Transcription Regulation And Gene Expression in Eukaryotes FS 2016 Graduate Course G2 P. Matthias and RG Clerc Pharmazentrum Hörsaal 2 16h15-18h00 RG. Clerc April 27. 2016 NUCLEAR HORMOME RECEPTORS • The nuclear receptor atlas • Structural and functional key features • Gene repertoire regulation in health and disease
60
Embed
Transcription Regulation And Gene Expression in …...2016/04/27 · Transcription Regulation And Gene Expression in Eukaryotes FS 2016 Graduate Course G2 P. Matthias and RG Clerc
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Transcription Regulation AndGene Expression in Eukaryotes
FS 2016 Graduate Course G2
P. Matthias and RG ClercPharmazentrum Hörsaal 2 16h15-18h00
RG. Clerc April 27. 2016
NUCLEAR HORMOME RECEPTORS
• The nuclear receptor atlas• Structural and functional key features• Gene repertoire regulation in health
and disease
The family of nuclear hormone receptors
Type I Type II Type III/orphanMembers Glucocorticoid receptor
Steroid Signaling Discovery Timeline : 100 years on
1902-1905 - Starling refers to bioactive chemicals extracted from glands as „hormones“1915 - Kendall crystallizes thyroid hormone1925 - Kendall and Reichstein complete structural analysis of cortisol from adrenal cortex1946 – Selye coins the term glucocorticoid, needed for survival and response to stress1949 – Hench administers cortisone to arthiritic patients with dramatic effects1950 – Kendall, Hench and Reichstein get the Nobel Prize1950-1985 – Classical model of steroid hormone action 1986 – today - Receptor identification : „reverse endocrinology“ RAR, RXR ..
Nuclear Receptors Discovery Timeline : What’s My Ligand ?
Evans RM and Mangelsdorf DJ (2014). Cell 157:255
Nuclear Receptors and Small Lipophilic Ligands
RXR
The adrenal cortex is responsible for production of 3 major classes of steroid hormones: glucocorticoids, which regulate carbohydrate metabolism; mineralocorticoids, which regulate the body levels of sodium and potassium; and androgens, whose actions are similar to that of
Uterus Increased stimulation of uterine lining and muscle
Heavier cycles, increased risk of uterine cancer
No periods
Vagina Increased thickening of skin, better blood supply to tissue
Vaginal discharge, feelings of pelvic congestion
Dryness, vaginal infections, painful sex, incontinence of urine, pelvic weakness
Molecular Action of Estradiol
Adapted from Howell A, Osborne CK, Morris C, Wakeling AE. ICI 182, 780 . Cancer 2000; 89: 819.
Selective Estrogen Receptor Modulators
Estrogens
Anti Estrogens
SERMs
SERMs- designed to act in specific ways at each of the estrogen receptor sites in different tissues
ERDR
Phytoestrogens
Selective Estrogen Receptor Modulator
The ideal SERM is one that prevents bone loss, has no risk of uterine or breast cancer, no adversed effect on lipids & cardiovascular system, relieves PMS and maintains cognitive function of the brain
Adapted from Howell A, Osborne CK, Morris C, Wakeling AE. ICI 182, 780. Cancer 2000; 89: 819.
Molecular Action of Tamoxifen (SERM)About 1 in 8 women (about 12%) will develop invasive breast cancer over the course of her lifetimeIn 2016, an estimated 246,660 new cases of invasive breast cancer are expected to be diagnosed
Only patients that express nuclear receptor (ER-positive tumors) benefit from Tamoxifen. Other breast cancers are either ER-negative HER2 positive and so-called triple negative
Molecular Bases for Agonism vs, Antagonism: ERα
Co-regulator box LXXLLDES : diethylstilbestrol TAM : tamoxifen
Adapted from Howell A, Osborne CK, Morris C, Wakeling AE. ICI 182, 780 (Faslodex®), development of a novel, "pure" antiestrogen. Cancer2000; 89: 819.
Molecular Action of Tamoxifen (SERM) as a prodrugKaplan Meier - metabolizer status
Goetz et al. 2008. Clin Pharm Ther 83:160
Regulation of ERBB2 by ER-PAX2 determinesTamoxifen response (Hurtado et al. (2008 )Nature 456:663-667)
Regulation of ERBB2 by ER-PAX2 determinesTamoxifen response (Hurtado et al. (2008 )Nature 456:663-667)
Regulation of ERBB2 by ER-PAX2 determinesTamoxifen response
Deteriorated
Impaired
Impaired
Lipid profile
Insulin sensitivityInsulinemiaGlycemia
Susceptibilityto thrombosis
Inflammationmarkers
Endothelialfunction
CHD Risk LowHigh
AbdominallyobeseHigh waist
Improved
Improved
Improved
Improved
Improved
ReducedobeseLow waist
Visceraladiposetissue
Visceraladiposetissue
Subcutaneous ATSubcutaneous AT
DietPhysical activity
10% Weight loss~ 30 % Visceral AT loss
Clinical Endpoint: Metabolic Syndrome
Adapted from Després et al. BMJ (2001) 322:716-720
Defective insulin secretion
Increased glucose output
Decreased glucose disposal
Insulin resistance
HYPERGLYCEMIA
Adipose tissue
Dyslipidemia
Obesity
Metabolic Syndrome and Tissue-Tissue Cross Talk
Integrated Physiology by PPAR Isoforms
−β
Originally Discovered as PeroxysomeProliferator-Activated Receptor (PPARs)
W.Wahli et al. (1992) Cell 68: 879-887
catabolism of long chain FA, reduction of ROS, etc
NHR are the final effectors of a complex cytoplasmic/nuclear transduction cascade
PPARγ2 adipose - elevated in obese subjectsvery low in muscle & liver
PPARγ3 macrophage, adipose, colon epithelium
28 aa N-terminal addition in PPARγ2increases ligand-independent activation 5X
hPPARγ Isoforms
Association of PPARγ polymorphisms with the metabolic syndrome ?
Haplotype analysis of the PPARgamma Pro12Ala and C1431T variants reveals opposing associations with BMIDoney et al. 2002. BMC Genetics 3:1-8.
Association of PPARγ polymorphisms with the metabolic syndrome ?
Is the Ala12 variant of the PPARgamma gene an „unthrifty“ allele ?
(subject to negative selection during human evolution)
Ruiz-Narvaez et al. 2005. J. Med Genet 42:547
The Ala allele was originally associated with a protective effet against type 2 diabetes.
Increased weight and body mass index, which themselves predispose to type 2 diabetes have however been inconsistently associated with the Pro12Ala polymorphism
studies indicate that the Ala allele is associated with a higher BMI, or a lower BMI or no change at all !
See Doney et al. 2002. BMC Genetics 3:1-8.
Association of PPARγ polymorphisms with the metabolic syndrome ?
The Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity.Proline to Alanine substitution at codon 12 of PPARgamma2The codon Ala confers reduced activity compared to the Pro isoform