Block3 3.nuclear Receptor Signaling

Front 1

Nuclear Receptors and Ligands

Back 1

Can pass right thru plasma membrane and bind the receptors within the cell.
EstrogenR
ProgesteroneR
GlucocorticoidR
ThroxineR
Retinoic AcidR
NOTE: the receptors themselves are the TF's! They all have variable region, DNA binding region, and a ligand-binding domain

Front 2

DNA Consensus Elements

Back 2

Know there are different consensus sequences and that some of these have inverted repeats and others have direct repeats

Front 3

Type I Nuclear Receptor Signaling

Back 3

In the absence of the ligand the receptor is actually kind of closed. An inhibitor (Heat Shock protein) binds these at ligand-binding domain and keeps them in restricted form. The ligand has higher affinity for the receptor, it will displace inhibitor. Receptor changes conformation, it opens up sort of. Translocates into nucleus and forms homodimer, and then binds DNA.

Front 4

Type II Nuclear Receptor Signaling

Back 4

Already inside the nucleus. Type II nuclear receptor bound in a heterodimer already on DNA consensus sequence
. There are repressor molecules on it normally. RXR helps binds DNA and also binds other stuff. Retinoids, Vit D, Thyroid hormone go in and bind, activating transcription by causing exchange of a repressor for a coactivator.

Front 5

Type I vs. Type II

Back 5

Type I:
-Steroid-based (estrogens, androgens, mineralocorticoids, glucocorticoids).
-(-) Ligand, receptor exists in cytosol associated with Heat Shock Proteins.
-(+) Ligand, loss of HSP and inhibition, nuclear translocation, DNA binding and recruitment of coactivators → euchromatin and transcription.
-Receptors bind as homodimers to INVERTED repeat responsive elements.

Type II
-Vitamin D, Retinoic Acid, Thyroid, Orphans
-(-) Ligand, receptor bound to DNA, associated with corepressors → suppresses transcription.
-(+) Ligand, loss of corepressors, recruitment of coactivators → euchromatin and transcription.
-Receptors bind as heterodimers with RXR to DIRECT repeat responsive elements.

Front 6

CLINICAL: Tamoxifen Treatment in ER (+) Breast Cancer

Back 6

Estrogen receptor positive breast cancer. Proliferation is controlled by estrogen receptor and can be stopped by Tamoxifen. Does not work in estrogen R negative breast cancer. Different tissues will have different responses, you increase the risk of uterine cancer with use of tamoxifen because it actually stimulates growth in those tissues.

Front 7

CLINICAL: Advanced Prostate Cancer

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PSA is regulated by androgens coming from blood vessels, they hit Androgen receptors in the stroma and survival/growth factors are released by cells in the epithelium into the lumen
*elevated serum levels of prostate specific antigen (PSA) a good indicator of cancer.

Front 8

Androgen Ablation Therapy

Back 8

LHRH agonists (LUPRON or ZOLADEX). Injectable medication. Blocks further androgen synthesis. Get a big boost at first but it causes you to stop making it. Secondary androgen source - Adrenals: Blocked by anti-androgen drugs (FLUTAMIDE replaced by CASODEX). Oral medications. Competes for AR.

Front 9

Hormone Refractive Prostate Cancer

Back 9

The patient returns after 7 years with a dramatic increase in PSA.
•Developed hormone refractory prostate cancer.
•Metastatic disease that is very often lethal
•No effective therapy

Front 10

Mechanisms for refractive prostate cancer:
Pathway crosstalk vs. Alternative pathways

Back 10

1. Pathway cross-talk: In addition to normal nuclear receptor signaling, the nuclear receptors can also become activated by other pathways, even involving G protein coupled receptors or Receptor tyrosine kinases. This can cause ligand independent AR activation.
2. Alternative pathways. selective activation of an
alternative oncogenic pathway Mutations in an alternate
pathway can provides the
cellular effects that the ablation
therapy eliminated. For example, if survival and growth factors were eliminated by the ablation therapy,
perhaps a mutation in Her2 could hyperstimulate these survival and/or growth factors. The factors need not
come from AR signaling. As long as they are provided, that is all that counts.

Front 11

3rd way refractive cancer: receptor changes

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A third possibility is a mutation
in the Androgen Receptor. Under normal
conditions, androgens such as
testosterone (purple pentagon)
can bind to the AR and stimulate
its signaling. Flutamide is the
antagonist of testosterone used to
prevent AR signaling. However,
perhaps a mutation alters the
binding site, such that when
flutamide binds, it now provides
the structural basis for efficient
AR signaling. Perhaps a
mutation can allow other low
affinity agonists to bind and
stimulate AR signaling. Finally,
perhaps the mutation allows the
low affinity agonist to bind with
high affinity. In each case, the adrogen ablation therapy would be ineffective.

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One last one!

Back 12

Lastly, the receptor could become overexpressed, or the coactivators (Steroid Receptor Coactivator, SRC) and/or cosuppressors (Nuclear Receptor Corepressor, NCoR) could become altered in their expression levels. In either situation, the AR signaling could be more efficiently stimulated, even in the presence of the ablation therapy.