Vets 111/Biov 111 – Cell Signalling-4

Signal transduction by nuclear receptors

Steroid hormones are lipid-soluble i.e. incontrast to polypeptide and other hormonesthey will easily pass through target cellplasma membranes.

They bind and activate receptor moleculeswithin target cells. The receptor moleculesare all transcription factors that regulategene expression directly. Consequently,responses to steroid hormones often involvecell growth and/or differentiation.

That different classes of steroid moleculeexert such distinct physiological effects isdue to small structural differences thatallow interactions with distinct receptormolecules (transcription factors).

Androgens (e.g. testosterone),synthesised in the testes, areresponsible for the developmentof male secondary sexcharacteristics.

Estrogens, synthesized in theovaries, are required for thedevelopment of femalesecondary sex characteristics.

Estrogens, along withprogesterone, also participate inthe ovarian cycle.

Glucocorticoids (e.g. cortisol) stimulate gluconeogenesis andenhance the breakdown of fat and protein and inhibit theinflammatory response – they enable animals to respond to stress.

Mineralocorticoids (e.g. aldosterone) act on the kidneys to stimulatesodium re-uptake – which leads to an increase in blood pressure.

These hormones are synthesised in the adrenal cortex.

Steroid and thyroid hormones act directly to regulate geneexpression at the level of transcription.

Examples -

Metallothioneins (bind heavy metals and decrease their toxicity)– induced by glucocorticoids.Pro-opiomelanocortin, the precursor of adrenocorticotrophin(ACTH) repressed by glucocorticoids. The main role of ACTH is tostimulate synthesis of glucocorticoids in adrenal cortex, so this isan important feedback mechanism.Ovalbumin, conalbumin and ovomucoids, the major proteins ofegg white induced by progesterone in the oviduct of birds.Vitellogenins, the major proteins of egg yolk induced byestrogens in the livers of birds.Fatty acid synthase and malic enzyme induced by thyroidhormone in the liver.Thyrotropin repressed by thyroid hormone – thyrotropinstimulates thyroid hormone release so this is another feedbackmechanism.

Estrogen action

When inside a cell, estrogens bind to highly specific, solublereceptor proteins.

Estrogen receptors are members of a large family of proteins (thenuclear hormone receptors) that act as receptors for a wide rangeof hydrophobic molecules, including other steroid hormones, thyroidhormones and retinoids.

On binding estrogen, the steroid/receptor complex modifies theexpression of particular genes by binding to specific controlelements in promoter DNA.

Estrogen receptors bind to specific DNA sites – estrogen responseelements or EREs that contain the consensus sequence:

5’-AGGTCANNNTGACCT-3’

This sequence is symmetrical; consequently, the receptors bind asdimers.

Estrogen binding to the receptor leads to a substantial structuralrearrangement in the protein.

Hormone binding does not greatly alter the ability of the receptorto bind DNA.

Co-activator proteins bind to the receptor - but only in thepresence of the hormone. The resulting transcription complexstimulates gene expression.

Co-activator Recruitment

Steroid hormone receptors as targets for drugs

Athletes sometimes take natural andsynthetic agonists (‘anabolic steroids’ e.g.nandrolone) of the androgen receptor – theandrogen receptor stimulates the expressionof genes that enhance the development ofmuscle mass.

In men, excessive use leads to a decreasein the secretion of testosterone which mayin turn lead to testicular atrophy or breastenlargement.

In women, excess testosterone causes adecrease in ovulation and estrogen secretion,breast regression and growth of facial hair.

Nandrolone

Positive drug (nandrolone) tests have been blamed on eatingspaghetti bolognese which contained beef from cattle that hadbeen fed steroids.

Some important drugs areantagonists of the estrogenreceptor.

Tamoxifen is used in thetreatment (and prevention) ofbreast cancer, because somebreast tumours rely on estrogen-mediated pathways for growth.

These antagonists block thebinding of co-activators to thereceptor and therefore inhibitactivation of gene expression.

Tamoxifen

Veterinary uses of corticosteroids

Commonly used veterinary steroids include the corticosteroids – drugs thatmimic the action of cortisol. These include hydrocortisone, dexamethasone andtriamcinolone.

Long-term treatment is not without problems - suppression of the immunesystem may lead to the animal being prone to infection. Even short-term usageis associated with problems – the drugs should be discontinued in a taperingfashion in order to prevent problems associated with steroid-dependentsuppression of the adrenal gland (i.e. suppression of endogenous cortisolsecretion).

Aspirin is extremely toxic to cats therefore steroids are used as anti-inflammatory drugs. They are used to treat allergic and asthmatic conditions(e.g. flea bite allergy) and long-term therapy is used for seriously ill cats (e.g.malignant cancers).

Veterinary use of anabolic steroids

Anabolic steroids can be used for food animals(cattle) as growth implants (as pellets orimplanted silicone under the skin of the ear) thatincrease muscle mass, feed conversion efficiencyand ‘carcass quality’.

The eating quality of beef from implanted anduntreated cattle is apparently similar andresidues in the meat are extremely low. (The earsare discarded after slaughter – so there is nodanger of accidental human consumption of awhole implant).

These growth promoting implants are banned inthe EU – the ban extends to imported beef fromimplanted cattle. A number of these implants arestill approved for use in the US and many othercountries, including Australia, Canada and NewZealand.

Summary

Steroid hormones are lipid-soluble and freely pass through theplasma membrane into the cell.

When inside a cell, steroid hormones bind to highly specific,soluble receptor proteins.

The steroid/receptor protein complex modifies the expressionof particular genes by binding to specific control elements inpromoter DNA.

Some important (anti-cancer) drugs are antagonists of theestrogen receptor.

Both corticosteroids and anabolic steroids have verterinaryuses.