跳到主要內容

臺灣博碩士論文加值系統

(18.97.9.172) 您好!臺灣時間:2025/01/20 17:38
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

我願授權國圖
: 
twitterline
研究生:陳韻茹
研究生(外文):Yun-Ju Chen
論文名稱:卵泡促素與乙型轉型生長因子調控大鼠卵巢顆粒細胞
論文名稱(外文):The Crucial Signaling Mechanism in Follicle-Stimulating Hormone and Transforming Growth Factor ��1- Stimulated Steroidogenesis in Rat Ovarian Granulosa Cells
指導教授:黃娟娟黃娟娟引用關係柯逢春
指導教授(外文):Jiuan-Jiuan HwangFerng-Chun Ke
學位類別:博士
校院名稱:國立陽明大學
系所名稱:生理學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2008
畢業學年度:96
語文別:英文
論文頁數:63
中文關鍵詞:卵泡促素乙型轉型生長因子雌激素接受器類固醇生成卵巢顆粒細胞
外文關鍵詞:FSHTGFbeta1ERsteroidogenesisovarian granulosa cell
相關次數:
  • 被引用被引用:0
  • 點閱點閱:285
  • 評分評分:
  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:0
卵泡發育過程,卵子藉由周邊的卵巢顆粒細胞提供營養而發育成熟,形成具備受孕能力的生殖細胞。過去研究已知,卵巢內的乙型轉型生長因子(TGF��1) 可強化卵泡促素(FSH)誘發大鼠卵巢顆粒細胞的分化,此含括增進黃體酮和雌激素的合成。然而,FSH與TGF��1作用訊息間的相互誘導至今尚不明確。本論文研究目的主要分為兩部分,第一研究目的是探討FSH與TGF��1刺激大鼠卵巢顆粒細胞類固醇生成的過程中,cAMP/PKA和PI3K/Akt訊息間的相互調控影響,以及mTORC1之參與性。此含括證實(一) FSH與TGF��1活化大鼠卵巢顆粒細胞cAMP-PKA和PI3K/Akt訊息傳遞路徑分子,以及(二)利用PKA拮抗劑(PKAI)、PI3K拮抗劑(wortmannin)和mTORC1拮抗劑(rapamycin)檢視FSH與TGF��1活化cAMP/PKA和PI3K/Akt訊息傳遞路徑對於大鼠卵巢顆粒細胞類固醇生成的影響。雌激素也可以增強FSH刺激大鼠卵巢顆粒細胞黃體酮生成。因此,第二研究目的為探討雌激素接受器(ER)在FSH與TGF��1誘發大鼠卵巢顆粒細胞分化所扮演的角色。此含括證實(一) ER�悀咶R�狾bFSH與TGF��1增進黃體酮生成及生成過程之主要蛋白分子的專一性參與角色,以及(二) FSH與TGF��1藉由ERα與輔助調節分子增進類固醇生成相關基因表現的分子相互作用機制。本研究是利用初級卵巢顆粒細胞培養系統進行實驗,細胞是取自性促素所誘發未成熟大鼠之中大型空腔卵泡。
PKAI 及wortmanin 可藉由抑制3��-HSD酵素以降低FSH所引發的黃體酮生成,而此兩種藥物可藉由抑制StAR蛋白、P450scc和3��-HSD酵素以降低FSH與TGF��1所引發的黃體酮生成。此外,FSH活化PI3K訊息傳導路徑,包含增強ILK活性,並增進下游分子Akt(S473)、mTOR(S2481)和S6K(T389)及轉錄因子FoxO1(S256) 和FoxO3a(S253)的磷酸化;此現象受wortmannin所抑制,卻不受PKAI處理的影響。我們還觀察到一有趣現象,wortmannin可消減PKAI抑制FSH所引發的CREB(S133)磷酸化,推測wortmannin可能影響顆粒細胞內訊息傳遞分子的分佈位置。此外,TGF��1並不影響FSH活化CREB及PI3K訊息傳遞分子。我們更進一步發現rapamycin降低TGF��1強化FSH所增進類固醇生成的效應,卻不影響FSH作用。令人驚訝的是rapamycin在不影響mTORC1活性的劑量下依然有此抑制效應。綜合以上結果,顯示FSH與TGF��1調控大鼠卵巢顆粒細胞類固醇生成作用中,cAMP/PKA及PI3K訊息傳遞路徑彼此相互影響。同時,我們首次發現TGF��1藉由rapamycin高敏感度且不經由mTORC1作用的方式來強化FSH所誘發大鼠卵巢顆粒細胞類固醇生成。
本研究進一步探索ER在FSH與TGF��1調控大鼠卵巢顆粒細胞類固醇生成的角色。很有趣地,我們發現ER�捁嚝靬坅�抗劑(MPP)及ER拮抗劑(ICI)皆可降低FSH±TGF��1所引發黃體酮的生成,然而雄性素接受器(AR)拮抗劑(HF),尤其是ER�瓵嚝靬坅�抗劑(PHTPP)則沒有顯著影響效應。與此一致的是ER�瓵嚝靬坅P進劑(DPN)不同於雌二醇,並不影響FSH±TGF��1所刺激類固醇生成。利用西方點墨法及染色質免疫沉澱法證實,MPP/ICI可藉由抑制ER�悝@用而減低FSH±TGF��1所增進3��-HSD及P450scc酵素,而不是StAR蛋白質的表現。我們更進一步證實FSH±TGF��1可增進ER�捋P組織蛋白甲基酶(CBP及SRC-1)和輔助活化分子PGC-1�悛熙s結,而MPP/ICI很顯著地減弱此連結效應。此外,FSH±TGF��1增進CBP、SRC-1和PGC-1�捋P3��-HSD及P450scc基因的結合。綜合此部分結果,我們首先發現ER�捋P轉錄輔助活化分子(CBP/SRC-1和PGC-1��)的結合對於FSH與TGF��1增進3��-HSD及P450scc酵素表現扮演重要功能,並藉此促進大鼠卵巢顆粒細胞黃體酮生成。
總括言之,本論文研究啟動瞭解FSH 與TGF��1誘發大鼠卵巢顆粒細胞類固醇生成過程,cAMP/PKA及PI3K訊息傳遞路徑之分子相互調控影響。有趣的是,TGF��1強化FSH所刺激的類固醇生成是包含rapamycin高敏感性之機制。更進一步證實,ER�悁bFSH與TGF��1刺激類固醇生成過程扮演重要角色,可藉由調控ER�捋P轉錄輔助調節分子之結合作用以增進類固醇生成基因的表現。
During ovarian folliculogenesis, oocytes grow in size and mature into fertilization-competent germ cells, this requires well nurture by the surrounding somatic cells, granulosa cells. Intra-ovarian TGF��1 greatly facilitates FSH-induced differentiation of rat ovarian granulosa cells with increased synthesis of progesterone and estrogen. The signaling crosstalk between FSH and TGF��1 remains unclear. There were two objectives in this thesis study. First objective was to investigate the interplay of cAMP/PKA and PI3K/Akt signaling including mTORC1-dependence in FSH and TGF��1-stimulated steroidogenesis in rat granulosa cells. This includes investigating (1) FSH and TGF��1-induced signaling activation of cAMP-PKA and PI3K/Akt pathways, and (2) the effect of inhibitors of PKA (PKAI), PI3K (wortmannin) and mTORC1 (rapamycin) on FSH and TGF��1-induced steroidogenesis. Estrogen also enhances FSH-stimulated progesterone production. And second objective was to explore the role of estrogen reptor (ER) in FSH and TGF��1-promoted differentiation of rat ovarian granulosa cells. This includes investigating (1) the specific role of ER�� and ER�� in FSH and TGF��1-stimulated progesterone production and the associated key steroidogenic proteins, and (2) the molecular interaction of ER�� and coregulators in FSH and TGF��1 upregulation of steroidogenic gene expression. Primary culture of granulosa cells from ovarian antral follicles of gonadotropin-primed immature rats was used.
PKAI and wortmannin suppression of the FSH-increased progesterone production was partly attributed to decreased level of 3��-HSD, and their suppression of the FSH plus TGF��1 effect was attributed to the reduction of all three key players, StAR protein, P450scc and 3��-HSD. Further, FSH activated the PI3K pathway including increased integrin-linked kinase (ILK) activity and phosphorylation of Akt(S473), mTOR(S2481), S6K(T389) and transcription factors particularly FoxO1(S256) and FoxO3a(S253), which were reduced by wortmannin treatment but not by PKAI. Interestingly, PKAI suppression of FSH-induced phosphorylation of CREB(S133) disappeared in the presence of wortmannin, suggesting that wortmannin may affect intracellular compartmentalization of signaling molecule(s). Additionally, TGF��1 had no effect on FSH-activated CREB and PI3K signaling mediators. We further found that rapamycin reduced the TGF��1-enhancing effect of FSH-stimulated steroidogenesis, yet it exhibited no effect on FSH action. Surprisingly, rapamycin displayed suppressive effect at concentrations that had no effect on mTORC1 activity. Together, this study demonstrates a delicate interplay between cAMP/PKA and PI3K signaling in FSH and TGF��1 regulation of steroidogenesis in rat granulosa cells. Furthermore, we demonstrate for the first time that TGF��1 acts in a rapamycin-hypersensitive and mTORC1-independent manner in augmenting FSH-stimulated steroidogenesis in rat granulosa cells.
This study further explored estrogen receptor (ER) involvement in FSH and TGF��1-stimulated steroidogenesis in rat ovarian granulosa cells. Interestingly, a selective ER�� antagonist MPP (like ER antagonist ICI) decreased FSH±TGF��1-stimulated progesterone production, whereas an AR antagonist hydroxyflutamide and particularly a selective ER�� antagonist PHTPP had no significant effect. Consistent with this, a selective ER�� agonist DPN (unlike 17��-estradiol) also had no effect on FSH±TGF��1-stimulated progesterone production. Immunoblotting and ChIP analyses indicate MPP/ICI suppression of FSH±TGF��1 action is partly attributed to the reduced ER��-mediated expression of 3��-HSD and P450scc enzymes, but not StAR protein. Furthermore, FSH±TGF��1 increased ER�� association with histone acetylases (CBP and SRC-1) and coactivator PGC-1��, and MPP/ICI dramatically reduced these interactions. Additionally, FSH�bTGF��1 increased CBP, SRC-1 and PGC-1�� binding to 3��-HSD and P450scc genes. Together, we demonstrate for the first time that ER�� interaction with transcription coregulators, histone acetylases (CBP/SRC-1) and coactivator PGC-1�� is crucial to FSH and TGF��1-upregulated expression of 3��-HSD and P450scc enzymes, and thus progesterone production in rat ovarian granulosa cells.
In conclusion, this thesis study initiates the understanding of molecular interplay of PI3K and cAMP/PKA signaling in FSH and TGF��1-induced steroidogenesis in rat ovarian granulosa cells. And interestingly, TGF��1 displays rapamycin-hypersensitivity in enhancement of FSH-stimulated steroidogenesis. Furthermore, ER�� plays a crucial role in FSH and TGF��1-stimulated steroidogenesis through recruitment of transcription coregulators to upregulate steroidogenic gene expression.
Abstract……………………………………………………………………………… 1
中文摘要..................................................................................................................... 3
I. Introduction……………………………………………………………………….. 5
1. The ovary and folliculogenesis………………………………………………… 5
2. FSH and the signaling transduction……………………………………………. 6
3. TGF�� and the signaling transduction…………………………………………... 6
4. PI3K/Akt/mTOR signaling regulates ovarian cell functions…………………... 8
5. Biological functions of estrogen and estrogen receptor actions……………….. 9
II. Objective…………………………………………………………………………. 12
III. Materials and Methods………………………………………………………...... 13
Materials………………………………………………………………….………. 13
Animals…………………………………………………………….……….…….. 13
Cell culture and treatment………………………………………………………… 14
Enzyme-linked immunoassay………………………………………………..…… 14
Immunoblotting…………………………………………………………………... 15
ILK kinase activity assay……………………………………………………..….. 15
Coimmunoprecipitation…………………………………………………………... 16
Chromatin immunoprecipitation (ChIP) assay…………………………….……... 16
Statistics………………………………………………………………………….. 17
IV. Results (Objective 1)……………………………………………………………. 19
1. Effects of PKA and PI3K inhibitors on the FSH and TGF��1-regulated
steroidogenesis………………………………………………………………… 19
2. Regulatory effects of FSH and TGF��1 on PI3K signaling molecules………… 20
3. Involvement of mTOR complex (mTORC) in TGF��1 enhancement of FSH
action…………………………………………………………………………... 21
V. Discussion (Objective 1)…………………………………………………….…… 32
VI. Results (Objective 2)……………………………………………………………. 36
1. Specific involvement of ER�� in FSH and TGF��1-stimulated
steroidogenesis…………………………………………………………………. 36
2. Molecular interaction of ER�� with transcription coregulators in FSH and TGF��1 upregulation of steroidogenic gene expression…………………………….. ….. 37
VII. Discussion (Objective 2)………………………………………………………... 47
1. Specific involvement of ER�� in FSH and TGF��1-stimulated steroidogenesis… 47
2. Molecular interaction of ER�� with transcription coregulators in FSH and TGF��1
upregulation of steroidogenic gene expression……………………………...…. 47
VIII. References……………………………………………………………………... 51
IX. Acknowledgements……………………………………………………………… 63
Accili D, Arden KC. FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell 2004; 117: 421-426
Acconcia F, Kumar R. Signaling regulation of genomic and nongenomic functions of estrogen receptors. Cancer Lett 2006; 238: 1-14
Alam H, Maizels ET, Park Y, Ghaey S, Feiger ZJ, Chandel NS, Hunzicker-Dunn M. Follicle-stimulating hormone activation of hypoxia-inducible factor-1 by the phosphatidylinositol 3-kinase/AKT/Ras homolog enriched in brain (Rheb)/Mammalian target of rapamycin (mTOR) pathway is necessary for induction of select protein markers of follicular differentiation. J Biol Chem 2004; 279: 19431-19449
Arnold SF, Melamed M, Vorojeikina DP, Notides AC, Sasson S. Estradiol-binding mechanism and binding capacity of the human estrogen receptor is regulated by tyrosine phosphorylation. Mol Endocrinol 1997; 11: 48-53
Bakin AV, Tomlinson AK, Bhowmick NA, Moses HL, Artega C. Phosphatidylinositol 3-kinase function is required for transforming growth factor β-mediated epithelial to mesenchymal transition and cell migration. J Biol Chem 2000; 275: 36803-36810
Balasubramanian K, Lavoie HA, Garmey JC, Stocco DM, Veldhuis JD. Regulation of porcine granulosa cell steroidogenic acute regulatory protein (StAR) by insulin-like growth factor I: synergism with follicle-stimulating hormone or protein kinase A agonist. Endocrinology 1997; 138: 433-439
Birkenkamp KU, Coffer PJ. Regulation of cell survival and proliferation by the FOXO (Forkhead box, class 0) subfamily of Forkhead transcription factors. Biochem Soc Trans 2003; 31: 292-297
Bourdoncle A, Labesse G, Margueron R, Castet A, Cavaillès V, Royer CA. The nuclear receptor coactivator PGC-1alpha exhibits modes of interaction with the estrogen receptor distinct from those of SRC-1. J Mol Biol 205; 347: 921-934
Brazil DP, Yang ZZ, Hemmings BA. Advances in protein kinase B signaling: AKTion on multiple fronts. Trends Biochem Sci 2004; 29: 33-242
Brunet A, Park J, Tran H, Hu LS, Hemming BA, Greenberg ME. Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a). Mol Cell Biol 2001; 21: 52-965
Burgering BMT, Kops GJPL. Cell cycle and death control: long liver forkheads. Trends Biochem Sci 2002; 27: 52-360
Byers M, Kuiper GGJM, Gustafsson JA, Park-Sarge OK. Estrogen receptor-β mRNA expression in rat ovary: down-regulation by gonadotropins. Mol Endocrinol 1997; 11: 172-182
Castrillon DH, Miao L, Kollipara R, Horner JW, DePinho RA. Suppression of ovarian follicle activation in mice by the transcription factor FoxO3a. Science 2003; 301: 15-218
Chang H, Matzuk MM. Smad5 required for mouse primordial germ cell development. Mech Dev 2001; 104: 61-67
Chen YG, Liu F, Massague J. Mechanism of TGFbeta receptor inhibition by FKBP12. EMBO J 1997; 16: 3866-3876
Chen RH, Su YH, Chuang RL, Chang TY. Suppression of transforming growth factor-β-induced apoptosis through a phosphatidylinositol 3-kinase/Akt-dependent pathway. Oncogene 1998; 17: 1959-1968
Chen YJ, Hsiao PW, Lee MT, Mason JI, Ke FC, Hwang JJ. Interplay of PI3K and cAMP/PKA signaling, and raprmycin-hypersensitivity in TGFβ1 enhancement of FSH-stimulated steroidogenesis in rat ovarian granulosa cells. J Endocrinol 2007; 192: 405-419
Cheung E, Acevedo ML, Cole PA, Kraus WL. Altered pharmacology and distinct coactivator usage for estrogen receptor-dependent transcription through activating protein-1. Proc Natl Acad Sci USA 2005; 102: 559-564
Chiang GG, Abraham RT. Phosphorylation of mammalian target of rapamycin (mTOR) at Ser-2448 is mediated by p70S6 kinase. J Biol Chem 2005; 280: 25485-25490
Clark BJ, Wells J, King SR, Stocco DM. The purification, cloning, and expression of a novel luteinizing hormone-induced mitochondrial protein in MA-10 mouse Leydig tumor cells. Characterization of the steroidogenic acute regulatory protein (StAR). J Biol Chem 1994; 269: 28314-28322
Clarke TR, Bain PA, Greco TL, Payne AH. A novel mouse kidney 3 beta-hydroxysteroid dehydrogenase complementary DNA encodes a 3-ketosteroid reductase instead of a 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase. Mol Endocrinol 1993; 7: 1569-1578
Clemens JW, Lala DS, Parker KL, Richards JS. Steroidogenic factor-1 binding and transcriptional activity of the cholesterol side-chain cleavage promoter in rat granulosa cells. Endocrinology 1994; 134: 1499-1508
Conery AR, Cao Y, Thompson EA, Townsed CM Jr, Ko TC, Luo K. Akt interacts directly with Smad3 to regulate the sensitivity to TGF-beta induced apoptosis. Nat Cell Biol 2004; 6: 366-372
Conkright MD, Montminy M. TORCs: transducers of regulated CREB activity. Trends Cell Biol 2005; 15: 457-459
Couse JF, Hewitt SC, Korach KS. Receptor null mice reveal contrasting roles for estrogen receptor α and β in reproductive tissue. J Steroid Biochem Mol Biol 2000; 74: 287-296
Cunningham MA, Zhu Q, Unterman TG, Hammond JM. Follicle-stimulating hormone promotes nuclear exclusion of the forkhead transcription factor Foxo1a via phosphatidylinositol 3-kinase in porcine granulosa cells. Endocrinology 2003; 144: 5585-5594
Danielpour D, Song K. Cross-talk between IGF-I and TGF-beta signaling pathways. Cytokine Growth Factor Rev 2006; 17: 59-74
Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-β family signaling. Nature 2003; 425: 577-584
Di Guglielmo GM, Le Roy C, Goodfellow AF, Wrana JL. Distinct endocytic pathways regulate TGF-beta signaling and turnover. Nat Cell Biol 2003; 5: 410-421
Dickson MC, Martin JS, Cousins FM, Kulkarni AB, Karlsson S, Akhurst RJ. Defective haematopoiesis and vasculogenesis in transforming growth factor-β1 knock out mice. Development 1995; 121: 1845-1854
Dodson WD, Schomberg DW. The effect of transforming growth factor-β on follicle-stimulating hormone-induced differentiation of cultured rat granulosa cells. Endocrinology 1987; 120: 512-516
Dunkel L, Tilly JL, Shikone T, Nishimori K, Hsueh AJ. Follicle-stimulating hormone receptor expression in the rat ovary: increases during prepubertal development and regulation by the opposing actions of transforming growth factors beta and alpha. Biol Reprod 1994; 50: 940-948
Dupont S, Krust A, Gansmuller A, Dierich A, Chambon P, Mark M. Effect of single and compound knockouts of estrogen receptor α (ERα) and ERβ (ERβ) on mouse reproductive phenotypes. Development 2000; 127: 4277-4291
Enserink JM, Christensen AE, de Rooij J, van Triest M, Schwede F, Genieser HG, Doskeland SO, Blank JL, Bos JL. A novel Epac-specific cAMP analogue demonstrates independent regulation of Rap1 and ERK. Nat Cell Biol 2002; 4: 901-906
Fanjul LF, Ruiz de Galarreta CM, Hsueh AJ. Estrogen regulation of progestin biosynthetic enzymes in cultured rat granulosa cells. Biol Reprod 1984; 30: 903-912
Gburcik V, Picard D. The cell-specific activity of the estrogen receptor α may be fine-tuned by phosphorylation-induced structural gymanastics. Nucl Recept Signal 2006; 4: e005
Gillies RJ, Didier N, Denton M. Determination of the cell number in monolayer cultures. Anal Biochem 1986; 159: 109-113
Gitay-Goren H, Kim IC, Miggans ST, Schombergm DW. Transforming growth factor beta modulates gonadotropin receptor expression in porcine and rat granulosa cells differently. Biol Reprod 1993; 48: 1284-1289
Gonzalez-Robayna IJ, Falender AE, Ochsner S, Firestone GL, Richards JS. FSH stimulates phosphorylation and activation of protein kinase B (PKB/Akt) and serum and glucocorticoid-induced kinase (Sgk): evidence for A-kinase independent signaling in granulosa cells. Mol Endocrinol 2000; 14: 1283-1300
Greer EL, Brunet A. FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene 2005; 24: 7410-7425
Hanada M, Feng J, Hemmings BA. Structure, regulation and function of PKB/Akt-a major therapeutic target. Biochim Biophys Acta 2004; 1697: 3-16
Holz MK, Blenis J. Identification of S6 kinase 1 as a novel mammalian target of rapamycin (mTOR)-phosphorylating kinase. J Biol Chem 2005; 280: 26089-26093
Hosaka T, Biggs WH 3rd, Tieu D, Boyer AD, Varki NM, Cavenee WK, Arden KC. Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification. Proc Natl Acad Sci USA 2004; 101: 2975-2980
Hu MC, Guo IC, Lin JH, Chung BC, Hu MC, Guo IC, Lin JH, Chung BC. Regulated expression of cytochrome P-450scc (cholesterol-side-chain cleavage enzyme) in cultured cell lines detected by antibody against bacterially expressed human protein. Biochem J 1991; 274: 813-817
Hulas-Stasiak M, Gawron A. Immunohistochemical localization of estrogen receptors ERalpha and ERbeta in the spiny mouse (Acomys cahirinus) ovary during postnatal development. J Mol Histol 2007; 38: 25-32
Ingman WV, Robker RL, Woittiez K, Robertson SA. Null mutation in transforming growth factor beta1 disrupts ovarian function and causes oocyte incompetence and early embryo arrest. Endocrinology 2006; 147: 835-845
Inoki K, Ouyang H, Li Y, Guan KL. Signaling by target of rapamycin protein in cell growth control. Microbiol Mol Biol Rev 2005; 69: 79-100
Inoue K, Nakamura K, Abe K, Hirakawa T, Tsuchiya M, Matsuda H, Miyamoto K, Minegishi T. Effect of transforming growth factor beta on the expression of luteinizing hormone receptor in cultured rat granulosa cells. Biol Reprod 2002; 67: 610-615
Itoh Y, Tanaka H, Iwase H, Karamatsu S, Yamashita H, Itoh K, Yamashita T, Toyama T, Omoto Y, Kobayashi H. Readministration of tamoxifen after adjuvant therapy for recurrent breast cancer. Breast Cancer 2000; 7: 149-152
Javelaud D, Mauviel A. Molecules in focus mammalian transforming growth factor-bs: Smad signaling and physio-pathological roles. Int J Biochem Cell Biol 2004; 36: 1161-1165
Joel PB, Traish AM, Lannigan DA. Estradiol and phorbol ester cause phosphorylation of serine 118 in the human estrogen receptor. Mol Endocrinol 1995; 9: 1041-1052
Joel PB, Traish AM, Lannigan DA. Estradiol-induced phosphorylation of Serine 118 in the estrogen receptor is independent of p42/p44 mitogen-activated protein kinase. J Biol Chem 1998a; 273: 13317-13323
Joel PB, Smith J, Sturgill TW, Fisher TL, Blenis J, Lannigan DA. Pp90rsk1 regulates estrogen receptor-mediated transcription through phosphorylation of Ser-167. Mol Cell Biol 1998b; 18: 1978-1984
Jones RE. 1991 The female reproductive system. In: Human reproductive biology. Academic Press, Inc. p39-72
Ju EM, Choi KC, Hong SH, Lee CH, Kim BC, Kin SJ, Kim IH., Park SH. Apoptosis of mink lung epithelial cells by co-treatment of low-dose staurosporine and transforming growth factor-beta1 depends on the enhanced TGF-beta signaling and requires the decreased phosphorylation of PKB/Akt. Biochem Biophys Res Commun 2005; 328: 1170-1181
Kaestner KH, Knochel W, Matinex DE. Unified nomenclature for the winged helix/forkhead transcription factors. Genes Dev 2000; 14: 42-146
Ke FC, Chuang LC, Lee MT, Chen YJ, Lin SW, Wang PS, Stocco DM, Hwang JJ. The modulatory role of TGFβ1 and androstenedione on FSH-induced gelatinase secretion and steroidogenesis in rat granulosa cells. Biol Reprod 2004; 70: 1292-1298
Ke FC, Fang SH, Lee MT, Sheu SY, Lai SY, Chen YJ, Huang FL, Wang PS, Stocco DM, Hwang JJ. Lindane, a gap junction blocker, suppresses FSH and transforming growth factor β1-induced connexin43 gap junction formation and steroidogenesis in rat granulosa cells. J Endocrinol 2005; 184: 555-566
Kelley DP, Scarpulla RC. Transcriptional regulatory circuits controlling mitochondrial biogenesis and function. Genes Dev 2004; 18: 357-368
Kitisin K, Saha T, Blake T, Golestaneh N, Deng M, Kim C, Tang Y, Shetty K, Mishra B, Mishra L. TGF-beta signaling in development. Sci STKE 2007; 14: cm1
Klinge CM. Estrogen receptor interaction with estrogen response element. Nucleic Acids Res 2001; 29: 2905-2919
Knight PG. Glister C. Local roles of TGFβ superfamily members in the control of ovarian follicle development. Anim Reprod Sci 2003; 78: 165-183
Komar CM, Braissant O, Wahli W, Curry TE Jr. Expression and localization of PPARs in the rat ovary during follicular development and the periovulatory period. Endocrinology 2001; 142: 4831-4838
Lannigan DA. Estrogen receptor phosphorylation. Steroids 2003; 68: 1-9
Le Roy C, Wrana JL. Signaling and endocytosis: a team effort for cell migration. Nat Rev Mol Cell Biol 2005; 6: 112-126
Lee HY, Sherwood OD. The effects of blocking the actions of estrogen and progesterone on the rates of proliferation and apoptosis of cervical epithelial and stromal cells during the second half of pregnancy in rats. Biol Reprod 2005; 73: 790-797
Leong H, Riby JE, Firestone GL, Bjeldanes LF. Potent ligand-independent estrogen receptor activation by 3,3’-diindolylmethane is mediated by cross talk between the protein kinase A and mitogen-activated protein kinase signaling pathways. Mol Endocrinol 2004; 18: 291-302
Lien SC, Usami S, Chien S, Chiu JJ. Phosphatidylinositol 3-kinase/Akt pathway is involved in transforming growth factor-beta-1-induced phenotypic modulation of 10T1/2 cells to smooth muscle cells. Cell Signal 2006; 18: 270-1278
Likhite VS, Stossi F, Kim K, Katzenellenbogen BS, Katzenellenbogen JA. Kinase-specific phosphorylation of the estrogen receptor changes receptor interactions with ligand, deoxyribonucleic acid, and coregulators associated with alteraction in estrogen and tamoxifen activity. Mol Endocrinol 2006; 20: 3120-3232
Manna PR, Dyson MT, Eubank DW, Clark BJ, Lalli E, Sassone-Corsi P, Zeleznik AJ, Stocco DM. Regulation of steroidogenesis and the steroidogenic acute regulatory protein by a member of the cAMP response-element binding protein family. Mol Endocrinol 2002; 16: 184-199
Manna PR, Stocco DM. Regulation of the Steroidogenic acute regulatory protein expression: functional and physiological consequences. Curr Drug Targets-Immune Endocr Metabol Disord 2005; 5: 93-108
Marchese A, Chen C, Kim YM, Benovic JL. The ins and outs of G protein-coupled receptor trafficking. Trends Biochem Sci 2003; 28: 369-376
Martin DM, Hall MN. The expanding TOR signaling network. Curr Opin Cell Biol 2005; 17: 58-166
Massagué J, Blain SW, Lo RS. TGFb signaling in growth control, cancer, and heritable disorders. Cell 2000; 103: 295-309
Matsuda T, Yamamoto T, Muraguchi A, Saatcioglu F. Cross-talk between transforming growth factor-beta and estrogen receptor signaling through Smad3. J Biol Chem 2001; 276: 42908-42914
Mayr B, Montminy M. Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat Rev Mol Cell Biol 2001; 2: 599-609
McVey MJ, Cooke GM, Curran IH. Altered testicular microsomal steroidogenic enzyme activities in rats with lifetime exposure to soy isoflavones. J Steroid Biolchem Mol Biol 2004; 92: 435-446
Miaczynska M, Pelkmans L, Zerial M. Not just a sink: endosomes in control of signal transduction. Curr Opin Cell Biol 2004; 16: 400-406
Michalides R, Griekspoor A, Balkenende A, Verwoerd D, Janssen L, Jalink K, Floore A, Velds A, van’t Veer L, Neefjes J. Tamoxifen resistance by a conformational arrest of the estrogen receptor alpha after PKA activation in breast cancer. Cancer Cell 2004; 5: 597-605
Minegishi T, Hirakawa T, Kishi H, Abe Y, Mizutani T, Miyamoto K. A role of insulin-like growth factor I for follicle-stimulating hormone receptor expression in rat granulosa cells. Biol Reprod 2000; 62: 325-333
Misao R, Nakanishi Y, Sun WS, Fujimoto J, lwagaki S, Hirose R, Tamaya T. Expression of oestrogen receptor α and β mRNA in corpus luteum of human subjects. Mol Hum Reprod 1999; 5: 17-21
Mulholland DJ, Dedhar S, Coetzee GA, Nelson CC. Interaction of nuclear receptors with the Wnt/beta-catenin/Tcf signaling axis: Wnt you like to know? Endocr Rev 2005; 26: 898-915
Mutoh J, Taketoh J, Okamura K, Kagawa T, Ishida T, Ishida Y, Yamada H. Fetal pituitary gonadotropin as an initial target of dioxin in its impairment of cholesterol transportation and steroidogenesis in rats. Endocrinology 2006; 147: 927-936
Naga Prasad SV, Barak LS, Rapacciuolo A, Caron MG, Rockman HA. Agonist-dependent recruitment of phosphoinositide 3-kinase to the membrane by beta-adrenergic receptor kinase 1. A role in receptor sequestration. J Biol Chem 2001; 276: 18953-18959
Nawshad A, Lagamba D, Polad A, Hay ED. Transforming growth factor-beta signaling during epithelial-mesenchymal transformation: implications for embryogenesis and tumor metastasis. Cells Tissues Organs 2005; 179: 11-23
Nomura M, Li E. Smad2 role in mesoderm formation, left-right patterning and craniofacial development. Nature 1998; 393: 786-790
Palter SF, Tavares AB, Hourvutz A, Veldhuis JD, Adashi EY. Are estrogen of important to primate/human ovarian folliculogenesis? Endocr Rev 2001; 22: 389-424
Palermo R. Differential actions of FSH and LH during folliculogenesis. Reprod Biomed Online 2007; 15: 326-337
Park Y, Maizels ET, Feiger ZJ, Alam H, Peters CA, Woodruff TK, Unterman TG, Lee EJ, Jameson JL. Induction of cyclin D2 in rat granulosa cells requires FSH-dependent relief from FOXO1 repression coupled with positive signals from Smad. J Biol Chem 2005; 280: 9135-9148
Pangas SA, Matzuk MM. Genetic models for transforming growth factor β superfamily signalingin ovarian follicle development. Mol Cell Endocrinol 2004; 225: 83-91
Pescador N, Houde A, Stocco DM, Murphy BD. Follicle-stimulating hormone and intracellular second messengers regulate steroidogenic acute regulatory protein messenger ribonucleic acid in luteinized porcine granulosa cells. Biol Reprod 1997; 57: 660-668
Polo S, Di Fiore PP. Endocytosis conducts the cell signaling orchestra. Cell 2006; 124: 897-900
Puigserver P, Adelmant G, Wu Z, Fan M, Xu J, O’Malley B, Spiegelman BM. Activation of PPARgamma coactivator-1 through transcription factor docking. Science 1999; 286: 1368-1371
Pullen N, Dennis PB, Andjelkovic M, Dufner A, Kozma SC, Hemmings BA, Thomas G. Phosphorylation and activation of p70s6k by PDK1. Science1998; 279: 707-710
Remy I, Montmarquette A, Michnick SW. PKB/Akt modulates TGF-beta signaling through a direct interaction with Smad3. Nat Cell Biol 2004; 6: 358-365
Richards JS. New signaling pathways for hormones and cyclic adenosine 3',5'-monophosphate action in endocrine cells. Mol Endocrinol 2001; 15: 209-218
Richards JS, Sharma SC, Falender AE, Lo YH. Expression of FKHR, FKHRL1, and AFX genes in the rodent ovary: evidence for regulation by IGF-I, estrogen, and the gonadotropin. Mol Endocrinol 2002; 16: 580-599
Riggs BL, Hartmann LC. Selective estrogen-receptor modulators mechanisms of action and application to clinical practice. N Engl J Med 2003; 348: 618-629
Rosenfeld CS, Roberts RM, Lubahn DB. Estrogen receptor- and aromatase-deficient mice provide insight into the roles of estrogen within the ovary and uterus. Mol Reprod Dev 2001; 59: 336-346
Sandhoff TW, Hales DB, Hales KH, McLean MP. Transcriptional regulation of the rat steroidogenic acute regulatory protein gene by steroidogenic factor 1. Endocrinology 1998; 139: 4820-4831
Sarbassov DD, Guerrtin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005; 307: 098-1101
Schuur ER, Loktev AV, Sharma M, Sun Z, Roth RA. Ligand-dependent interaction of estrogen receptor-α with members of the forkhead transcription factor family. J Biol Chem 2001; 276: 33554-33560
Sewer MB, Waterman MR. Insights into the transcriptional regulation of steroidogenic enzymes and StAR. Rev Endocr Metab Disord 2001; 2: 269-274
Shang Y, Brown M. Molecular determinants for the tissue specificity of SERMs. Science 2002; 295: 2465-2468
Sharma SC, Clemens JW, Pisarska MD, Richards JS. Expression and function of estrogen receptor subtypes in granulosa cells: regulation by estradiol and forskolin. Endocrinology 1999; 140: 4320-4334
Shea-Eaton W, Sandhoff TW, Lopez D, Hales DB, McLean MP. Transcriptional repression of the rat steroidogenic acute regulatory (StAR) protein gene by the AP-1 family member c-Fos. Mol Cell Endocrinol 2002; 188: 161-170
Sher N, Yivgi-Phana N, Orly J. Transcriptional regulation of the cholesterol side chain cleavage cytochrome P450 gene (CYP11A1) revisited: binding of GATA, cyclic adenosine 3’,5;-monophosphate response element-binding protein and activating protein (AP)-1 proteins to a distal novel cluster of cis-regulatory elements potentiates AP-2 and steroidogenic factor-1-dependent gene expression in the rodent placenta and ovary. Mol Endocrinol 2007; 21: 948-962
Shi W, Sun C, He B, Xiong W, Shi X, Yao D, Cao X. GADD34-PP1c recruited by Smad7 dephosphorylates TGFβ type I receptor. J Cell Biol 2004; 164: 291-300
Shull MM, Doetschman T. Transforming growth factor β1 in reproduction and development. Mol Reprod Dev 1994; 39: 239-246
Song K, Wang H, Krebs TL, Danielpour D. Novel roles of Akt and mTOR in suppressing TGF-beta/ALK5-mediated Smad3 activation. EMBO J 2006; 25: 58-69
Stocco DM, Wang XJ, Jo Y, Manna PR. Multiple signaling pathway regulating steroidogenesis and steroidogenic acute regulatory protein expression: more complicated than we thought. Mol Endocrinol 2005; 19: 2647-2659
Stokes K, Alston-Mills B, Teng C. Estrogen response element and the promoter context of the human and mouse lactoferrin genes influence estrogen receptor alpha-mediated transactivation activity in mammary gland cells. J Mol Endocrinol 2004; 33: 315-334
Tcherepanova I, Puigserver P, Norris JD, Spiegelman BM, McDonnell DP. Modulation of estrogen receptor-α transcriptional activity by the coactivator PGC-1. J Biol Chem 2000; 275: 16302-16308
Teerds KJ, Dorrington JH. Immunohistochemical localization of transforming growth factor-β1 and β2 during follicular development in the adult rat ovary. Mol Cell Endocrinol 1992; 84: R7-R13
ten Dijke P, Miyazono K, Heldin CH. Signaling inputs converge on nuclear effectors in TGF-β signaling. Trends Biochem Sci 2000; 25: 64-70
Thomas JL, Mason JI, Brand S, Spencer BR Jr, Norris W. Structure/function relationships responsible for the kinetic differences between human type 1 and type 2 3β-hydroxysteroid dehydrogenase and for the catalysis of the type 1 activity. J Biol Chem 2002; 277: 42795-42801
Tomic D, Brodie SG, Deng C, Hickey RJ, Babus JK, Malkas LH, Flaws JA. Smad3 may regulate follicular growth in the mouse ovary. Biol Reprod 2002; 66: 917-923
Tran H, Brunet A, Griffith EC, Greenberg ME. The many Forks in FOXO’s road. Sci STKE 2003; 172: ref5
Troussard AA, Mawji NM, Ong C, Mui A, St-Arnaud R, Dedhar S. Conditional knock-out of integrin-linked kinase demonstrates an essential role in protein kinase B/Akt activation. J Biol Chem 2003; 278: 22374-22378
Truica CI, Byers S, Gelmann EP. Beta-catenin affects androgen receptor transcriptional activity and ligand specificity. Can Res 2000; 60: 4709-4713
Vanhaesebroeck B, Ali K, Bilancio A, Geering B, Foukas LC. Signalling by PI3K isoforms: insights from gene-target mice. Trends Biochem Sci 2005; 30: 194-204
Vegetti W, Alagna F. FSH and folliculogenesis: from physiology to ovarian stimulation. Reprod Biomed Online 2006; 12: 684-694
Weinstein M, Yang X, Li C, Xu X, Gotay J, Deng CX. Failure of egg cylinder elongation and mesoderm induction in mouse embryos lacking the tumor suppressor Smad2. Proc Natl Acad Sci USA 1998; 95: 9378-9383
Weis KE, Ekena K, Thomas JA, Lazennec G, Katzenellenbogen BS. Constitutively active human estrogen receptors containing amino acid substitutions for tyrosine 537 in the receptor protein. Mol Endocrinol 1996; 10: 1388-1398
Welsh TH Jr, Zhuang LZ, Hsueh AJ. Estrogen augmentation of gonadotropin-stimulated progestin biosynthesis in cultured rat granulosa cells. Endocrinology 1983; 112: 1916-1924
Woodgett JR. Recent advances in the protein kinase B signaling pathway. Curr Opin Cell Biol 2005; 17: 50-157
Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell 2006; 124: 71-484
Wymann MP, Zvelebill M, Laffargue M. Phosphoinositide 3-kinase gamma: a key modulator in inflammation and allergy. Trends Pharmacol Sci 2003; 24: 366-376
Wymann MP, Marone R. Phosphoinositide 3-kinase in disease: timing, location, and scaffolding. Curr Opin Cell Biol 2005; 17: 141-149
Zeleznik AJ, Saxena D, Little-Ihrig L. Protein kinase B is obligatory for follicle-stimulating hormone-induced granulosa cell differentiation. Endocrinology 2003; 144: 3985-3994
Zhang L, Duan CJ, Binkley C, Li G, Uhler MD, Logsdon CD, Simeone DM. A transforming growth factor beta-induced Smad3/Smad4 complex directly activates protein kinase A. Mol Cell Biol 2004; 24: 2169-2180
Zhiwen ZW, Findlay JK, Carson RS, Herington AC, Burger HG. Transforming growth factor β enhances basal and FSH-stimulated inhibin production by rat granulosa cells in vitro. Mol Cell Endocrinol 1988; 58: 161-166
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top
無相關期刊