid domain that replaces the last 138 amino acids encoded by exons 7 and 8 of the ER-a66 gene.
The purpose of this study was to investigate the function and the underlying mechanisms of ER-a36 in growth regulation of endometrial Ishikawa cancer cells. The cellular localization of ER-a36 and ER-a66 were determined by immunofluorescence in the Ishikawa cells.Immunofluorescence staining of Ishikawa cells demonstrated that ER-a36 was expressed mainly on the plasma membrane and in the cytoplasm, while ER-a66 was predominantly localized in the cell nucleus. PKC isoforms are involved in a variety of cellular functions, including growth, differentiation, tumor promotion, aging, and apoptosis.Although early studies of the effect of PKC8 on cell proliferation suggested that PKC8 suppresses proliferation. However, several reports have demonstrated that PKC5 could act as a positive regulator of cell proliferation. Here, we found that both E2 and E2-BSA stimulated the activation of PKC5 signaling pathway in Ishikawa cells, and knockdown of ER-a36 expression with the shRNA abrogated E2-induced PKC5 phosphorylation. These indicated that ER-a36 mediates membrane-initiated PKC8 pathway induced by E2. In general, increased PKCαactivity is associated with increased motility and proliferation of cancer cells. In addition, PKCαhas been shown to inhibit or facilitate apoptosis of cancer cells. Here, we found that E2 was unable to induce PKCa phosphorylation. cAMP is a second messenger that plays a role in intracellular signal transduction of various stimuli. A major function of cAMP in eukaryotes is activation of cAMP-dependent protein kinase (PKA). In the present study, only E2 was able to induce cAMP-dependent protein kinase A (PKA) phosphorylation. E2-and E2-BSA-induced ERK phosphorylation required ER-α36 and PKCδ. Furthermore, E2 enhances cyclin D1/cdk4 expression via ER-α36.
Our results demonstrated that E2 activates the PKCδ/ERK pathway and enhances cyclin D1/cdk4 expression via the membrane-initiated signaling pathways mediated by ER-α36, suggesting a possible involvement of ER-α36 in E2-dependent growth-promoting effects in endometrial cancer cells.
Icaritin, a compound from Epimedium Genus, Icaritin exhibits many pharmacological and biological activities, such as stimulation of neuronal and cardiac differentiation, enhancement of osteoblastic and suppressed osteoclastic differentiation and activity, prevention of steroid-associated osteonecrosis, induction of human prostatic smooth muscle cells apoptosis via ERK1/2 pathway. Previously, it was reported that icaritin exhibits estrogen-like activity in estrogen receptor-positive breast cancer MCF-7 cells at sub-micromolar concentrations. At micromolar range, however, icaritin inhibited growth of prostate cancer PC-3 cells. These results indicated that icaritin has both agonist and antagonist activities depending on concentrations and may function as an estrogen receptor modulator to regulate cell growth. However, there are no reports on activity of Icaritin against endometrial cancer.
Mitogen-activated protein (MAP) kinases participate in diverse cellular functions such as cell proliferation, cell differentiation, cell motility, and cell death. There are three major MAPK family subgroups:extracellular signal-regulated kinase1/2 (ERK1/2),c-Jun N-terminal of stress-activated protein kinasesl/2 (JNK1/2) and the p38 protein kinases. The signaling cascades involving JNK and p38, activated by extracellular stress signals, are involved in cell differentiation and apoptosis. Previous studies have demonstrated that transient activation of ERK1/2 plays a pivotal role in cell proliferation and that sustained ERK1/2 activation induces cell cycle arrest and differentiation.
Here,we examined Icaritin effect on cell growth of human endometrial cancer Hecl A cells and found that Icaritin potently inhibited proliferation of Hecl A cells. Icaritin-inhibited cell growth was associated with increased levels of p21 and p27 expression and reduced cyclinDl and cdk 4 expression. Icaritin also induced cell apoptosis accompanied by activation of caspases as evidenced by the cleavage of endogenous substrate Poly (ADP-ribose) polymerase (PARP) and cytochrome c release, which was abrogated by pretreatment with the pan-caspase inhibitor z-VAD-fmk. Icaritin treatment also induced expression of pro-apoptotic protein Bax with a concomitant decrease of Bcl-2 expression. Furthermore, Icaritin induced sustained phosphorylation of extracellular signal-regulated kinase 1/2 (the MAPK/ERK1/2) in Hecl A cells and U0126, a specific MAP kinase kinase (MEK1/2) inhibitor, blocked the ERK activation by Icaritin and abolished the Icaritin-induced growth inhibition and apoptosis. Our results demonstrated that Icaritin induced sustained ERK activation and inhibited growth of endometrial cancer Hecl A cells, and provided a rational for preclinical and clinical evaluation of Icaritin for endometrial cancer therapy.
引文
[1]Wang Z, Zhang X, Shen P, Loggie BW, Chang Y, et al. Identification, cloning, and expression of human estrogen receptor-alpha36, a novel variant of human estrogen receptor-alpha66 [J]. Biochem Biophys Res Commun,2005, 336:1023-1027.
[2]Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, et al. Molecular basis of agonism and antagonism in the oestrogen receptor [J]. Nature,1997, 389:753-758.
[3]Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA Cloning of a novel receptor expressed in rat prostate and ovary [J]. Proc Natl Acad Sci U S A,1996,93:5925-5930.
[4]Heldring N, Pike A, Andersson S, Matthews J, Cheng G, et al. Estrogen receptors:how do they signal and what are their targets [J]. Physiol Rev, 2007.87:905-931.
[5]. Lorenzo J. A new hypothesis for how sex steroid hormones regulate bone mass [J].JClin Invest.2003,111:1641-1643.
[6]Baulieu EE, Binart N, Cadepond F, Catelli MG Chambraud B, et al. Receptor-associated nuclear proteins and steroid/antisteroid action. Ann N Y Acad Sci,1990,595:300-315.
[7]Gasc JM, Baulieu EE. Steroid hormone receptors:intracellular distribution [J].BiolCell,1986,56:1-6.
[8]Kumar V, Chambon P. The estrogen receptor binds tightly to its responsive element as a ligand-induced homodimer [J]. Cell,1988,55:145-156.
[9]McKenna NJ, O'Malley BW. Nuclear receptors, coregulators, ligands, and selective receptor modulators:making sense of the patchwork quilt [J]. Ann NY Acad Sci.2001,949:3-5.
[10]Leers J. Treuter E, Gustafsson JA. Mechanistic principles in NR box- dependent interaction between nuclear hormone receptors and the coactivator TIF2 [J]. Mol Cell Biol,1998,18:6001-6013.
[11]Hall JM, McDonnell DP, Korach KS. Allosteric regulation of estrogen receptor structure, function, and coactivator recruitment by different estrogen response elements [J]. Mol Endocrinol,2002,16:469-486.
[12]Kim MY, Hsiao SJ. Kraus WL. A role for coactivators and histone acetylation in estrogen receptor alpha-mediated transcription initiation [J]. EMBO J, 2001.20:6084-6094.
[13]Jepsen K, Rosenfeld MG. Biological roles and mechanistic actions of co-repressor complexes [J]. J Cell Sci.2002,115:689-698.
[14]Gaub MP, Bellard M. Scheuer I, Chambon P, Sassone-Corsi P. Activation of the ovalbumin gene by the estrogen receptor involves the fos-jun complex [J]. Cell.1990,63:1267-1276.
[15]Umayahara Y, Kawamori R, Watada H, Imano E, Iwama N, et al. Estrogen regulation of the insulin-like growth factor I gene transcription involves an AP-1 enhancer [J]. J Biol Chem.1994,269:16433-16442.
[16]Schmitt M. Bausero P, Simoni P, Queuche D, Geoffroy V. et al. Positive and negative effects of nuclear receptors on transcription activation by AP-1 of the human choline acetyltransferase proximal promoter [J]. J Neurosci Res. 1995,40:152-164.
[17]Webb P. Nguyen P, Valentine C, Lopez GN. Kwok GR. et al. The estrogen receptor enhances AP-1 activity by two distinct mechanisms with different requirements for receptor transactivation functions [J]. Mol Endocrinol,1999, 13:1672-1685.
[18]Teyssier C, Belguise K, Galtier F, Chalbos D. Characterization of the physical interaction between estrogen receptor alpha and JUN proteins [J]. J Biol Chem.2001.276:36361-36369.
[19]Li C. Briggs MR. Ahlborn TE, Kraemer FB, Liu J. Requirement of Spl and estrogen receptor alpha interaction in 17beta-estradiol-mediated transcriptional activation of the low density lipoprotein receptor gene expression [J]. Endocrinology,2001,142:1546-1553.
[20]Duan R, Porter W, Safe S. Estrogen-induced c-fos protooncogene expression in MCF-7 human breast cancer cells:role of estrogen receptor Spl complex formation [J]. Endocrinology,1998,139:1981-1990.
[21]Castro-Rivera E, Samudio I, Safe S. Estrogen regulation of cyclin Dl gene expression in ZR-75 breast cancer cells involves multiple enhancer elements [J]. J Biol Chem,2001,276:30853-30861.
[22]. Bjornstrom L, Sjoberg M. Mutations in the estrogen receptor DNA-binding domain discriminate between the classical mechanism of action and cross-talk with Stat5b and activating protein 1 (AP-1) [J]. J Biol Chem,2002, 277:48479-48483.
[23]Levin ER. Membrane oestrogen receptor alpha signalling to cell functions [J]. J Physiol,2009,587:5019-5023.
[24]Bjornstrom L, Sjoberg M. Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes [J]. Mol Endocrinol,2005,19:833-842.
[25]Nadal A, Ropero AB, Fuentes E, Soria B. The plasma membrane estrogen receptor:nuclear or unclear [J]? Trends Pharmacol Sci,2001,22:597-599.
[26]Rader JI, Howard GA, Feist E, Turner RT, Baylink DJ. Bone mineralization and metabolism of 3H-25-hydroxyvitamin D3 in thyroparathyroidectomized rats treated with parathyroid extract [J]. Calcif Tissue Int,1979,29:21-26.
[27]Sak K, Everaus H.Nongenomic effects of 17beta-estradiol--iversity of membrane binding sites [J].J Steroid Biochem Mol Biol,2004,88:323-335.
[28]Migliaccio A, Di Domenico M, Castoria G, de Falco A, Bontempo P, et al. Tyrosine kinase/p21ras/MAP-kinase pathway activation by estradiol-receptor complex in MCF-7 cells [J]. EMBO J,1996,15:1292-1300.
[29]Kelly MJ, Levin ER. Rapid actions of plasma membrane estrogen receptors [J]. Trends Endocrinol Metab.2001.12:152-156.
[30]Levin ER. Integration of the extranuclear and nuclear actions of estrogen [J]. Mol Endocrinol,2005,19:1951-1959.
[31]Pietras RJ, Szego CM. Specific binding sites for oestrogen at the outer surfaces of isolated endometrial cells [J]. Nature,1977,265:69-72.
[32]Pappas TC, Gametchu B, Watson CS. Membrane estrogen receptors identified by multiple antibody labeling and impeded-ligand binding [J]. FASEBJ,1995.9:404-410.
[33]Fimiani M, Rubegni P, de Aloe G, Bilenchi R, Andreassi L. Squamous cell carcinoma of the leg in a patient with prolidase deficiency [J]. Br J Dermatol, 1999,140:362-363.
[34]Smart EJ, Graf GA. McNiven MA. Sessa WC, Engelman JA, et al. Caveolins, liquid-ordered domains, and signal transduction [J]. Mol Cell Biol,1999,19: 7289-7304.
[35]Zhang YW, Morita I. Zhang L, Shao G, Yao XS, et al. Screening of anti-hypoxia/reoxygenation agents by an in vitro method [J]. Part 2: Inhibition of tyrosine kinase activation prevented hypoxia/reoxygenation-induced injury in endothelial gap junctional intercellular communication [J]. Planta Med,2000.66:119-123.
[36]Zhao X, Liu Y. Ma Q, Wang X. Jin H, et al. Caveolin-1 negatively regulates TRAIL-induced apoptosis in human hepatocarcinoma cells [J]. Biochem Biophys Res Commun,2009.378:21-26.
[37]Dong C, Filipeanu CM, Duvernay MT, Wu G. Regulation of G protein-coupled receptor export trafficking [J]. Biochim Biophys Acta,2007, 1768:853-870.
[38]Wright LP, Philips MR. Thematic review series:lipid posttranslational modifications. CAAX modification and membrane targeting of Ras [J]. J Lipid Res.2006.47:883-891.
[39]Song RX. Zhang Z. Santen RJ. Estrogen rapid action via protein complex formation involving ERalpha and Src [J]. Trends Endocrinol Metab.2005.16: 347-353.
[40]Lin SL, Yan LY, Zhang XT, Yuan J, Li M, et al. ER-alpha36, a variant of ER-alpha, promotes tamoxifen agonist action in endometrial cancer cells via the MAPK/ERK and PI3K/Akt pathways [J]. PLoS One 5:e9013.
[41]Lin SL, Yan LY, Liang XW, Wang ZB, Wang ZY, et al. A novel variant of ER-alpha, ER-alpha36 mediates testosterone-stimulated ERK and Akt activation in endometrial cancer Hecl A cells [J]. Reprod Biol Endocrinol, 2009,7:102.
[42]Tong JS, Zhang QH, Wang ZB, Li S, Yang CR, et al. ER-alpha36, a Novel Variant of ER-alpha, Mediates Estrogen-Stimulated Proliferation of Endometrial Carcinoma Cells via the PKCdelta/ERK Pathway [J]. PLoS One 5:e15408.
[43]Santen RJ, Song RX, McPherson R, Kumar R, Adam L, et al. The role of mitogen-activated protein (MAP) kinase in breast cancer [J]. J Steroid Biochem Mol Biol,2002,80:239-256.
[44]Razandi M, Pedram A, Levin ER. Plasma membrane estrogen receptors signal to antiapoptosis in breast cancer [J]. Mol Endocrinol,2000,14: 1434-1447.
[45]Barletta F, Wong CW, McNally C, Komm BS, Katzenellenbogen B, et al. Characterization of the interactions of estrogen receptor and MNAR in the activation of cSrc [J]. Mol Endocrinol,2004,18:1096-1108.
[46]Tremblay GB, Tremblay A, Labrie F, Giguere V. Dominant activity of activation function 1 (AF-1) and differential stoichiometric requirements for AF-1 and-2 in the estrogen receptor alpha-beta heterodimeric complex [J]. Mol Cell Biol,1999,19:1919-1927.
[47]Franke TF. PI3K/Akt:getting it right matters [J]. Oncogene,2008,27: 6473-6488.
[48]. Martiny-Baron G, Fabbro D. Classical PKC isoforms in cancer [J]. Pharmacol Res,2007,55:477-486.
[49]Ricciardolo FL. Multiple roles of nitric oxide in the airways [J]. Thorax, 2003,58:175-182.
[50]Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor [J]. Nature,1987, 327:524-526.
[51]Lenninger S. Should we ignore any skin changes without taking measures [J] Lakartidningen,1992,89:4125-4126.
[52]Guo X, Razandi M, Pedram A, Kassab G, Levin ER. Estrogen induces vascular wall dilation:mediation through kinase signaling to nitric oxide and estrogen receptors alpha and beta [J]. J Biol Chem,2005,280:19704-19710.
[53]Raicu M, Florea S, Costache G,Popov D, Simionescu M. Clotrimazole inhibits smooth muscle cell proliferation and has a vasodilator effect on resistance arteries [J]. Fundam Clin Pharmacol,2000,14:477-485.
[54]Zhang YH, Hancox JC. Regulation of cardiac Na+-Ca2+exchanger activity by protein kinase phosphorylation--still a paradox [J]?Cell Calcium.2009, 45:1-10.
[55]Nagamune K. Moreno SN. Chini EN. Sibley LD. Calcium regulation and signaling in apicomplexan parasites [J]. Subcell Biochem,2008,47:70-81.
[56]Bouhoute A, Leclercq G. Estradiol derivatives bearing the side-chain of tamoxifen antagonize the association between the estrogen receptor and calmodulin[J].Biochem Pharmacol,1994,47:748-751.
[57]Benten WP, Stephan C, Lieberherr M, Wunderlich F. Estradiol signaling via sequestrable surface receptors [J].Endocrinology,2001,142:1669-1677.
[58]Lieberherr M. Grosse B, Kachkache M, Balsan S. Cell signaling and estrogens in female rat osteoblasts:a possible involvement of unconventional nonnuclear receptors [J].J Bone Miner Res,1993,8:1365-1376.
[59]Kerr JF. Wyllie AH, Currie AR. Apoptosis:a basic biological phenomenon with wide-ranging implications in tissue kinetics [J].Br J Cancer.1972,26: 239-257.
[60]Elmore S. Apoptosis:a review of programmed cell death [J]. Toxicol Pathol, 2007,35:495-516.
[61]Hacker G. The morphology of apoptosis [J]. Cell Tissue Res,2000,301: 5-17.
[62]Abdel Aziz A. Apoptosis and histopathological lesions in parasite-infected species of bivalve molluscs [J]. J Egypt Soc Parasitol,2009,39:811-820.
[63]Jiao XT, Liu XQ, Huang LS, Zhang YJ, Han LS. Role of caspase-3,-8, and-9 in apoptosis of copper induced primary cortical neurons [J]. Zhongguo Dang Dai Er Ke Za Zhi,2009,11:917-922.
[64]Zhivotovsky B, Samali A, Gahm A, Orrenius S. Caspases:their intracellular localization and translocation during apoptosis [J]. Cell Death Differ,1999,6: 644-651.
[65]Levrero M, De Laurenzi V, Costanzo A, Gong J, Melino G, et al. Structure, function and regulation of p63 and p73 [J]. Cell Death Differ,1999,6: 1146-1153.
[66]Nakagawa T, Zhu H, Morishima N, Li E, Xu J, et al. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta [J]. Nature,2000,403:98-103.
[67]Karmakar S, Davis KA, Choudhury SR, Deeconda A, Banik NL, et al. Bcl-2 inhibitor and apigenin worked synergistically in human malignant neuroblastoma cell lines and increased apoptosis with activation of extrinsic and intrinsic pathways [J]. Biochem Biophys Res Commun,2009,388: 705-710.
[68]Antonsson B, Montessuit S, Lauper S, Eskes R, Martinou JC.Bax oligomerization is required for channel-forming activity in liposomes and to trigger cytochrome c release from mitochondria [J].Biochem J,2000,345 Pt 2:271-278.
[69]Dijkers PF, Medema RH, Lammers JW, Koenderman L,Coffer PJ. Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1 [J]. Curr Biol,2000,10:1201-1204.
[70]Buchholz TA, Davis DW, McConkey DJ, Symmans WF, Valero V, et al. Chemotherapy-induced apoptosis and Bcl-2 levels correlate with breast cancer response to chemotherapy [J]. Cancer J,2003,9:33-41.
[71]Hacki J, Egger L, Monney L, Conus S, Rosse T, et al. Apoptotic crosstalk between the endoplasmic reticulum and mitochondria controlled by Bcl-2 [J]. Oncogene,2000,19:2286-2295.
[72]Lee YK, Park S Y Kim YM, Park OJ. Regulatory effect of the AMPK-COX-2 signaling pathway in curcumin-induced apoptosis in HT-29 colon cancer cells [J]. AnnN YAcad Sci,2009.1171:489-494.
[73]Zhou JH, Yu DV, Cheng J. Shapiro DJ. Delayed and persistent ERK1/2 activation is required for 4-hydroxytamoxifen-induced cell death [J]. Steroids, 2007,72:765-777.
[74]Zheng A, Kallio A, Harkonen P. Tamoxifen-induced rapid death of MCF-7 breast cancer cells is mediated via extracellularly signal-regulated kinase signaling and can be abrogated by estrogen [J]. Endocrinology.2007,148: 2764-2777.
[75]Fernando RI. Wimalasena J. Estradiol abrogates apoptosis in breast cancer cells through inactivation of BAD:Ras-dependent nongenomic pathways requiring signaling through ERK and Akt [J]. Mol Biol Cell,2004,15: 3266-3284.
[76]Li DW, Liu JP, Mao YW, Xiang H. Wang J, et al. Calcium-activated RAF/MEK/ERK signaling pathway mediates p53-dependent apoptosis and is abrogated by alpha B-crystallin through inhibition of RAS activation [J]. Mol Biol Cell,2005,16:4437-4453.
[77]Xue Q. Chen J, Gong S, Xie J. He J. et al. Study of the effect of JNK signal transduction pathway in intense noise-induced apoptosis in cochlea of guinea pig [J]. Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi.2009.23: 1138-1142.
[78]Chathoth S, Thayyullathil F, Hago A, Shahin A, Patel M, et al. UVC-induced apoptosis in Dubca cells is independent of JNK activation and p53(Ser-15) phosphorylation [J]. Biochem Biophys Res Commun,2009,383:426-432.
[79]Chen YR, Wang X, Templeton D, Davis RJ, Tan TH. The role of c-Jun N-terminal kinase (JNK) in apoptosis induced by ultraviolet C and gamma radiation. Duration of JNK activation may determine cell death and proliferation [J]. J Biol Chem,1996,271:31929-31936.
[80]Teraishi F, Wu S, Zhang L, Guo W, Davis JJ, et al. Identification of a novel synthetic thiazolidin compound capable of inducing c-Jun NH2-terminal kinase-dependent apoptosis in human colon cancer cells [J]. Cancer Res, 2005,65:6380-6387.
[81]Lorin S, Borges A, Ribeiro Dos Santos L, Souquere S, Pierron G, et al. c-Jun NH2-terminal kinase activation is essential for DRAM-dependent induction of autophagy and apoptosis in 2-methoxyestradiol-treated Ewing sarcoma cells [J]. Cancer Res,2009,69:6924-6931.
[82]Wang JH, Yu B, Niu HY, Li H, Zhang Y, et al. C-jun N-terminal kinase-mediated signaling is essential for Staphylococcus aureus-induced U937 apoptosis [J]. Chin Med Sci J,2009,24:26-29.
[83]Huang HM, Liu JC. c-Jun blocks cell differentiation but not growth inhibition or apoptosis of chronic myelogenous leukemia cells induced by STI571 and by histone deacetylase inhibitors [J]. J Cell Physiol,2009,218: 568-574.
[84]Yeste-Velasco M, Folch J, Pallas M, Camins A. The p38(MAPK) signaling pathway regulates neuronal apoptosis through the phosphorylation of the retinoblastoma protein [J]. Neurochem Int,2009,54:99-105.
[85]Liu AL, Wang XW, Liu AH, Su XW, Jiang WJ, et al. JNK and p38 were involved in hypoxia and reoxygenation-induced apoptosis of cultured rat cerebellar granule neurons [J]. Exp Toxicol Pathol,2009.61:137-143.
[86]Wang Y. Sun L, Xia C. Ye L. Wang B. P38MAPK regulates caspase-3 by binding to caspase-3 in nucleus of human hepatoma Bel-7402 cells during anti-Fas antibody-and actinomycin D-induced apoptosis [J]. Biomed Pharmacother,2009.63:343-350.
[87]Khosravi-Far R, Esposti MD. Death receptor signals to mitochondria [J]. Cancer Biol Ther,2004,3:1051-1057.
[88]Ashkenazi A. Targeting death and decoy receptors of the tumour-necrosis factor superfamily [J]. Nat Rev Cancer,2002,2:420-430.
[89]Viktorsson K, Lewensohn R, Zhivotovsky B. Apoptotic pathways and therapy resistance in human malignancies [J]. Adv Cancer Res,2005,94: 143-196.
[90]Arch RH, Gedrich RW, Thompson CB. Tumor necrosis factor receptor-associated factors (TRAFs)--a family of adapter proteins that regulates life and death [J]. Genes Dev,1998,12:2821-2830.
[91]Kharbanda S, Saxena S, Yoshida K, Pandey P, Kaneki M, et al. Translocation of SAPK/JNK to mitochondria and interaction with Bcl-x(L) in response to DNA damage [J]. J Biol Chem.2000.275:322-327.
[92]Debatin KM, Krammer PH. Death receptors in chemotherapy and cancer [J]. Oncogene.2004,23:2950-2966.
[93]Shang Y. Molecular mechanisms of oestrogen and SERMs in endometrial carcinogenesis [J]. Nat Rev Cancer.2006.6:360-368.
[94]Chaudhry P. Asselin E. Resistance to chemotherapy and hormone therapy in endometrial cancer [J]. Endocr Relat Cancer.2009.16:363-380.
[95]Henderson BE, Feigelson HS. Hormonal carcinogenesis [J]. Carcinogenesis, 2000.21:427-433.
[96]Muramatsu M. Inoue S. Estrogen receptors:how do they control reproductive and nonreproductive functions [J]? Biochem Biophys Res Commun.2000, 270:1-10.
[97]Acconcia F. Ascenzi P, Bocedi A. Spisni E. Tomasi V. et al. Palmitoylation-dependent estrogen receptor alpha membrane localization: regulation by 17beta-estradiol [J]. Mol Biol Cell,2005,16:231-237.
[98]Newton AC. Regulation of protein kinase C [J]. Curr Opin Cell Biol,1997,9: 161-167.
[99]Nishizuka Y. Studies and perspectives of protein kinase C [J]. Science,1986, 233:305-312.
[100]Nishizuka Y. The molecular heterogeneity of protein kinase C and its implications for cellular regulation [J]. Nature,1988,334:661-665.
[101]Nishizuka Y. Protein kinase C and lipid signaling for sustained cellular responses [J]. FASEB J,1995,9:484-496.
[102]Way KJ, Chou E, King GL. Identification of PKC-isoform-specific biological actions using pharmacological approaches [J]. Trends Pharmacol Sci,2000, 21:181-187.
[103]Boyan BD, Sylvia VL, Frambach T, Lohmann CH, Dietl J, et al. Estrogen-dependent rapid activation of protein kinase C in estrogen receptor-positive MCF-7 breast cancer cells and estrogen receptor-negative HCC38 cells is membrane-mediated and inhibited by tamoxifen [J]. Endocrinology,2003, 144:3812-1824.
[104]Wang Z, Zhang X, Shen P, Loggie BW, Chang Y, et al. A variant of estrogen receptor-{alpha}, hER-{alpha} 36:transduction of estrogen-and antiestrogen-dependent membrane-initiated mitogenic signaling [J]. Proc Natl Acad Sci USA,2006,103:9063-9068.
[105]Marino M, Galluzzo P, Ascenzi P. Estrogen signaling multiple pathways to impact gene transcription [J]. Curr Genomics,2006,7:497-508.
[106]Zou Y, Ding L, Coleman M, Wang Z. Estrogen receptor-alpha (ER-alpha) suppresses expression of its variant ER-alpha 36 [J]. FEBS Lett,2009,583: 1368-1374.
[107]Hsieh YC, Yu HP, Frink M, Suzuki T? Choudhry MA. et al. G protein-coupled receptor 30-dependent protein kinase A pathway is critical in nongenomic effects of estrogen in attenuating liver injury after trauma- hemorrhage [J]. Am J Pathol,2007,170:1210-1218.
[108]Muchekehu RW, Harvey BJ.17beta-estradiol rapidly mobilizes intracellular calcium from ryanodine-receptor-gated stores via a PKC-PKA-Erk-dependent pathway in the human eccrine sweat gland cell line NCL-SG3 [J]. Cell Calcium,2008,44:276-288.
[109]Guo RX, Wei LH, Tu Z, Sun PM, Wang JL, et al.17 beta-estradiol activates PI3K/Akt signaling pathway by estrogen receptor (ER)-dependent and ER-independent mechanisms in endometrial cancer cells [J].J Steroid Biochem Mol Biol,2006,99:9-18.
[110]Collins P,Webb C.Estrogen hits the surface [J].Nat Med,1999,5: 1130-1131.
[111]Watson CS, Campbell CH, Gametchu B. Membrane oestrogen receptors on rat pituitary tumour cells:immuno-identification and responses to oestradiol and xenoestrogens [J]. Exp Physiol,1999,84:1013-1022.
[112]Zhang L, Li X, Zhao L, Zhang G, Wang J, et al. Nongenomic effect of estrogen on the MAPK signaling pathway and calcium influx in endometrial carcinoma cells[J].J Cell Biochem,2009,106:553-562.
[113]Deucher A, Efimova T, Eckert RL.Calcium-dependent involucrin expression is inversely regulated by protein kinase C (PKC)alpha and PKCdelta [J].J Biol Chem,2002,277:17032-17040.
[114]Reyland ME.Protein kinase Cdelta and apoptosis [J].Biochem Soc Trans, 2007,35:1001-1004.
[115]Brodie C,Blumberg PM.Regulation of cell apoptosis by protein kinase c delta [J].Apoptosis,2003,8:19-27.
[116]Liu JF, Crepin M, Liu JM, Barritault D,Ledoux D.FGF-2 and TPA induce matrix metalloproteinase-9 secretion in MCF-7 cells through PKC activation of the Ras/ERK pathway [J].Biochem Biophys Res Commun,2002,293: 1174-1182.
[117]Li W, Jiang YX,Zhang J.Soon L,Flechner L,et al.Protein kinase C-delta is an important signaling molecule in insulin-like growth factor I receptor-mediated cell transformation [J]. Mol Cell Biol,1998,18:5888-5898.
[118]Grossoni VC, Falbo KB, Kazanietz MG, de Kier Joffe ED, Urtreger AJ. Protein kinase C delta enhances proliferation and survival of murine mammary cells [J]. Mol Carcinog,2007,46:381-390.
[119]Sinha R, Kiley SC, Lu JX, Thompson HJ, Moraes R, et al. Effects of methylselenocysteine on PKC activity, cdk2 phosphorylation and gadd gene expression in synchronized mouse mammary epithelial tumor cells [J]. Cancer Lett,1999,146:135-145.
[120]Nakagawa S, Fujii T, Yokoyama G, Kazanietz MG, Yamana H, et al. Cell growth inhibition by all-trans retinoic acid in SKBR-3 breast cancer cells: involvement of protein kinase Calpha and extracellular signal-regulated kinase mitogen-activated protein kinase [J]. Mol Carcinog,2003,38: 106-116.
[121]Koivunen J, Aaltonen V, Peltonen J. Protein kinase C (PKC) family in cancer progression [J]. Cancer Lett,2006,235:1-10.
[122]Kolch W, Heidecker G, Kochs G, Hummel R, Vahidi H, et al. Protein kinase C alpha activates RAF-1 by direct phosphorylation [J]. Nature,1993,364: 249-252.
[123]Jiang XH, Tu SP, Cui JT, Lin MC, Xia HFL et al. Antisense targeting protein kinase C alpha and betal inhibits gastric carcinogenesis [J]. Cancer Res, 2004,64:5787-5794.
[124]Leirdal M, Sioud M. Ribozyme inhibition of the protein kinase C alpha triggers apoptosis in glioma cells [J]. Br J Cancer,1999,80:1558-1564.
[125]Singleton DW, Feng Y, Burd CJ, Khan SA. Nongenomic activity and subsequent c-fos induction by estrogen receptor ligands are not sufficient to promote deoxyribonucleic acid synthesis in human endometrial adenocarcinoma cells [J]. Endocrinology,2003,144:121-128.
[126]Zhang Z, Maier B, Santen RJ, Song RX. Membrane association of estrogen receptor alpha mediates estrogen effect on MAPK activation [J].Biochem Biophys Res Commun,2002,294:926-933.
[127]Ueda Y, Hirai S, Osada S, Suzuki A, Mizuno K, et al. Protein kinase C activates the MEK-ERK pathway in a manner independent of Ras and dependent on Raf [J]. J Biol Chem,1996.271:23512-23519.
[128]Qiu ZH, Leslie CC. Protein kinase C-dependent and-independent pathways of mitogen-activated protein kinase activation in macrophages by stimuli that activate phospholipase A2 [J]. J Biol Chem,1994.269:19480-19487.
[129]Quelle DE. Ashmun RA, Shurtleff SA. Kato JY, Bar-Sagi D, et al. Overexpression of mouse D-type cyclins accelerates Gl phase in rodent fibroblasts [J]. Genes Dev,1993.7:1559-1571.
[130]Knudsen KE. Arden KC, Cavenee WK. Multiple Gl regulatory elements control the androgen-dependent proliferation of prostatic carcinoma cells [J]. J Biol Chem.1998.273:20213-20222.
[131]Cao QJ. Einstein MH. Anderson PS, Runowicz CD. Balan R. et al. Expression of COX-2. Ki-67. cyclin Dl. and P21 in endometrial endometrioid carcinomas [J]. Int J Gynecol Pathol.2002.21:147-154.
[132]. Schmitt JM. Abell E. Wagner A. Davare MA ERK activation and cell growth require CaM kinases in MCF-7 breast cancer cells [J]. Mol Cell Biochem 335: 155-171.
[133]Shiozawa T. Miyamoto T, Kashima H, Nakayama K, Nikaido T. et al. Estrogen-induced proliferation of normal endometrial glandular cells is initiated by transcriptional activation of cyclin Dl via binding of c-Jun to an AP-1 sequence [J]. Oncogene.2004,23:8603-8610.
[134]Jemal A, Siegel R, Ward E, Hao Y, Xu J, et al. Cancer statistics [J]. CA Cancer J Clin.2009.59:225-249.
[135]Sorosky JI. Endometrial cancer [J]. Obstet Gynecol.2008,111:436-447.
[136]Navaratnarajah R. Pillay OC, Hardiman P. Polycystic ovary syndrome and endometrial cancer [J]. Semin Reprod Med.2008.26:62-71.
[137]Yang JZ, O'Flatharta C, Harvey BJ, Thomas W. Membrane ERalpha-dependent activation of PKCalpha in endometrial cancer cells by estradiol [J]. Steroids,2008,73:1110-1122.
[138]He J, Wang Y, Duan F, Jiang H, Chen MF, et al. Icaritin induces apoptosis of HepG2 cells via the JNK1 signaling pathway independent of the estrogen receptor [J]. Planta Med 76:1834-1839.
[139]Zhu DY, Lou YJ. Inducible effects of icariin, Icaritin, and desmethyllcaritin on directional differentiation of embryonic stem cells into cardiomyocytes in vitro [J]. Acta Pharmacol Sin,2005,26:477-485.
[140]Zhu D, Qu L, Zhang X, Lou Y. Icariin-mediated modulation of cell cycle and p53 during cardiomyocyte differentiation in embryonic stem cells [J]. Eur J Pharmacol,2005,514:99-110.
[141]Wang Z, Zhang X, Wang H, Qi L, Lou Y. Neuroprotective effects of Icaritin against beta amyloid-induced neurotoxicity in primary cultured rat neuronal cells via estrogen-dependent pathway [J]. Neuroscience,2007,145:911-922.
[142]Huang J, Yuan L, Wang X, Zhang TL, Wang K. Icaritin and its glycosides enhance osteoblastic, but suppress osteoclastic, differentiation and activity in vitro [J]. Life Sci,2007,81:832-840.
[143]Huang X, Zhu D, Lou Y. A novel anticancer agent, Icaritin, induced cell growth inhibition, Gl arrest and mitochondrial transmembrane potential drop in human prostate carcinoma PC-3 cells [J]. Eur J Pharmacol,2007,564: 26-36.
[144]Wang ZQ, Lou YJ. Proliferation-stimulating effects of Icaritin and desmethyllcaritin in MCF-7 cells [J]. Eur J Pharmacol,2004,504:147-153.
[145]Wang ZQ, Weber N, Lou YJ, Proksch P. Prenylflavonoids as nonsteroidal phytoestrogens and related structure-activity relationships [J]. Chem Med Chem.2006,1:482-488.
[146]Pearson G Robinson F, Beers Gibson T, Xu BE. Karandikar M, et al. Mitogen-activated protein (MAP) kinase pathways:regulation and physiological functions [J].Endocr Rev,2001,22:153-183.
[147]Tournier C, Hess P, Yang DD, Xu J, Turner TK, et al. Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway [J]. Science,2000,288:870-874.
[148]Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME. Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis [J]. Science,1995,270: 1326-1331.
[149]Kim BW, Lee ER. Min HM, Jeong HS, Ahn JY, et al. Sustained ERK activation is involved in the kaempferol-induced apoptosis of breast cancer cells and is more evident under 3-D culture condition [J]. Cancer Biol Ther, 2008,7:1080-1089.
[150]Green DR, Reed JC. Mitochondria and apoptosis [J]. Science,1998,281: 1309-1312.
[151]Rao L, White E. Bcl-2 and the ICE family of apoptotic regulators:making a connection [J]. Curr Opin Genet Dev,1997,7:52-58.
[152]Kluck RM, Bossy-Wetzel E. Green DR. Newmeyer DD. The release of cytochrome c from mitochondria:a primary site for Bcl-2 regulation of apoptosis [J]. Science,1997.275:1132-1136.
[153]Marshall CJ. Specificity of receptor tyrosine kinase signaling:transient versus sustained extracellular signal-regulated kinase activation [J]. Cell, 1995.80:179-185.
[154]Ramos JW. The regulation of extracellular signal-regulated kinase (ERK) in mammalian cells [J]. Int J Biochem Cell Biol,2008,40:2707-2719.
[155]Stanciu M, Wang Y, Kentor R. Burke N, Watkins S, et al. Persistent activation of ERK contributes to glutamate-induced oxidative toxicity in a neuronal cell line and primary cortical neuron cultures [J]. J Biol Chem.2000. 275:12200-12206.
[156]Yu C, Rahmani M, Almenara J. Sausville EA. Dent P, et al. Induction of apoptosis in human leukemia cells by the tyrosine kinase inhibitor adaphostin proceeds through a RAF-1/MEK/ERK-and AKT-dependent process [J]. Oncogene,2004,23:1364-1376.
[157]Wang Z, Wang H, Wu J, Zhu D, Zhang X, et al. Enhanced co-expression of beta-tubulin III and choline acetyltransferase in neurons from mouse embryonic stem cells promoted by Icaritin in an estrogen receptor-independent manner [J]. Chem Biol Interact,2009,179:375-385.
[158]Chen MF, Qi L, Li Y, Zu XB, Dai YQ, et al. Icaritin induces growth inhibition and apoptosis of human prostatic smooth muscle cells in an estrogen receptor-independent manner [J].Amino Acids 2007,38:1505-1513.
[2]Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, et al. Molecular basis of agonism and antagonism in the oestrogen receptor [J]. Nature,1997, 389:753-758.
[3]Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA Cloning of a novel receptor expressed in rat prostate and ovary [J]. Proc Natl Acad Sci U S A,1996,93:5925-5930.
[4]Heldring N, Pike A, Andersson S, Matthews J, Cheng G, et al. Estrogen receptors:how do they signal and what are their targets [J]. Physiol Rev, 2007.87:905-931.
[5]. Lorenzo J. A new hypothesis for how sex steroid hormones regulate bone mass [J].JClin Invest.2003,111:1641-1643.
[6]Baulieu EE, Binart N, Cadepond F, Catelli MG Chambraud B, et al. Receptor-associated nuclear proteins and steroid/antisteroid action. Ann N Y Acad Sci,1990,595:300-315.
[7]Gasc JM, Baulieu EE. Steroid hormone receptors:intracellular distribution [J].BiolCell,1986,56:1-6.
[8]Kumar V, Chambon P. The estrogen receptor binds tightly to its responsive element as a ligand-induced homodimer [J]. Cell,1988,55:145-156.
[9]McKenna NJ, O'Malley BW. Nuclear receptors, coregulators, ligands, and selective receptor modulators:making sense of the patchwork quilt [J]. Ann NY Acad Sci.2001,949:3-5.
[10]Leers J. Treuter E, Gustafsson JA. Mechanistic principles in NR box- dependent interaction between nuclear hormone receptors and the coactivator TIF2 [J]. Mol Cell Biol,1998,18:6001-6013.
[11]Hall JM, McDonnell DP, Korach KS. Allosteric regulation of estrogen receptor structure, function, and coactivator recruitment by different estrogen response elements [J]. Mol Endocrinol,2002,16:469-486.
[12]Kim MY, Hsiao SJ. Kraus WL. A role for coactivators and histone acetylation in estrogen receptor alpha-mediated transcription initiation [J]. EMBO J, 2001.20:6084-6094.
[13]Jepsen K, Rosenfeld MG. Biological roles and mechanistic actions of co-repressor complexes [J]. J Cell Sci.2002,115:689-698.
[14]Gaub MP, Bellard M. Scheuer I, Chambon P, Sassone-Corsi P. Activation of the ovalbumin gene by the estrogen receptor involves the fos-jun complex [J]. Cell.1990,63:1267-1276.
[15]Umayahara Y, Kawamori R, Watada H, Imano E, Iwama N, et al. Estrogen regulation of the insulin-like growth factor I gene transcription involves an AP-1 enhancer [J]. J Biol Chem.1994,269:16433-16442.
[16]Schmitt M. Bausero P, Simoni P, Queuche D, Geoffroy V. et al. Positive and negative effects of nuclear receptors on transcription activation by AP-1 of the human choline acetyltransferase proximal promoter [J]. J Neurosci Res. 1995,40:152-164.
[17]Webb P. Nguyen P, Valentine C, Lopez GN. Kwok GR. et al. The estrogen receptor enhances AP-1 activity by two distinct mechanisms with different requirements for receptor transactivation functions [J]. Mol Endocrinol,1999, 13:1672-1685.
[18]Teyssier C, Belguise K, Galtier F, Chalbos D. Characterization of the physical interaction between estrogen receptor alpha and JUN proteins [J]. J Biol Chem.2001.276:36361-36369.
[19]Li C. Briggs MR. Ahlborn TE, Kraemer FB, Liu J. Requirement of Spl and estrogen receptor alpha interaction in 17beta-estradiol-mediated transcriptional activation of the low density lipoprotein receptor gene expression [J]. Endocrinology,2001,142:1546-1553.
[20]Duan R, Porter W, Safe S. Estrogen-induced c-fos protooncogene expression in MCF-7 human breast cancer cells:role of estrogen receptor Spl complex formation [J]. Endocrinology,1998,139:1981-1990.
[21]Castro-Rivera E, Samudio I, Safe S. Estrogen regulation of cyclin Dl gene expression in ZR-75 breast cancer cells involves multiple enhancer elements [J]. J Biol Chem,2001,276:30853-30861.
[22]. Bjornstrom L, Sjoberg M. Mutations in the estrogen receptor DNA-binding domain discriminate between the classical mechanism of action and cross-talk with Stat5b and activating protein 1 (AP-1) [J]. J Biol Chem,2002, 277:48479-48483.
[23]Levin ER. Membrane oestrogen receptor alpha signalling to cell functions [J]. J Physiol,2009,587:5019-5023.
[24]Bjornstrom L, Sjoberg M. Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes [J]. Mol Endocrinol,2005,19:833-842.
[25]Nadal A, Ropero AB, Fuentes E, Soria B. The plasma membrane estrogen receptor:nuclear or unclear [J]? Trends Pharmacol Sci,2001,22:597-599.
[26]Rader JI, Howard GA, Feist E, Turner RT, Baylink DJ. Bone mineralization and metabolism of 3H-25-hydroxyvitamin D3 in thyroparathyroidectomized rats treated with parathyroid extract [J]. Calcif Tissue Int,1979,29:21-26.
[27]Sak K, Everaus H.Nongenomic effects of 17beta-estradiol--iversity of membrane binding sites [J].J Steroid Biochem Mol Biol,2004,88:323-335.
[28]Migliaccio A, Di Domenico M, Castoria G, de Falco A, Bontempo P, et al. Tyrosine kinase/p21ras/MAP-kinase pathway activation by estradiol-receptor complex in MCF-7 cells [J]. EMBO J,1996,15:1292-1300.
[29]Kelly MJ, Levin ER. Rapid actions of plasma membrane estrogen receptors [J]. Trends Endocrinol Metab.2001.12:152-156.
[30]Levin ER. Integration of the extranuclear and nuclear actions of estrogen [J]. Mol Endocrinol,2005,19:1951-1959.
[31]Pietras RJ, Szego CM. Specific binding sites for oestrogen at the outer surfaces of isolated endometrial cells [J]. Nature,1977,265:69-72.
[32]Pappas TC, Gametchu B, Watson CS. Membrane estrogen receptors identified by multiple antibody labeling and impeded-ligand binding [J]. FASEBJ,1995.9:404-410.
[33]Fimiani M, Rubegni P, de Aloe G, Bilenchi R, Andreassi L. Squamous cell carcinoma of the leg in a patient with prolidase deficiency [J]. Br J Dermatol, 1999,140:362-363.
[34]Smart EJ, Graf GA. McNiven MA. Sessa WC, Engelman JA, et al. Caveolins, liquid-ordered domains, and signal transduction [J]. Mol Cell Biol,1999,19: 7289-7304.
[35]Zhang YW, Morita I. Zhang L, Shao G, Yao XS, et al. Screening of anti-hypoxia/reoxygenation agents by an in vitro method [J]. Part 2: Inhibition of tyrosine kinase activation prevented hypoxia/reoxygenation-induced injury in endothelial gap junctional intercellular communication [J]. Planta Med,2000.66:119-123.
[36]Zhao X, Liu Y. Ma Q, Wang X. Jin H, et al. Caveolin-1 negatively regulates TRAIL-induced apoptosis in human hepatocarcinoma cells [J]. Biochem Biophys Res Commun,2009.378:21-26.
[37]Dong C, Filipeanu CM, Duvernay MT, Wu G. Regulation of G protein-coupled receptor export trafficking [J]. Biochim Biophys Acta,2007, 1768:853-870.
[38]Wright LP, Philips MR. Thematic review series:lipid posttranslational modifications. CAAX modification and membrane targeting of Ras [J]. J Lipid Res.2006.47:883-891.
[39]Song RX. Zhang Z. Santen RJ. Estrogen rapid action via protein complex formation involving ERalpha and Src [J]. Trends Endocrinol Metab.2005.16: 347-353.
[40]Lin SL, Yan LY, Zhang XT, Yuan J, Li M, et al. ER-alpha36, a variant of ER-alpha, promotes tamoxifen agonist action in endometrial cancer cells via the MAPK/ERK and PI3K/Akt pathways [J]. PLoS One 5:e9013.
[41]Lin SL, Yan LY, Liang XW, Wang ZB, Wang ZY, et al. A novel variant of ER-alpha, ER-alpha36 mediates testosterone-stimulated ERK and Akt activation in endometrial cancer Hecl A cells [J]. Reprod Biol Endocrinol, 2009,7:102.
[42]Tong JS, Zhang QH, Wang ZB, Li S, Yang CR, et al. ER-alpha36, a Novel Variant of ER-alpha, Mediates Estrogen-Stimulated Proliferation of Endometrial Carcinoma Cells via the PKCdelta/ERK Pathway [J]. PLoS One 5:e15408.
[43]Santen RJ, Song RX, McPherson R, Kumar R, Adam L, et al. The role of mitogen-activated protein (MAP) kinase in breast cancer [J]. J Steroid Biochem Mol Biol,2002,80:239-256.
[44]Razandi M, Pedram A, Levin ER. Plasma membrane estrogen receptors signal to antiapoptosis in breast cancer [J]. Mol Endocrinol,2000,14: 1434-1447.
[45]Barletta F, Wong CW, McNally C, Komm BS, Katzenellenbogen B, et al. Characterization of the interactions of estrogen receptor and MNAR in the activation of cSrc [J]. Mol Endocrinol,2004,18:1096-1108.
[46]Tremblay GB, Tremblay A, Labrie F, Giguere V. Dominant activity of activation function 1 (AF-1) and differential stoichiometric requirements for AF-1 and-2 in the estrogen receptor alpha-beta heterodimeric complex [J]. Mol Cell Biol,1999,19:1919-1927.
[47]Franke TF. PI3K/Akt:getting it right matters [J]. Oncogene,2008,27: 6473-6488.
[48]. Martiny-Baron G, Fabbro D. Classical PKC isoforms in cancer [J]. Pharmacol Res,2007,55:477-486.
[49]Ricciardolo FL. Multiple roles of nitric oxide in the airways [J]. Thorax, 2003,58:175-182.
[50]Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor [J]. Nature,1987, 327:524-526.
[51]Lenninger S. Should we ignore any skin changes without taking measures [J] Lakartidningen,1992,89:4125-4126.
[52]Guo X, Razandi M, Pedram A, Kassab G, Levin ER. Estrogen induces vascular wall dilation:mediation through kinase signaling to nitric oxide and estrogen receptors alpha and beta [J]. J Biol Chem,2005,280:19704-19710.
[53]Raicu M, Florea S, Costache G,Popov D, Simionescu M. Clotrimazole inhibits smooth muscle cell proliferation and has a vasodilator effect on resistance arteries [J]. Fundam Clin Pharmacol,2000,14:477-485.
[54]Zhang YH, Hancox JC. Regulation of cardiac Na+-Ca2+exchanger activity by protein kinase phosphorylation--still a paradox [J]?Cell Calcium.2009, 45:1-10.
[55]Nagamune K. Moreno SN. Chini EN. Sibley LD. Calcium regulation and signaling in apicomplexan parasites [J]. Subcell Biochem,2008,47:70-81.
[56]Bouhoute A, Leclercq G. Estradiol derivatives bearing the side-chain of tamoxifen antagonize the association between the estrogen receptor and calmodulin[J].Biochem Pharmacol,1994,47:748-751.
[57]Benten WP, Stephan C, Lieberherr M, Wunderlich F. Estradiol signaling via sequestrable surface receptors [J].Endocrinology,2001,142:1669-1677.
[58]Lieberherr M. Grosse B, Kachkache M, Balsan S. Cell signaling and estrogens in female rat osteoblasts:a possible involvement of unconventional nonnuclear receptors [J].J Bone Miner Res,1993,8:1365-1376.
[59]Kerr JF. Wyllie AH, Currie AR. Apoptosis:a basic biological phenomenon with wide-ranging implications in tissue kinetics [J].Br J Cancer.1972,26: 239-257.
[60]Elmore S. Apoptosis:a review of programmed cell death [J]. Toxicol Pathol, 2007,35:495-516.
[61]Hacker G. The morphology of apoptosis [J]. Cell Tissue Res,2000,301: 5-17.
[62]Abdel Aziz A. Apoptosis and histopathological lesions in parasite-infected species of bivalve molluscs [J]. J Egypt Soc Parasitol,2009,39:811-820.
[63]Jiao XT, Liu XQ, Huang LS, Zhang YJ, Han LS. Role of caspase-3,-8, and-9 in apoptosis of copper induced primary cortical neurons [J]. Zhongguo Dang Dai Er Ke Za Zhi,2009,11:917-922.
[64]Zhivotovsky B, Samali A, Gahm A, Orrenius S. Caspases:their intracellular localization and translocation during apoptosis [J]. Cell Death Differ,1999,6: 644-651.
[65]Levrero M, De Laurenzi V, Costanzo A, Gong J, Melino G, et al. Structure, function and regulation of p63 and p73 [J]. Cell Death Differ,1999,6: 1146-1153.
[66]Nakagawa T, Zhu H, Morishima N, Li E, Xu J, et al. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta [J]. Nature,2000,403:98-103.
[67]Karmakar S, Davis KA, Choudhury SR, Deeconda A, Banik NL, et al. Bcl-2 inhibitor and apigenin worked synergistically in human malignant neuroblastoma cell lines and increased apoptosis with activation of extrinsic and intrinsic pathways [J]. Biochem Biophys Res Commun,2009,388: 705-710.
[68]Antonsson B, Montessuit S, Lauper S, Eskes R, Martinou JC.Bax oligomerization is required for channel-forming activity in liposomes and to trigger cytochrome c release from mitochondria [J].Biochem J,2000,345 Pt 2:271-278.
[69]Dijkers PF, Medema RH, Lammers JW, Koenderman L,Coffer PJ. Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1 [J]. Curr Biol,2000,10:1201-1204.
[70]Buchholz TA, Davis DW, McConkey DJ, Symmans WF, Valero V, et al. Chemotherapy-induced apoptosis and Bcl-2 levels correlate with breast cancer response to chemotherapy [J]. Cancer J,2003,9:33-41.
[71]Hacki J, Egger L, Monney L, Conus S, Rosse T, et al. Apoptotic crosstalk between the endoplasmic reticulum and mitochondria controlled by Bcl-2 [J]. Oncogene,2000,19:2286-2295.
[72]Lee YK, Park S Y Kim YM, Park OJ. Regulatory effect of the AMPK-COX-2 signaling pathway in curcumin-induced apoptosis in HT-29 colon cancer cells [J]. AnnN YAcad Sci,2009.1171:489-494.
[73]Zhou JH, Yu DV, Cheng J. Shapiro DJ. Delayed and persistent ERK1/2 activation is required for 4-hydroxytamoxifen-induced cell death [J]. Steroids, 2007,72:765-777.
[74]Zheng A, Kallio A, Harkonen P. Tamoxifen-induced rapid death of MCF-7 breast cancer cells is mediated via extracellularly signal-regulated kinase signaling and can be abrogated by estrogen [J]. Endocrinology.2007,148: 2764-2777.
[75]Fernando RI. Wimalasena J. Estradiol abrogates apoptosis in breast cancer cells through inactivation of BAD:Ras-dependent nongenomic pathways requiring signaling through ERK and Akt [J]. Mol Biol Cell,2004,15: 3266-3284.
[76]Li DW, Liu JP, Mao YW, Xiang H. Wang J, et al. Calcium-activated RAF/MEK/ERK signaling pathway mediates p53-dependent apoptosis and is abrogated by alpha B-crystallin through inhibition of RAS activation [J]. Mol Biol Cell,2005,16:4437-4453.
[77]Xue Q. Chen J, Gong S, Xie J. He J. et al. Study of the effect of JNK signal transduction pathway in intense noise-induced apoptosis in cochlea of guinea pig [J]. Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi.2009.23: 1138-1142.
[78]Chathoth S, Thayyullathil F, Hago A, Shahin A, Patel M, et al. UVC-induced apoptosis in Dubca cells is independent of JNK activation and p53(Ser-15) phosphorylation [J]. Biochem Biophys Res Commun,2009,383:426-432.
[79]Chen YR, Wang X, Templeton D, Davis RJ, Tan TH. The role of c-Jun N-terminal kinase (JNK) in apoptosis induced by ultraviolet C and gamma radiation. Duration of JNK activation may determine cell death and proliferation [J]. J Biol Chem,1996,271:31929-31936.
[80]Teraishi F, Wu S, Zhang L, Guo W, Davis JJ, et al. Identification of a novel synthetic thiazolidin compound capable of inducing c-Jun NH2-terminal kinase-dependent apoptosis in human colon cancer cells [J]. Cancer Res, 2005,65:6380-6387.
[81]Lorin S, Borges A, Ribeiro Dos Santos L, Souquere S, Pierron G, et al. c-Jun NH2-terminal kinase activation is essential for DRAM-dependent induction of autophagy and apoptosis in 2-methoxyestradiol-treated Ewing sarcoma cells [J]. Cancer Res,2009,69:6924-6931.
[82]Wang JH, Yu B, Niu HY, Li H, Zhang Y, et al. C-jun N-terminal kinase-mediated signaling is essential for Staphylococcus aureus-induced U937 apoptosis [J]. Chin Med Sci J,2009,24:26-29.
[83]Huang HM, Liu JC. c-Jun blocks cell differentiation but not growth inhibition or apoptosis of chronic myelogenous leukemia cells induced by STI571 and by histone deacetylase inhibitors [J]. J Cell Physiol,2009,218: 568-574.
[84]Yeste-Velasco M, Folch J, Pallas M, Camins A. The p38(MAPK) signaling pathway regulates neuronal apoptosis through the phosphorylation of the retinoblastoma protein [J]. Neurochem Int,2009,54:99-105.
[85]Liu AL, Wang XW, Liu AH, Su XW, Jiang WJ, et al. JNK and p38 were involved in hypoxia and reoxygenation-induced apoptosis of cultured rat cerebellar granule neurons [J]. Exp Toxicol Pathol,2009.61:137-143.
[86]Wang Y. Sun L, Xia C. Ye L. Wang B. P38MAPK regulates caspase-3 by binding to caspase-3 in nucleus of human hepatoma Bel-7402 cells during anti-Fas antibody-and actinomycin D-induced apoptosis [J]. Biomed Pharmacother,2009.63:343-350.
[87]Khosravi-Far R, Esposti MD. Death receptor signals to mitochondria [J]. Cancer Biol Ther,2004,3:1051-1057.
[88]Ashkenazi A. Targeting death and decoy receptors of the tumour-necrosis factor superfamily [J]. Nat Rev Cancer,2002,2:420-430.
[89]Viktorsson K, Lewensohn R, Zhivotovsky B. Apoptotic pathways and therapy resistance in human malignancies [J]. Adv Cancer Res,2005,94: 143-196.
[90]Arch RH, Gedrich RW, Thompson CB. Tumor necrosis factor receptor-associated factors (TRAFs)--a family of adapter proteins that regulates life and death [J]. Genes Dev,1998,12:2821-2830.
[91]Kharbanda S, Saxena S, Yoshida K, Pandey P, Kaneki M, et al. Translocation of SAPK/JNK to mitochondria and interaction with Bcl-x(L) in response to DNA damage [J]. J Biol Chem.2000.275:322-327.
[92]Debatin KM, Krammer PH. Death receptors in chemotherapy and cancer [J]. Oncogene.2004,23:2950-2966.
[93]Shang Y. Molecular mechanisms of oestrogen and SERMs in endometrial carcinogenesis [J]. Nat Rev Cancer.2006.6:360-368.
[94]Chaudhry P. Asselin E. Resistance to chemotherapy and hormone therapy in endometrial cancer [J]. Endocr Relat Cancer.2009.16:363-380.
[95]Henderson BE, Feigelson HS. Hormonal carcinogenesis [J]. Carcinogenesis, 2000.21:427-433.
[96]Muramatsu M. Inoue S. Estrogen receptors:how do they control reproductive and nonreproductive functions [J]? Biochem Biophys Res Commun.2000, 270:1-10.
[97]Acconcia F. Ascenzi P, Bocedi A. Spisni E. Tomasi V. et al. Palmitoylation-dependent estrogen receptor alpha membrane localization: regulation by 17beta-estradiol [J]. Mol Biol Cell,2005,16:231-237.
[98]Newton AC. Regulation of protein kinase C [J]. Curr Opin Cell Biol,1997,9: 161-167.
[99]Nishizuka Y. Studies and perspectives of protein kinase C [J]. Science,1986, 233:305-312.
[100]Nishizuka Y. The molecular heterogeneity of protein kinase C and its implications for cellular regulation [J]. Nature,1988,334:661-665.
[101]Nishizuka Y. Protein kinase C and lipid signaling for sustained cellular responses [J]. FASEB J,1995,9:484-496.
[102]Way KJ, Chou E, King GL. Identification of PKC-isoform-specific biological actions using pharmacological approaches [J]. Trends Pharmacol Sci,2000, 21:181-187.
[103]Boyan BD, Sylvia VL, Frambach T, Lohmann CH, Dietl J, et al. Estrogen-dependent rapid activation of protein kinase C in estrogen receptor-positive MCF-7 breast cancer cells and estrogen receptor-negative HCC38 cells is membrane-mediated and inhibited by tamoxifen [J]. Endocrinology,2003, 144:3812-1824.
[104]Wang Z, Zhang X, Shen P, Loggie BW, Chang Y, et al. A variant of estrogen receptor-{alpha}, hER-{alpha} 36:transduction of estrogen-and antiestrogen-dependent membrane-initiated mitogenic signaling [J]. Proc Natl Acad Sci USA,2006,103:9063-9068.
[105]Marino M, Galluzzo P, Ascenzi P. Estrogen signaling multiple pathways to impact gene transcription [J]. Curr Genomics,2006,7:497-508.
[106]Zou Y, Ding L, Coleman M, Wang Z. Estrogen receptor-alpha (ER-alpha) suppresses expression of its variant ER-alpha 36 [J]. FEBS Lett,2009,583: 1368-1374.
[107]Hsieh YC, Yu HP, Frink M, Suzuki T? Choudhry MA. et al. G protein-coupled receptor 30-dependent protein kinase A pathway is critical in nongenomic effects of estrogen in attenuating liver injury after trauma- hemorrhage [J]. Am J Pathol,2007,170:1210-1218.
[108]Muchekehu RW, Harvey BJ.17beta-estradiol rapidly mobilizes intracellular calcium from ryanodine-receptor-gated stores via a PKC-PKA-Erk-dependent pathway in the human eccrine sweat gland cell line NCL-SG3 [J]. Cell Calcium,2008,44:276-288.
[109]Guo RX, Wei LH, Tu Z, Sun PM, Wang JL, et al.17 beta-estradiol activates PI3K/Akt signaling pathway by estrogen receptor (ER)-dependent and ER-independent mechanisms in endometrial cancer cells [J].J Steroid Biochem Mol Biol,2006,99:9-18.
[110]Collins P,Webb C.Estrogen hits the surface [J].Nat Med,1999,5: 1130-1131.
[111]Watson CS, Campbell CH, Gametchu B. Membrane oestrogen receptors on rat pituitary tumour cells:immuno-identification and responses to oestradiol and xenoestrogens [J]. Exp Physiol,1999,84:1013-1022.
[112]Zhang L, Li X, Zhao L, Zhang G, Wang J, et al. Nongenomic effect of estrogen on the MAPK signaling pathway and calcium influx in endometrial carcinoma cells[J].J Cell Biochem,2009,106:553-562.
[113]Deucher A, Efimova T, Eckert RL.Calcium-dependent involucrin expression is inversely regulated by protein kinase C (PKC)alpha and PKCdelta [J].J Biol Chem,2002,277:17032-17040.
[114]Reyland ME.Protein kinase Cdelta and apoptosis [J].Biochem Soc Trans, 2007,35:1001-1004.
[115]Brodie C,Blumberg PM.Regulation of cell apoptosis by protein kinase c delta [J].Apoptosis,2003,8:19-27.
[116]Liu JF, Crepin M, Liu JM, Barritault D,Ledoux D.FGF-2 and TPA induce matrix metalloproteinase-9 secretion in MCF-7 cells through PKC activation of the Ras/ERK pathway [J].Biochem Biophys Res Commun,2002,293: 1174-1182.
[117]Li W, Jiang YX,Zhang J.Soon L,Flechner L,et al.Protein kinase C-delta is an important signaling molecule in insulin-like growth factor I receptor-mediated cell transformation [J]. Mol Cell Biol,1998,18:5888-5898.
[118]Grossoni VC, Falbo KB, Kazanietz MG, de Kier Joffe ED, Urtreger AJ. Protein kinase C delta enhances proliferation and survival of murine mammary cells [J]. Mol Carcinog,2007,46:381-390.
[119]Sinha R, Kiley SC, Lu JX, Thompson HJ, Moraes R, et al. Effects of methylselenocysteine on PKC activity, cdk2 phosphorylation and gadd gene expression in synchronized mouse mammary epithelial tumor cells [J]. Cancer Lett,1999,146:135-145.
[120]Nakagawa S, Fujii T, Yokoyama G, Kazanietz MG, Yamana H, et al. Cell growth inhibition by all-trans retinoic acid in SKBR-3 breast cancer cells: involvement of protein kinase Calpha and extracellular signal-regulated kinase mitogen-activated protein kinase [J]. Mol Carcinog,2003,38: 106-116.
[121]Koivunen J, Aaltonen V, Peltonen J. Protein kinase C (PKC) family in cancer progression [J]. Cancer Lett,2006,235:1-10.
[122]Kolch W, Heidecker G, Kochs G, Hummel R, Vahidi H, et al. Protein kinase C alpha activates RAF-1 by direct phosphorylation [J]. Nature,1993,364: 249-252.
[123]Jiang XH, Tu SP, Cui JT, Lin MC, Xia HFL et al. Antisense targeting protein kinase C alpha and betal inhibits gastric carcinogenesis [J]. Cancer Res, 2004,64:5787-5794.
[124]Leirdal M, Sioud M. Ribozyme inhibition of the protein kinase C alpha triggers apoptosis in glioma cells [J]. Br J Cancer,1999,80:1558-1564.
[125]Singleton DW, Feng Y, Burd CJ, Khan SA. Nongenomic activity and subsequent c-fos induction by estrogen receptor ligands are not sufficient to promote deoxyribonucleic acid synthesis in human endometrial adenocarcinoma cells [J]. Endocrinology,2003,144:121-128.
[126]Zhang Z, Maier B, Santen RJ, Song RX. Membrane association of estrogen receptor alpha mediates estrogen effect on MAPK activation [J].Biochem Biophys Res Commun,2002,294:926-933.
[127]Ueda Y, Hirai S, Osada S, Suzuki A, Mizuno K, et al. Protein kinase C activates the MEK-ERK pathway in a manner independent of Ras and dependent on Raf [J]. J Biol Chem,1996.271:23512-23519.
[128]Qiu ZH, Leslie CC. Protein kinase C-dependent and-independent pathways of mitogen-activated protein kinase activation in macrophages by stimuli that activate phospholipase A2 [J]. J Biol Chem,1994.269:19480-19487.
[129]Quelle DE. Ashmun RA, Shurtleff SA. Kato JY, Bar-Sagi D, et al. Overexpression of mouse D-type cyclins accelerates Gl phase in rodent fibroblasts [J]. Genes Dev,1993.7:1559-1571.
[130]Knudsen KE. Arden KC, Cavenee WK. Multiple Gl regulatory elements control the androgen-dependent proliferation of prostatic carcinoma cells [J]. J Biol Chem.1998.273:20213-20222.
[131]Cao QJ. Einstein MH. Anderson PS, Runowicz CD. Balan R. et al. Expression of COX-2. Ki-67. cyclin Dl. and P21 in endometrial endometrioid carcinomas [J]. Int J Gynecol Pathol.2002.21:147-154.
[132]. Schmitt JM. Abell E. Wagner A. Davare MA ERK activation and cell growth require CaM kinases in MCF-7 breast cancer cells [J]. Mol Cell Biochem 335: 155-171.
[133]Shiozawa T. Miyamoto T, Kashima H, Nakayama K, Nikaido T. et al. Estrogen-induced proliferation of normal endometrial glandular cells is initiated by transcriptional activation of cyclin Dl via binding of c-Jun to an AP-1 sequence [J]. Oncogene.2004,23:8603-8610.
[134]Jemal A, Siegel R, Ward E, Hao Y, Xu J, et al. Cancer statistics [J]. CA Cancer J Clin.2009.59:225-249.
[135]Sorosky JI. Endometrial cancer [J]. Obstet Gynecol.2008,111:436-447.
[136]Navaratnarajah R. Pillay OC, Hardiman P. Polycystic ovary syndrome and endometrial cancer [J]. Semin Reprod Med.2008.26:62-71.
[137]Yang JZ, O'Flatharta C, Harvey BJ, Thomas W. Membrane ERalpha-dependent activation of PKCalpha in endometrial cancer cells by estradiol [J]. Steroids,2008,73:1110-1122.
[138]He J, Wang Y, Duan F, Jiang H, Chen MF, et al. Icaritin induces apoptosis of HepG2 cells via the JNK1 signaling pathway independent of the estrogen receptor [J]. Planta Med 76:1834-1839.
[139]Zhu DY, Lou YJ. Inducible effects of icariin, Icaritin, and desmethyllcaritin on directional differentiation of embryonic stem cells into cardiomyocytes in vitro [J]. Acta Pharmacol Sin,2005,26:477-485.
[140]Zhu D, Qu L, Zhang X, Lou Y. Icariin-mediated modulation of cell cycle and p53 during cardiomyocyte differentiation in embryonic stem cells [J]. Eur J Pharmacol,2005,514:99-110.
[141]Wang Z, Zhang X, Wang H, Qi L, Lou Y. Neuroprotective effects of Icaritin against beta amyloid-induced neurotoxicity in primary cultured rat neuronal cells via estrogen-dependent pathway [J]. Neuroscience,2007,145:911-922.
[142]Huang J, Yuan L, Wang X, Zhang TL, Wang K. Icaritin and its glycosides enhance osteoblastic, but suppress osteoclastic, differentiation and activity in vitro [J]. Life Sci,2007,81:832-840.
[143]Huang X, Zhu D, Lou Y. A novel anticancer agent, Icaritin, induced cell growth inhibition, Gl arrest and mitochondrial transmembrane potential drop in human prostate carcinoma PC-3 cells [J]. Eur J Pharmacol,2007,564: 26-36.
[144]Wang ZQ, Lou YJ. Proliferation-stimulating effects of Icaritin and desmethyllcaritin in MCF-7 cells [J]. Eur J Pharmacol,2004,504:147-153.
[145]Wang ZQ, Weber N, Lou YJ, Proksch P. Prenylflavonoids as nonsteroidal phytoestrogens and related structure-activity relationships [J]. Chem Med Chem.2006,1:482-488.
[146]Pearson G Robinson F, Beers Gibson T, Xu BE. Karandikar M, et al. Mitogen-activated protein (MAP) kinase pathways:regulation and physiological functions [J].Endocr Rev,2001,22:153-183.
[147]Tournier C, Hess P, Yang DD, Xu J, Turner TK, et al. Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway [J]. Science,2000,288:870-874.
[148]Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME. Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis [J]. Science,1995,270: 1326-1331.
[149]Kim BW, Lee ER. Min HM, Jeong HS, Ahn JY, et al. Sustained ERK activation is involved in the kaempferol-induced apoptosis of breast cancer cells and is more evident under 3-D culture condition [J]. Cancer Biol Ther, 2008,7:1080-1089.
[150]Green DR, Reed JC. Mitochondria and apoptosis [J]. Science,1998,281: 1309-1312.
[151]Rao L, White E. Bcl-2 and the ICE family of apoptotic regulators:making a connection [J]. Curr Opin Genet Dev,1997,7:52-58.
[152]Kluck RM, Bossy-Wetzel E. Green DR. Newmeyer DD. The release of cytochrome c from mitochondria:a primary site for Bcl-2 regulation of apoptosis [J]. Science,1997.275:1132-1136.
[153]Marshall CJ. Specificity of receptor tyrosine kinase signaling:transient versus sustained extracellular signal-regulated kinase activation [J]. Cell, 1995.80:179-185.
[154]Ramos JW. The regulation of extracellular signal-regulated kinase (ERK) in mammalian cells [J]. Int J Biochem Cell Biol,2008,40:2707-2719.
[155]Stanciu M, Wang Y, Kentor R. Burke N, Watkins S, et al. Persistent activation of ERK contributes to glutamate-induced oxidative toxicity in a neuronal cell line and primary cortical neuron cultures [J]. J Biol Chem.2000. 275:12200-12206.
[156]Yu C, Rahmani M, Almenara J. Sausville EA. Dent P, et al. Induction of apoptosis in human leukemia cells by the tyrosine kinase inhibitor adaphostin proceeds through a RAF-1/MEK/ERK-and AKT-dependent process [J]. Oncogene,2004,23:1364-1376.
[157]Wang Z, Wang H, Wu J, Zhu D, Zhang X, et al. Enhanced co-expression of beta-tubulin III and choline acetyltransferase in neurons from mouse embryonic stem cells promoted by Icaritin in an estrogen receptor-independent manner [J]. Chem Biol Interact,2009,179:375-385.
[158]Chen MF, Qi L, Li Y, Zu XB, Dai YQ, et al. Icaritin induces growth inhibition and apoptosis of human prostatic smooth muscle cells in an estrogen receptor-independent manner [J].Amino Acids 2007,38:1505-1513.