Samuels Mol Pharm 11 03

Slide1: 

A/B C D E/F Nuclear Hormone Receptor Superfamily Steroid family Non-steroid family ER a, b GR TR a, b RAR a, b, g PPAR a, g, d VDR RXR a, b, g PR AR DBD Type I family Type II family Helix 12 AF1 LBD - AF2 CAR, SXR/PXR MR LXR a, b, FXR

Diverse Structure of Ligands for Nuclear Receptors : 

Diverse Structure of Ligands for Nuclear Receptors

PPAR Ligands : 

PPAR Ligands

Slide4: 

Receptor Disease or Target ER PR Breast Cancer, Infertility VDR Osteoporosis, Certain Cancers AR Prostate Cancer AR-A/B-polyQ Kennedy Syndrome TR Hyperthyroidism, Metabolic Disorders, CNS Development RAR Breast, Cervical, and Lung Cancer PML-RAR Acute Promyelocytic Leukemia RXR Diabetes, Obesity Breast, Ovarian, Lung, and Prostate Cancer PPARs Diabetes, Obesity, Lipid Metabolism, Cancer LXR, FXR Cholesterol and Bile Salt Metabolism CAR, SXR/PXR Drug and Xenobiotic Metabolism Orphan Receptors ? Nuclear Receptors in Human Disease and as Therapeutic Targets Available crystal structure of 8 receptors (AR, ER, PPAR, PR, RAR, RXR, TR, VDR) allows for the rational discovery of agonists and antagonists.

Slide5: 

A/B C D E/F Nuclear Hormone Receptor Superfamily Steroid family Non-steroid family ER a, b GR TR a, b RAR a, b, g PPAR a, g, d VDR RXR a, b, g PR AR DBD Type I family Type II family Helix 12 AF1 LBD - AF2 CAR, SXR/PXR MR LXR a, b, FXR

Thyroid Hormone Receptor Response Elements: 

Thyroid Hormone Receptor Response Elements Yen, Physiological Rev. 2001

Retinoic Acid Receptor Isoforms: 

Retinoic Acid Receptor Isoforms

Slide9: 

A/B C D E/F Nuclear Hormone Receptor Superfamily Steroid family Non-steroid family ER a, b GR TR a, b RAR a, b, g PPAR a, g, d VDR RXR a, b, g PR AR HRE GR ER DBD Type I family Type II family Helix 12 AF1 LBD - AF2 CAR, SXR/PXR MR LXR a, b, FXR GR

Slide10: 

A/B C D E/F Nuclear Hormone Receptor Superfamily Steroid family Non-steroid family ER a, b GR TR a, b RAR a, b, g PPAR a, g, d VDR RXR a, b, g PR AR HRE TR RXR DBD Type I family Type II family Helix 12 AF1 LBD - AF2 CAR, SXR/PXR MR LXR a, b, FXR

Slide15: 

A/B C D E/F Nuclear Hormone Receptor Superfamily Steroid family Non-steroid family ER a, b GR TR a, b RAR a, b, g PPAR a, g, d VDR RXR a, b, g PR AR HRE TR RXR DBD Type I family Type II family Helix 12 AF1 LBD - AF2 CAR, SXR/PXR MR LXR a, b, FXR

Repression and Activation by a Subset of NRs: 

Repression and Activation by a Subset of NRs

Regulation of Gene Expression by TR-Repression-: 

Regulation of Gene Expression by TR -Repression- Yen, Physiological Rev. 2001

Structure of the Co-Repressors NCoR and SMRT: 

Structure of the Co-Repressors NCoR and SMRT Yen, Physiological Rev. 2001

Repression and Activation by a Subset of NRs: 

Repression and Activation by a Subset of NRs

Slide20: 

Transcriptional Regulation by Nuclear Receptors Aranda, Pascual Physiological Rev. 2001 LxxLL Ligand

Ligand induces a conformational change in the LBD that repositions helix 12: 

Ligand induces a conformational change in the LBD that repositions helix 12

Slide22: 

Ligand Induces a Conformational Change in the LBD that Repositions helix 12 No Ligand Agonist

Slide23: 

NR Antagonists Alter the Position of Helix 12 No Ligand Agonist (ER) Antagonist (ER)

The LxxLL motif of the Coactivator docks to the hydrophobic cleft in the agonist bound NR LBD: 

The LxxLL motif of the Coactivator docks to the hydrophobic cleft in the agonist bound NR LBD

Slide25: 

Transcriptional Regulation by Nuclear Receptors Aranda, Pascual Physiological Rev. 2001 LxxLL Ligand

Structure of SRC-1/p160 Co-Activators and CBP/p300: 

Structure of SRC-1/p160 Co-Activators and CBP/p300 Aranda, Pascual, Physiological Rev. 2001

The SRC-1/p160 Family of Co-Activators: 

The SRC-1/p160 Family of Co-Activators Yen, Physiological Rev. 2001

Structure of SRC-1/p160 Co-Activators and CBP/p300: 

Structure of SRC-1/p160 Co-Activators and CBP/p300 Aranda, Pascual, Physiological Rev. 2001

Interaction of CBP/p300 with Transcription Factors: 

Interaction of CBP/p300 with Transcription Factors Goodman, Smolik Genes Dev. 2000

Crosstalk Among Signaling Pathways : 

Crosstalk Among Signaling Pathways

Slide31: 

Transcriptional Regulation by Nuclear Receptors Aranda, Pascual Physiological Rev. 2001 LxxLL Ligand

The TRAP/DRIP Complex: 

The TRAP/DRIP Complex Ito, Roeder Trends Endo. Metab. 2002

Slide33: 

Transcriptional Regulation by Nuclear Receptors Aranda, Pascual Physiological Rev. 2001 LxxLL Ligand

Co-Activator Recruitment by Thyroid Hormone Receptor in GH3 Cells: 

Co-Activator Recruitment by Thyroid Hormone Receptor in GH3 Cells Sharma, Fondell PNAS, 2002

Slide35: 

Transcriptional Regulation by Nuclear Receptors Aranda, Pascual Physiological Rev. 2001 LxxLL Ligand

Slide36: 

1 2063 1429 1153 AD1 AD2 849 995 LxxLL-1 LxxLL-2 Q Q/P S/T/L Regulatory region CBP p300 NIF-1 NRs NRC acts as a co-activator for: Nuclear receptors (NRs) type I and type II cFos, cJun NF-kB CREB Stat2 p53 ER LXR Modular Structure of the NRC-1 Co-Activator TRAP 150

Structure of NRC-1 and NIF-1: 

Structure of NRC-1 and NIF-1 1 2063 1429 1153 AD1 AD2 NR Box 1342 1 2 3 4 5 6 LZ 184 743 LxxLL NRC-ID D/E 1 NIF-1 NRC-1 NIF-ID 1041 1151 849 995 LxxLL-1 LxxLL-2 Regulatory domain Interacts with Rcd1, Histone H3, MLL5

Slide38: 

NRC Null MEFs undergo apoptosis

Slide39: 

NRC knockdown of wild-type MEFs leads to apoptosis Null Null

Structure of NRIF3, a TR- RXR-Specific Co-Regulator: 

Structure of NRIF3, a TR- RXR-Specific Co-Regulator RID: receptor interacting domain AD: activation domain RepD: repression domain

Slide41: 

NRIF3 Expression Leads to Apoptosis in Breast Cancer Cells GFP-NRIF3 Tunnel Assay

General Scheme for Activation of Gene Transcription by Nuclear Hormone Receptors: 

General Scheme for Activation of Gene Transcription by Nuclear Hormone Receptors Robyr, Wolffe, Wahli Mol. Endocrinol 2000