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

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

✏

  • cytosolic: oestrogen
  • nucleus: thryoid, retinoid
    ~ diffuse across p. memb then n. memb too

✏ - hm + rec:
~ change confor, lose inh pros
~ -> nucl ; resp (altered gene transcription)
~ on dna (recruit dna polym),
mRNA translated into pros


✏ Compare diff N. rec fams eg gluco, es, vit d:

  • response els ~similar

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) ✏

  • 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

click to edit

(pic) ✏ 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

✏ Direct bc hm AND rec ; effect
-> TF that induce transcription