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Nuclear receptors

Nuclear receptors. Reshma Taneja Department of Molecular, Cell and Developmental Biology Mount Sinai School of Medicine Advanced Signal Transduction Course/ STKE March 31st, 2005. Nuclear Receptors. Introduction -Types -Domain Structure -DNA binding specificities

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Nuclear receptors

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  1. Nuclear receptors Reshma Taneja Department of Molecular, Cell and Developmental Biology Mount Sinai School of Medicine Advanced Signal Transduction Course/ STKE March 31st, 2005

  2. Nuclear Receptors • Introduction -Types • -Domain Structure • -DNA binding specificities • II.Mechanisms of transcriptional regulation -Interaction with coactivators and corepressors III.Modulation of nuclear receptor activity by phosphorylation -Estrogen receptor by MAPK -implications in breast cancer -Retinoic acid receptors by proline-directed kinases - role in differentiation of F9 cells • IV. Nuclear receptors in cancers • -Utility of retinoids in therapy and chemoprevention • -Acute Promyelocytic leukemia

  3. The nuclear receptor superfamily Mangelsdorf et al, (1995) Cell 83:835-839

  4. Activation of steroid and non-steroid nuclear receptors R S H RX RX Steroid receptors S R hsp hsp hsp hsp + R S S R Target gene HRE Non-steroid receptors R Target gene HRE R H Target gene HRE Adapted from: Weigel, N. (1996) Biochem J, 319: 657-667

  5. Domain structure of nuclear hormone receptors 2 Gronemeyer et al, (2004) Nat Rev Drug Discov 3:950-964

  6. DNA binding sites of retinoid receptors Bastein and Rochette-Egly (2004) Gene 328, 1-16

  7. Transcriptional repression and activation by nuclear receptors A Corepressors complexes HDAC NCoR /SMRT Repressed Transcription ligand Histones deacetylation RAR/RXR B Coactivators complexes HAT Kinase Histones/Acetylation / methylation /phosphorylation SWI/SNF HMT (CARM-1) P300 / CBP PCAF P160 P P Nucleosomes Translocation CH3 Ac Ac CH3 Ac Ac Ac Ac Ac Ac Ac Recruitment of the mediator and transcription machinery C Transcription P TAFs Mediator CH3 Ac Ac RNA pol II TBP TFIIF TATA TFIIH TFIIB TFIIA TFIIE Ac Ac Ac Bastein and Rochette-Egly (2004) Gene 328, 1-16

  8. Alternative activation and repression functions of nuclear receptors regulated by ligand (or signaling pathway) control of recruitment of either coactivators or corepressors Rosenfeld, M. et al. (2001) J. Biol. Chem. 276:36865-36868

  9. LXXLL KIX Br CH/2 CH/3 CH/1 RID SRC-1 pCIP HAT P/CAF Nuclear receptor coactivators LXXLL AD1 AD2 p160 coactivators SRC-1 TIF2 p/CIP Q bHLH PAS CBP CARM1 RID P/CAF HAT CBP/ p300

  10. Utilization of multiple coactivator complexes Glass C et al. (2000) Genes Dev. 14: 121-141

  11. Nuclear receptor corepressors Glass C et al. (2000) Genes Dev. 14: 121-141

  12. Integration of nuclear signaling events by coactivator and corepressor complexes Glass C et al., (2000) Genes Dev. 14: 121-141

  13. Regulation of nuclear receptor activity by phosphorylation Bastein and Rochette-Egly (2004) Gene 328, 1-16

  14. Phosphorylation of steroid nuclear receptors Rochette-Egly Cell Signal. 15, 355-366 (2003)

  15. Role of phosphorylation in transcriptional activation of ER (Kato et al, Science 1995; Bunone et al, EMBO J. 1996) The transcriptional activity of ER can be induced by growth factors (EGF, IGF) through the Ras-Raf-MAPK pathway. hER is phosphorylated by mitogen-activated protein kinase (MAPK) at Serine 118 located in AF-1. Phosphorylation of Ser118 results in stimulation of AF-1 of ER resulting in ligand-independent activation of ER.

  16. Phosphorylation of non-steroid nuclear receptors Rochette-Egly Cell Signal. 15, 355-366 (2003)

  17. Phosphorylation of RARa and RARg is required for differentiation of F9 cells into distinct cell types (Taneja et al, EMBO J. 1997) AF-1 of RARa1 and RARg2 are phosphorylated by proline directed kinases Phosphorylation of AF-1 in RARg2 is required for RA-induced differentiation into primitive endoderm, whereas phosphorylation of AF-1 in RARa1 is required for differentiation into parietal endoderm. AF-2 of RARa1 and RARg2 are phosphorylated by PKA Phosphorylation of AF-2 in RARa1, but not in RARg2, is required for differentiation into parietal endodermal cells.

  18. Ligand-independent activation of ER by Cyclin D1 (Zwijsen et al, Cell 1997; Genes & Dev. 1998). The transcriptional activity of ER is modulated in a ligand-independent manner by cyclin D1. Cyclin D1 directly interacts with, and activates ERa in a CDK- independent manner. Cyclin D1 also interacts with the co-activator SRC1 in a ligand-independent manner. By acting as a bridge between ERa and SRC1, cyclin D1 recruits SRC1 to ERa in the absence of ligand.

  19. The clinical use of retinoids in cancer therapies and chemoprevention • Trade name Retinoid Activity Some Therapeutic applications • Tretinoin ATRA Pan-RAR Promyelocytic leukemia, • Leukoplakia (prevention), Actinic keratosis (prevention) • Alitretinoin, 9-cis retinoic acid Pan-RAR Kaposi's sarcoma • Panretin Pan-RXR Breast cancer • Isotretinoin 13-cis retinoic acid Pan-RAR Oral leukoplakia, Skin cancer, Head and neck cancer (in combination with IFN), Neuroblastoma • Bexarotene LDG1069 RXR Cutaneous T-cell lymphoma (stage IA- IB, IIA), NSCLC • Fenretidine 4- HPR RAR Breast cancer • 4-hydroxy Leukoplakia • -phenylretinamide Ovarian cancer • Acyclic retinoid polyprenoic acid RAR, RXR, Hepatocellular carcinoma (prevention) • PPAR activities • Abbreviations: ATRA, all trans retinoic acid4-HRP, 4-hydroxy-phenylretinamide; APL, promyelocytic leukemia; IFN, interferon; PPAR, peroxisome proliferator activated receptor; RAR, retinoic acid receptor; RXR, retinoid X receptor. (Adapted from:Altucci and Gronemeyer, Nat. Rev Cancer, 2001 1:181)

  20. Lin et al (1999) Trends in Genetics 15:179

  21. Schematic representation of PML and PML-RARa fusion proteins Altucci et al (2004) The International Journal of Bicochem & Cell Biol 36:178

  22. Molecular basis of RA response in PML-RARa and PLZF-RARa APL cells Altucci et al (2004) The International Journal of Biochem & Cell Biol 36:178

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