von Dott. Raffaele La Montagna
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| [1.] Rlm/Fragment 025 01 - Diskussion Zuletzt bearbeitet: 2014-11-17 22:04:45 Hindemith | Fragment, Gesichtet, KomplettPlagiat, Rlm, SMWFragment, Schutzlevel sysop, Ward and Weigel 2009 |
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| Untersuchte Arbeit: Seite: 25, Zeilen: 1ff (entire page) |
Quelle: Ward and Weigel 2009 Seite(n): 7 (Author manuscript), Zeilen: 9ff |
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| A Ser578Ala substitution results in increased nuclear localization of AR in the absence of ligand but eliminates AR transcriptional response to EGF. AR Ser578Ala also exhibits increased binding to Ku-70/80 regulatory subunits of DNA dependent protein kinase in addition to nuclear retention of the AR in association with hyperphosphorylation at Ser 515(44).
Finally, the Ser515Ala mutant is not phosphorylated on Ser650, which is located in the hinge region of AR (45). One possible explanation for this effect is that phosphorylation at Ser515 mediates a conformational change of the AR thus making the Ser650 phosphosite either more available to phosphatases or less accessible to kinases. Attempting to assign function to the AR Ser650 phosphorylation site itself has produced conflicting reports. Early studies have suggested that blocking phosphorylation of this site resulted in 30% reduced activity with an MMTV-Luc reporter in CV1 cells . This was in direct contrast to later reports examining the function of Ser650 phosphorylation on AR activity in various cell lines using various reporters in which no phenotype was detected . 43) Ponguta, L. A., Gregory, C. W., French, F. S., and Wilson, E. M. (2008) Site-specific androgen receptor serine phosphorylation linked to epidermal growth factor-dependent growth of castration-recurrent prostate cancer. J. Biol. Chem. 283, 20989–21001. 44) Pierre Chymkowitch, Nicolas Le May, Pierre Charneau, Emmanuel Compe and Jean-Marc Egly. The phosphorylation of the androgen receptor by TFIIH directs the ubiquitin/proteasome process. EMBO J. 2011 Feb 2;30(3):468-79. Epub 2010 Dec 14 45) Wong, H. Y., Burghoorn, J. A., Van Leeuwen, M., De Ruiter, P. E., Schippers, E., Blok, L. J., Li, K. W., Dekker, H. L., De Jong, L., Trapman, J., Grootegoed, J. A., and Brinkmann, A. O. (2004) Phosphorylation of androgen receptor isoforms. Biochem. J. 383, 267–276. |
A Ser578Ala substitution results in increased nuclear localization of AR in the absence of ligand but eliminates AR transcriptional response to EGF. AR Ser578Ala also exhibits increased binding to Ku-70/80 regulatory subunits of DNA-dependent protein kinase in addition to nuclear retention of the AR in association with hyperphosphorylation at Ser515 (67). Finally, the Ser515Ala mutant is not phosphorylated on Ser650, which is located in the hinge region of AR (68). One possible explanation for this is that phosphorylation at Ser515 mediates a conformational change of the AR thus making the Ser650 phospho site either more available to phosphatases or less accessible to kinases. Attempting to assign function to the AR Ser650 phosphorylation site itself has produced conflicting reports. Early studies have suggested that blocking phosphorylation of this site resulted in 30% reduced activity with an MMTV-Luc reporter in CV1 cells (56). This was in direct contrast to later reports examining the function of Ser650 phosphorylation on AR activity in various cell lines using various reporters in which no phenotype was detected (59,68).
56. Zhou ZX, Kemppainen JA, Wilson EM. Identification of three proline-directed phosphorylation sites in the human androgen receptor. Mol Endocrinol. 1995; 9:605–615. [PubMed: 7565807] 59. Gioeli D, Ficarro SB, Kwiek JJ, Aaronson D, Hancock M, Catling AD, White FM, Christian RE, Settlage RE, Shabanowitz J, Hunt DF, Weber MJ. Androgen receptor phosphorylation. Regulation and identification of the phosphorylation sites. J Biol Chem. 2002; 277:29304–29314. [PubMed: 12015328] 67. Ponguta LA, Gregory CW, French FS, Wilson EM. Site-specific androgen receptor serine phosphorylation linked to epidermal growth factor-dependent growth of castration recurrent prostate cancer. J Biol Chem. 2008; 283:20989–21001. [PubMed: 18511414] 68. Wong HY, Burghoorn JA, Van Leeuwen M, De Ruiter PE, Schippers E, Blok LJ, Li KW, Dekker HL, De Jong L, Trapman J, Grootegoed JA, Brinkmann AO. Phosphorylation of androgen receptor isoforms. Biochem J. 2004; 383:267–276. [PubMed: 15239671] |
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