lecture10a Flashcards
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Response elements
DNA sequences bound by complex of steroid bound to its receptor/ part of promoter of gene
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GRE
glucocorticoid response element
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ERE
estrogen response element
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VDRE
vitamin D response element
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TRE
thyroid hormone response element
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RARE
retinoic acid response element
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GRE sequence
top 5’AGAACA(N)3 TGTTCT 3’ bottom 3’TCTTTGT(N)3 ACAAGA5’
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ERE sequence
top 5’AGGTCA(N)3 TGACCT 3’ bottom 3’TCCAGT(N)3 ACTGGA5’
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VDRE sequence
top 5’AGGTCA(N)3 AGGTCA3’ bottom 3’TCAAGT(N)3 TCCAGT5’
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TRE sequence
top 5’AGGTCA(N)4 AGGTCA3’ bottom 3’TCCAGT(N)4 TCCAGT5’
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RARE
top 5’AGGTCA(N)5 AGGTCA3’ bottom 3’TCCAGT(N)5 TCCAGT5’
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T3 ligand independent repression
if no T3; CoR binds to RXR/THR heterodimer bound to positive TRE and represses gene expression
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T3 ligand dependent transactivation
if T3 binds; RXR/THR binds CoA and activates gene expression
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where is T4 converted to T3
liver and thyroid
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what coverts T4 to T3 in liver
D1
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what inactivates T3
D3; and turns it into rT3 and T2
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what happens to T4 once it enters cell
it gets converted to T3 by D2
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What happens to T3 once in cell
it translocates into nucleus; binds to RXR/TR heterodimer bound to TRE and activates gene expression with bound activator
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What corepressors compete to bind with heterodimer?
NCor1; RAR; PPAR; VDR
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What coactivators compete to bind with heterodimer
P160/SRCS and TRAP 220; nuclear receptors AR; ER; RAR; GR; VAR; PPAR
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Does TR form dimer with RR?
yes
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What does TR bind to?
TRE located on promoter of T3 target genes
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If there is no T3; what does TR bind to?
TRE. Represses basal transcription.
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How do corepressors work?
bind to TR and limit access to transcriptional machinery
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What does T3 binding trigger
dynamic exchange of co-repressors for coactivators on TRs
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How do coactivators work
they render chromatin more accessible for transcription
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physiological effects of thyroid hormone
- TH viewed as tissue growth factors 2.promotes normal fetal and childhood growth and CNS development 3. normal whole body growth does not occur in absence of thyroid hormones even in presence of adequate GH levels 4. TH enhances GH production by increasing transcpriton of GH gene in pituitary 5. TH exerts effects on thermogenesis and temperature regulation 6. affects most aspects of carb and lipid metabolism (in part by elevating levels of hormone receptors such as epi receptor)
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structure of long bone
epiphysis; metaphysis; diaphysis; metaphysis; epiphysis
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ossification center
where cartilage cells arrange themselves in a row
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TH receptors in reserve zone
TRalpha1/alpha2/Beta1
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TH receptors in proliferative zone
TRalpha1/alpha2/Beta1
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TH receptors in prehypertrophic zone
TRalpha1/alpha2/Beta1
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TH receptors in hypertrophic zone
none
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TH receptors in primary spongiosum
TRalpha1/alpha2/Beta1
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TR in embryogenesis of frog development
TH response genes expressed at basal level. No TR and TH. Facilitate embryonic organ development.
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TR in frog development after tadpole hatches
TR expression increases. Highe levels when tadpole feeding begins. RXR highly expressed. TR/RXR bind to TH response genes and repress them. Ensure proper tadpole growth and prevent premature metamorphosis. Endo TH levels rise and TH bound TR/RXR then activates TH response genes
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metabolic processes modulated by TH
basal metabolic rate; adaptive thermogenesis; body weight regulation; cholesterol synthesis and efflux; fatty acid synthesis and oxidation; bile acid synthesis; glucose metabolism
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TH and basal metabolic rate
- stimulated by T3; metabolic processes 2. T3 ligand stimulates it 3. downregulates Na+K+ATPase; SERCA-1; UCPs; UPL 4. interacts with adrenergic pathway
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TH and adaptive thermogenesis
- stim. By cold exposure; food ingestion 2. T3 ligand stimulates 3. downreg. UCP1 and PEPCK 4. adrenergic; bile acids; gluconeogenesis
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TH and body weight regulation
- stimuted by nutrient intake 2. T3 ligand integrates balance with nutrient intake signal 3. downreg. TRH; TSH; spot 14(thrsp); D2 4. TRH; leptin; adrenergic; CART; neuropeptide Y; D2
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TH and cholesterol synthesis and efflux
- stim. By chol levels 2. T3 ligand; up reg chol synthesis and efflux 3. downreg LOL-R and ABCA1 4. in sterol signaling; PPARalpha; LXR
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TH and fatty acid synthesis and oxidation
- fat intake; storage; long-chair fatty acids 2. T3 ligand; promotes lypolysis and Beta oxidation 3. downreg GPTig 4. in PPARalpha; adrenergic; LXR
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TH and bile acid synthesis
- stim by fat intake 2. T3 ligand decrease synthesis 3. downreg CYPTA1 4. in TGRS; D2; FXR; PPARalpha
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TH and glucose metabolism
- stim by carb intake; serum glucose/insulin 2. T3 ligand; upreg gluconeogenesis; impairs insulin secretion 3. downreg ACCl; GLUTH; ChREPB 4. in glucose; insulin; PPARalpha; LXR; SREBD; RXR
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which TH is more powerful in rats with no thyroid
T3
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how do T3; T4 and TSH react to depletion of dietary iodine
T3 and T4 go down; TSH rises
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what does iodine or TH deficiency in perinatal period cause
severe mental and physical retardatation; defness; paralysis; known as cretinism
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sporadic cretinism
result of athyrotic fetus developing in normal mother
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how does iodine deficiency affect the world
intellectual ability of millions of infants worldwide is affected
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clinical signs of hypothyroidism
- weight gain; coarse skin; hoarse voice; 2. feels cold; lethargic and depressd 3. changed tendon reflexes; muscles contract normally but relax slowly; generalized muscle weakness 3. reduced cardiac output 4. menstrual irregularities
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causes of hypothyroidism
- iodine deficiency 2. mutation in gene encoding TSH component or in THR or in pendrin gene or other iodine transporter gene 3. selenium deficiency 4. thyroid gland malignancy 5. hashimoto’s thyroiditis
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how do low TH levels affect body
delay proper growth and bone maturation; low thyroxin; rise in TSH; short stature; delayed skeletal maturation (autoimmune thyroiditis)
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clinical signs of hyperthyroidism
- weight loss; sweating; tremors; goitre 2. agitated and nervous; easy fatigability; heat intolerance 3. tachycardia and atrial fibrillation 4. muscle weakness and loss of muscle mass 5. diarrhea; shortness of breath; infertility; amenorrhea; rapid growth rate and accelerated bone maturation in children
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signs of GRAVES disease
optical issues like upperlid retraction; stare…; pretibial myxoedema (thickening of skin); others - vitiligo; clubbing of fingers; premature greying of the hair
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causes of hyperthyroidism
elevated TSH secretion due to a tumor. 2. Grave’s disease (TSH receptor activating antibodies) 3. Thyroid adenoma (with TSH receptor mutation showing constitutive activation) 4. excess dietary or medication-related iodine ingestion
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what causes GRAVES disease
unregulated synthesis and secretion of T3 and T4
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how does GRAVES disease show up on lab tests
elevated T4 in serum; increased uptake of radioiodine; TSH suppressed in serum; palpitation and tachycardia; exopthalmos due to enlargement of retroorbital tissues; increase of appetite but weight loss
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antithyroid drugs
propylthiouracil or methyl mercaptoimidazole/ block iodination of thyroglobulin by antagonizing thyroid peroxidase; less T3 and T4
