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BC3004: Cell Signalling > Intracellular Signalling Mechanisms of Steroids, Thyroxine & Retinoic Acid > Flashcards

Intracellular Signalling Mechanisms of Steroids, Thyroxine & Retinoic Acid Flashcards

1
Q

What type of molecules are Steroids and Thyroxines (thyroid hormone) and what type of receptor do they bind?

A
  • Hydrophobic
  • Bind intracellular receptors
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2
Q

What precursor are Steroids synthesised from?

A

Cholesterol

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3
Q

How is Thyroxine synthesised?

A
  • Iodination and coupling of two tyrosine molecules
  • Involves thyroglobulin
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4
Q

What is the general structure of a steroid?

A
  • based on sterol structure
  • four fused rings - three hexane rings (6 carbons) and one pentane ring (5 carbons)
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5
Q

TRUE OR FALSE:
The core structure of steroids is almost planar and is relatively rigid, and the fused rings do not allow rotation about the C-C bonds

A

True

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6
Q

How many naturally occurring steroids are there?

A

More than 200

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7
Q

How are steroids transported to target cells?

A

In the blood by carrier proteins such as albumin and globulin

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8
Q

TRUE OR FALSE:
Active hormones are stored for later use

A

False.
Little or no storage of active hormones

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9
Q

What type of regulation does synthesis of steroids and thyroxine undergo?

A

Negative feedback

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10
Q

What is the mechanism of action for steroids acting on their target cell?

A
  1. Released by carrier protein and crosses the plasma membrane
  2. Interact with receptor proteins to form a complex
  3. Complexes bind DNA sequences called response elements
  4. Steroid hormone / receptor complex functions as a transcriptional regulator up- or down-regulating gene transcription
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11
Q

Do steroids have a long or short duration of action?

A

Long duration of action
* effective from hours to days

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12
Q

Which drug is a potent synthetic analogue of the steroid Cortisol?

A

Dexamethasone

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13
Q

Which amino acid is Thyroxine based on?

A

Tyrosine

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14
Q

What are the TWO thyroid hormones?

A
  1. Thyroxine (T4)
  2. Tri-iodothyronine (T3)
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15
Q

Which hormone does the Thyroid mostly secrete?

A

T4

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16
Q

How is Thyroxine (T4) produced?

A
  • Endocytosis and intracellular proteolysis involving lysosomes
  • Involves proteolytic cleavage of the very large (2800 AA) precursor called thyroglobulin
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17
Q

TRUE OR FALSE:
Thyroxines are actively transported across the plasma membrane

A

True

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18
Q

What happens to Thyroxine (T4) when it is taken up by cells in the body?

A
  • Converted to more biologically active ‘de-iodinated’ T3 form
  • Binds the Thyroid hormone receptor and regulates transcription
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19
Q

Is reverse T3 (rT3) biologically active or inactive?

A

Biologically inactive

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20
Q

What is the blood plasma lifespan of thyroid hormones?

A

Several days
* effects last hours to days

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21
Q

What controls the production of the Thyroid hormones?

A

Under hierarchiacal control of the brain

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22
Q

What tripeptide is secreted by the hypothalamus in the production of Thyroid hormones?

A

Thyroid Releasing Hormone (TRH)

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23
Q

What is the mechanism of action of TRH?

A
  • TRH acts on the anterior pituitary causing it to produce a large glycoprotein called Thyroid Stimulating Hormone (TSH
  • TSH stimulates the thyroid gland to produce the thyroid hormones
24
Q

How is production of TSH regulated?

A

Feedback control by circulating unbound thyroid hormones

25
Q

What can abnormal release of thyroxine by the thyroid gland affect?

A

Metabolism and lead to behavioural defects

26
Q

How is OVERACTIVITY (Hyperthyroidism) of the tyroid characterised?

A
  • Increased metabolism
  • Weight loss
  • Nervous and irritable personality
27
Q

How is UNDERACTIVITY (Hypothyroidism) of the tyroid characterised?

A
  • Decreased metabolism
  • Cold intolerance
  • Tiredness
28
Q

What is Goitre?

A

Enlarged thyroid gland

29
Q

How is Goitre treated?

A

Drugs such as heparin & aspirin can increase free T4 blood concentrations

30
Q

What is the function of Thyroxine?

A

Regulates body metabolism

31
Q

What are Retinoids?

A

Hormone-like substances derived from retinoic acid (Vit. A metabolite)

32
Q

What is the function of the steroid family of hormone receptors?

A

Act as transcription factors that regulate gene transcription

33
Q

What THREE domains do steroid hormone receptors consist of?

A
  1. N-terminal domain
  2. DNA binding domain
  3. Hormone binding domain
34
Q

What are the characteristics of the N-Terminal Domain on steroid hormone receptors?

A
  • Variable length
  • Low sequence homology between different receptors
35
Q

What are the characteristics of the DNA Binding Domain on steroid hormone receptors?

A
  • ~68 AA residues
  • Highly conserved
  • Binds to hormone response elements (HREs) near target gene
36
Q

What are the characteristics of the Hormone Binding Domain on steroid hormone receptors?

A
  • Intermediate sequence conservation (~225-285 AAs)
  • AAs which determine steroid binding may be over 100 residues apart
37
Q

TRUE OR FALSE:
Hormone binding is dependent on receptor secondary structure

A

False.
It is dependent on TERTIARY structure

38
Q

What is the mechanism of action of the Steroid Hormone Receptor?

A
  • Steroid hormone receptor is either in the cytoplasm or loosely associated with the nucleus
  • Receptor is bound by molecular chaperone proteins like heat shock protein (HSP) that hold the receptor in the right conformation
  • HSPs dissociate and leave the receptor-hormone complex free to enter the nucleus and bind HREs in DNA to activate or repress gene transcription
39
Q

Where are receptors for Thyroxine, Retinoids, and Vit. D3 located in the cell?

A

In the nucleus

40
Q

What do receptors for Thyroxine, Retinoids, and Vit. D3 bind to in the nucleus?

A

HREs even in the ABSENCE of ligand (hormone)
* act as transcription repressors

41
Q

What does the binding of Thyroxine, Retinoids, and Vit. D3 to the receptor cause?

A

Change in conformation to allow them to bind the transcription apparatus
* gene activation

42
Q

How many binding sites does the receptor for glucocorticoid (GR) steroid hormone have?

A

4 - 6 binding sites (HREs) on DNA

43
Q

What is the Glucocorticoid Response Element (GRE) and Estrogen Response Element (ERE) comprised of?

A

A pair of SIX nucleotide palindromic repeats, separated by any three bases

44
Q

What do the DNA binding sites (HRE) for the estrogen, vit. D3, thryroid, and retinoic acid receptors consist of?

A

A pair of SIX nucleotide direct repeats, separated by any 3-6 nucleotides

45
Q

How many C4 Zinc Finger Motifs do DNA binding domains contain?

A

Two

46
Q

Which amino acids do Zinc Finger Motifs on the DNA binding domain contain?

A

2x Cys
2x His

47
Q

What parts of the Zinc Finger Motif are often potent transcriptional regulators?

A
  • Leucine Zipper
  • Basic Helix-Loop-Helix (bHLH)
48
Q

What kind of Zinc Finger protein is the Glucocorticoid receptor?

A

Homodimeric C4 zinc finger protein

49
Q

TRUE OR FALSE:
Receptor expression is often under the control of other hormones

A

True.
E.g. estrogens can induce the expression of the progesterone receptor

50
Q

How are different subtypes of steroid hormone receptors generated?

A

From one gene by processes such as alternate mRNA splicing

51
Q

How do Heterodimeric receptors increase diversity?

A

By the pairing of different monomers
* allows receptor to have different activity to repress or activate a different gene

52
Q

How is gene expression enhanced in steroid hormone regulation?

A

The presence of multiple HREs in the vicinity of the target gene

53
Q

How do DNA binding proteins affect the action of hormone-receptor complexes?

A

They INHIBIT their action, particularly if they are bound close to the HRE

54
Q

What are Accessory Proteins in the hormone-receptor complex?

A

Proteins which bind steroid hormone-type receptors can inhibit (co-repressors) or stimulate (co-activators) the action of transcription factors

55
Q

What happens when transcription factors are targeted by protein kinases?

A

They are phosphorylated

BC3004: Cell Signalling (18 decks)

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