Lecture 6: Nuclear Receptors, Vitamin D, and Cancer

multicellular, plants and fungi, steroid hormones, lipids, small lipophilic molecules, inflammation, osmolarity, development, detoxification, cholesterol homeostasis

Nuclear receptors are found in all _____ but are absent in _____— they bind ____, ___, and ____ and are critical regulators of ____, ___, ___, ___, and ___

directly, DNA, DNA binding domains, fast, simple

Nuclear receptors activate genes ____ by binding ____ using ____, meaning they work ____ and the pathway is ____

isoform specific, NLS, weak, transactivation and NLS sequences, strong

Nuclear receptor transactivation domains are _____, the DNA binding domain contains ____ and has ____ dimerization activity, and the ligand binding domain contains ____ and has ____ dimerization activity

Group I Nuclear Receptors

Reside as homodimers in the cytoplasm when unbound by a ligand due to a cytoplasmic retention protein which is removed once a ligand is bound

Group II Nuclear Receptors

Reside in the nucleus and are bound to DNA even when unbound by a ligand

cholesterol, cytochrome P450 reactions, testes/ovaries, adrenal cortex, Cholesterol, androgens, testosterone, dihydro-testosterone, aromatase (cytochrome P450), liver, ovaries, estrogens, beta-estradiol, estrone, estriol

Sex hormones are derived from ____ by a series of _____ in the ____ and _____. ____ is turned into ____ (_____, _____) which can then be converted by _____ in the ____ and ____ into _____ (____, ____, ____)

partial or complete loss of androgen receptor function, X chromosome

Androgen Insensitivity Syndrome is characterised by ______; the gene for androgen receptor gene resides on _____

Agonist

Binds to an inactive receptor to displace the co-repressor and recruit a co-activator for transcriptional activation

Antagonist

Displaces agonists and co-activators but does not recruit co-repressors

Inverse Agonist

Binds to receptors which are active without the presence of the ligand (but must be bound by a co-activator); ligand binds and displaces co-activator

active, basal, basal or repressed

Agonists result in _____ transcription, antagonists result in ____ transcription, and inverse agonists result in _____ transcription

Beta-estradiol, estrone, estriol

_____ is dominant in pre-menopausal women, _____ in post-menopausal women, and _____ in pregnant women

Adrenal steroids

______ are often used to produce sex steroids

pollutants, prescription drugs, pesticides, and plant toxins

Xenobiotics include…

Detox Phase I

Modification of the molecule being dealt with by cytochrome P450 in order to make the molecule more water soluble

Detox Phase II

Conjugation where a new molecule (e.g. glutathione) is being added to the molecule being dealt with

Detox Phase III

Transport and excretion of the molecule being dealt with

Hyperforin

Molecule that naturally occurs in St. John’s wort which can be used as a mood booster in non-depressed patients but is widely used to treat depression; has lots of negative drug-drug interactions

PXR, xenobiotic sensor, enzymes that degrade toxins

Hyperforin directly activates _____— this is a problem because the receptor is a major ______ causing the production of _____

CYP3A4

Cytochrome P450 enzyme that is responsible for metabolizing 50-60% of all prescription drugs

Vitamin D

A steroid pro-hormone that, when metabolised, becomes a ligand for VDR

rickets in children and osteomalacia in adults due to reduced absorption of calcium

Consequences of severe vitamin D3 deficiency include:

malnutrition, pigmented skin, living in the northern hemisphere, obesity, and advanced age

Risk factors for vitamin D3 deficiency include:

7-dehydrocholesterol, CYP27A1, 25(OH)D3, 25(OH)D3, CYP27B1, calcitriol, calcitriol, VDR, calcitriol, growth arrest, apoptosis, differentiation, anti-inflammation

_____ in the skin is converted to vitamin D3 by sunlight, which is converted by ____ in the liver to ____ in the circulation. ____ can be converted by ____ in the kidneys to ___ or it can be directly converted to ____. ____ and ____ are then used in pathways for ___, ____, ____, and ____

80

Sunlight is ___% of the vitamin D3 source

colon cancer, anti-cancer pathways, calcitriol

Vitamin D supplementation prevents _____ in mice— _____ are regulated by vitamin D3 (in the form of ____)

arresting cells in G0/G1, macrophage, angiogenesis, cell adhesion, migration, invasiveness, VDR, CYP27B1, better overall survival

Calcitriol slows down cancer cell growth by _____; HL60 leukemia cells differentiate towards the _____ lineage upon incubation with calcitriol; calcitriol influences _____, alters ____ and ____, and reduces ____ of cancer cells; the presence of ___ in tumour cells is a pre-requisite for anti-cancer affects of calcitriol; in lung cancer high expression of ____ is associated with ____

Litocholic Acid

Low affinity ligand of VDR that is a secondary bile acid derived from chenodeoxycholic acid (which is derived from cholesterol)

dehydroxylated by bacteria, conjugated, conjugated bile acids, emulsify fats for intestinal absorption

Primary bile acids are _____ in the gut to create secondary bile acids which are then _____ in the liver to create _____. Bile acids function to…

lithocholic acid, vitamin D, activate, CYP3A11, lithocholic acid

____ is a low affinity VDR ligand while ____ is high affinity— they both ____ VDR which activates ____ (which has a negative feedback by inhibiting ____)

Fast Twitch Muscle

Muscle that uses anaerobic metabolism for fuel and provides short bursts of speed; fires rapidly, fatigues quickly

Slow Twitch Muscles

Muscle that uses oxygen for fuel and provides continuous energy; fires slowly, has high endurance

AMPK

AMP-activated protein kinase

PGC1a

Peroxisome proliferator-activated receptor gamma co-activator-1 alpha

PPARdelta

Peroxisome proliferator-activated receptor delta

Type I Fibres

Skeletal muscle fibres part of slow twitch muscles that are mitochondria-rich and mainly use oxidative metabolism for energy production and are fatigue-resistant

Type II Fibres

Skeletal muscle fibres part of fast twitch muscles that are sub-divided into 3 subtypes; rely on glycolytic metabolism as a major energy source and are susceptible to fatigue

IIb

Type ___ fibres have the lowest levels of mitochondrial content and oxidative enzymes

PPARdelta, GW1516, 70, AICAR, AMPK, PGC1a

____ is normally highly expressed in skeletal muscles; its natural ligand is not known, but ____ (synthetic agonist) in marathon mice led to ___% increased performance and ____ (indirect activator via ___ and ___) also affects its activity

Marathon Mouse

Transgenic mice containing VP16-PPARdelta fused receptors in their skeletal muscle, resulting in increased oxidative type I fibres

catabolic processes, glucose metabolism, autophagy, lipid oxidation, anabolic processes, lipid synthesis, gluconeogenesis and glycogen storage, protein synthesis

AMPK stimulates _____ that lead to ____, ____, and ____ but inhibits _____ that lead to ____, ____, and ____

ATP, AMP, AMPK, PGC1a

Exercise burns ___ to ____ which stimulates ____ which stimulates ____ which stimulates increased muscle performance

AMPK, fatty acids, AMPK

Exercise and fasting leads to increases in ____ and ____; AICAR stimulates increases in ____

PPARbeta/delta fatty acid catabolism, NRFs mitochondrial functions, and MEF2 oxidative fibre type switch

PGC1a stimulates…

1/3

Removing ovaries from women with breast cancer stops tumour growth in ___ patients

Tamoxifen

Drug that competes with estrogen— acts as an anti-estrogen and prevents correct estrogen receptor folding required for co-activator recruitment