18. Signal Transduction 1

Question 1

Describe the function of transcription factors.

Answer 1

Transcription factors are downstream of receptors - turn on/off genes

Question 2

Explain how transcription factors are turned on.

Answer 2

• when receptors are activated –> SMAD proteins (transcription factors) are phosphorylated
• SMADs form dimers/trimers and transport to the nucleus
• different multimers can influence gene transcription in different ways

Question 3

What are nuclear receptors?

Answer 3

Nuclear receptors are a type of transcription factor
* active in the nucleus
* example of how a receptor can be transcription factors

Question 4

Explain how ligand binding affects nuclear receptors.

Answer 4

After ligand binds –> proteins sequestered –>nuclear receptors dimerize
* the active dimer can promote transcription by binding to DNA and recruiting the transcription machinery

Question 5

Where are nuclear receptors located?

Answer 5

Nuclear receptors can be localized in the nucleus or tranlocate to the nucleus from the cytoplasm after ligand-binding
* steroid hormones can diffuse across the plasma membrane and bind to nuclear receptors
* hormone-receptor complex then enters the nucleus

Question 6

Are nuclear receptors homo dimers or hetero dimers?

Answer 6

Both. Nuclear receptors can be homo or hetero dimers.

Question 7

How are nuclear receptors integrated with drug efflux pumps?

Answer 7

• nuclear receptors are used to detect foreign substances, such as drugs
• binding of the drug to the receptor –> increased transcription of P-gp (which removes the drug from the cell)

Question 8

Give an example of a Type 1 nuclear receptor.

Answer 8

Estrogen receptors
(steroid hormone receptors)

Question 9

Give an example of Type 2 nuclear receptors.

Answer 9

Thyroid hormone receptors

Question 10

What is the main difference between Type 1 and Type 2 nuclear receptors?

Answer 10

Type 1 - found in either the cytoplasm or nucleus (inactive found in the cytoplasm then transported to the nucleus where they are activated)

Type 2 - found in the nucleus

Question 11

What are characteristics of Type 1 nuclear receptors?

Answer 11

• known as steroid hormone receptors
• can be found in the cytosol
• functions as homodimers
• in the absence of ligand –> complexed with heat shock proteins
• in the presence of ligand –> they dimerize and bind DNA

Question 12

What is the relation between binding affinity and pKa of drugs?

Answer 12

Larger pKa = greater binding affinity

Question 13

Describe the mechanism of Type 1-estrogen receptors.

Answer 13

estrogen receptor agonists and antagonists have opposite effects on gene transcription
* agonists - allow for transcription by recruiting co-activators (p300 complex)
* antagonists - prevent transcription by recruiting histone deacetylases –> making DNA tightly wound

Question 14

Describe the characteristics of Type 2 nuclear receptors.

Answer 14

• retained in the nucleus
• function as heterodimers
• in the absence of ligand - complexed with co-repressor
• NR1 subfamily –> thyroid hormone receptors

Question 15

Explain the role of thyroid hormone receptors (type 2 nuclear receptors).

Answer 15

There are negative and positive regulation pathways that reduce or increase the amount of produced thyroid hormone.