the role of ligand in the interaction of androgen receptor with dna ...

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Supervised by Docent Jorma J. Palvimo and Professor Olli A. Jänne Reviewed by Professor Anitta Mahonen University of Kuopio and Docent Veli Isomaa University of Oulu ISBN 952-10-1208-0 (nid.) ISBN 952-10-1111-4 (pdf) ISSN 1457-8433 http://ethesis.helsinki.fi Yliopistopaino Helsinki 2003
CONTENTS SUMMARY .................................................................................................................................... 5 LIST OF ORIGINAL PUBLICATIONS ........................................................................................ 6 ABBREVIATIONS......................................................................................................................... 7 REVIEW OF THE LITERATURE................................................................................................. 8 1. NUCLEAR RECEPTORS WITH A SPECIAL REFERENCE TO ANDROGEN RECEPTOR (AR) ....................................................................................................................... 8 1.1. Introduction ..................................................................................................................... 8 1.2. Hormone-induced effects ................................................................................................. 9 1.2.1. Hormone-induced conformational change.................................................................. 10 1.2.2. Trafficking and nuclear localization ........................................................................... 11 1.2.3. DNA binding............................................................................................................... 12 1.2.4. Nongenomic androgen action: AR-independent regulation by androgens ................. 13 1.3. Interactions with coregulators ........................................................................................ 13 1.3.1. ATP-dependent chromatin remodeling complexes and the TRAP-DRIP-ARC complex ................................................................................................................................. 14 1.3. 2. Acetyltransferases ......................................................................................................15 1.3.3. SRC/p160 coactivators............................................................................................... 16 1.3.4. Nuclear receptor- and promoter-specific coregulators................................................ 18 1.3.5. Nuclear receptor corepressors ..................................................................................... 20 1.3.6. Coactivators and corepressors as targets of signal transduction pathways ................. 21 1.4. Posttranslational modifications of AR ........................................................................... 22 1.4.1. Phosphorylation........................................................................................................... 22 1.4.2. Acetylation .................................................................................................................. 23 1.4.3. Ubiquitinylation .......................................................................................................... 23 1.4.4. Sumoylation and PIAS protein family ........................................................................ 25 2. ANDROGEN ANTAGONISTS ........................................................................................... 27 2.1. Effects of antiandrogens on transactivation ................................................................... 27 2.2. Prostate cancer and antiandrogens ................................................................................. 29 3. FUNCTIONAL ORGANIZATION OF THE NUCLEUS AND TRANSCRIPTIONAL REGULATION ..................................................................................................................... 30 3.1. Transcription sites .......................................................................................................... 31 3.2. Nuclear matrix................................................................................................................ 32 3.3. PML bodies ................................................................................................................... 33 3.3.1. Components of PML bodies........................................................................................ 33 3.3.2. PML............................................................................................................................. 34 3.3.3. SP100 .......................................................................................................................... 35 3.3.4. Regulation of PML body proteins by sumoylation ..................................................... 36
Page 1: Helsinki University Biomedical Diss
Page 5 and 6: SUMMARY Androgen receptor (AR) belo
Page 7 and 8: ABBREVIATIONS AF-1 activation domai
Page 9 and 10: A 25-600 66-68 50-70 220-250 NH 2-
Page 11 and 12: 1.2.2. Trafficking and nuclear loca
Page 13 and 14: 1.2.4. Nongenomic androgen action:
Page 15 and 16: Critical aspect of gene activation
Page 17 and 18: The p160 coactivator LXXLL motif ha
Page 19 and 20: coupling machinery (Zhao et al., 20
Page 21 and 22: 1999; Park et al., 1999). Lately, i
Page 23 and 24: MAPK by overexpression of ErB2/Her2
Page 25 and 26: 1.4.4. Sumoylation and PIAS protein
Page 27 and 28: 2002) and alleviate SUMO modificati
Page 29 and 30: aloxifene in the case of ER (Shang
Page 31 and 32: forms of the same protein may compe
Page 33 and 34: disruption of nuclear lamin organiz
Page 35 and 36: (Wang et al., 1998). PML is a tumor
Page 37 and 38: AIMS OF THE STUDY The main aim of t
Page 39 and 40: RESULTS AND DISCUSSION 1. FACTORS I
Page 41 and 42: Additionally, our PIA results sugge
Page 43 and 44: (Ylikomi et al., 1992; Tun et al.,
Page 45 and 46: The AR LBD was shown to contain ano
Page 47 and 48: distribution in tens of big round g
Page 49 and 50: 4.3. Effects of antiandrogens on AR
Page 51 and 52: structure map as a reference for GR
Page 53 and 54:
Fig 15. Confocal microscopy of PML-
Page 55 and 56:
6. FUTURE DIRECTIONS Characterizati
Page 57 and 58:
ACKNOWLEDGEMENTS Tämä väitöskir
Page 59 and 60:
Boisvert, F. M., Hendzel MJ, and Ba
Page 61 and 62:
Fondell JD, Ge H, Roeder RG 1996 Li
Page 63 and 64:
Hu Mc and Davidson N 1987 The induc
Page 65 and 66:
Kokontis JM, Liao S 1999 Molecular
Page 67 and 68:
McKenna NJ, Lanz RB, O’Malley BW
Page 69 and 70:
Palvimo JJ, Reinikainen P, Ikonen T
Page 71 and 72:
Savory JGA, Hsu B, Laquian IR, Giff
Page 73 and 74:
Veldscholte J, Berrevoets CA, Brink
Page 75:
Zhong S, Salomoni P, Ronchetti S, G
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