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CS II (17/10) (Rec Activation (Inactive recs bind to inh pros
~ stop dna…
CS II (17/10)
Rec Activation
- Inactive recs bind to inh pros
~ stop dna binding domain + dna
~ = x induce transcription
eg ER (estrogen?) + heat shock pros (hsp90)
- Lig binding induce conformational change,
release inh pro,
bind a co-activator pro to
induce gene transcription (bc can bind to dna)
eg co-repressores eg tamoxifen
Recs can be locatied:
- 1: cytosol (eg estrogen rec)
~ Transported to nucleus after lig is bound
- 2: nucleus (eg thyroid, retinoid recs)
Steps
- 1: Hm + serum binding pros → target T,
Diffuse across p. memb + specific rec pro in nucl
- 2: hm binding change rec conformation,
Forms homo/heterodimers w other hm-rec complexes,
Binds specific regulatory regions ("hm response els" - HRES) in DNA adj to specific genes
- 3: Rec attracts coactivator/corepressor pro(s)
& win them, regulate transcriptn of adj gene(s),
in/decrease rate of mRNA 🐝
- 4: Altered levels of the hm-regulated gene
; cellular response to the hm
:pencil2:
- cytosolic: oestrogen
- nucleus: thryoid, retinoid
~ diffuse across p. memb then n. memb too
:pencil2: - hm + rec:
~ change confor, lose inh pros
~ -> nucl ; resp (altered gene transcription)
~ on dna (recruit dna polym),
mRNA translated into pros
N. Rec Response Elements
(hm) Response els
- The (particular) nt binding seq that interact w N. Recs
- Lie adj to genes that the hm/lig regulate /affect/stimulate
- Consist of 6 base pair repeat seqs (qqf inverted /tandems) separated by 3-5 b-ps
- Despite similarity, ilya specificity in binding
~ only gluco bind to rec response els
:pencil2: Compare diff N. rec fams eg gluco, es, vit d:
In the Nucleus
- Binding of rec is to SPECIFIC SEQS in dna
→ Transcription
- SPECIFIC mrna is ;ed
→ Translation
- SPECIFIC pro is ;ed
SPECIFICITY in
- 1: Hm binding its specific rec
- 2: Hm-rec complex binding specific regions of DNA,
ultimately leading to up-regulation of specific pros
(change in gene transcription of certain pros)
- "What's the basis 4 this specificity to increase production of only certain pros?"
Steroid Hormones
Mode of Action - GENE PROMOTERS
- 1: Transcription req the enz RNA Polymerase
- 2: Steroid hm recs therefore must be influencing
RNA Polymerase
(pic) Red checkered - Response Element
- Binds the rec/hm complex, allows steroid hm to
INCREASE gene transcription
(pic) :pencil2:
- Transcriptional start site: +1
- Generalised transcription machinery + TATA box
- General TFs + RNA Polymerases
- Promoter region els: 5' of Transcriptional start site
~ These bind specific TFs, regulate transcription
(pic) :pencil2: 2
- the particular Nuclear rec fam we just talked abt work as TFs
~ lig + rec complex is a TF
~ translocate in nucleus,
~ recog specific response els in promoters of specific genes,
~ bind to that region,
~ induce transcription
- Ability of cell/gene to be influenced by hm require:
~ Target cell that has rec
~ Particular genes that have response els in promoters
(if not, that hm TF x bind rec, x induce transcription)
Signalling of Nuclear Recs - Direct
- Hm + Nuclear rec -> "Direct" Signal transduction
- No other intermediates involved
- Rec is the TF
- Interaction of hm + rec directly induce gene transcription
- Less opportunity 4 regulation by other factors & pathways
(more molcs, more steps to be regulated)
- Limited amplification of signal
-
-
Summary: Signalling of Nuclear Recs
- Lipophilic / hydrophobic molcs can cross c. memb
- Upon lig binding, cytosolic recs translocate to nucleus
- In nucl, recs initiate transcription
- Nuclear rec family contain a common domain structure:
variable region DBD & LBD
- Recs are activated by conformational changes induced thru hm binding
(that release inh pros, allow bind to dna)
- Recs bind to specific response els to induce transcription of target genes