Endocrinology 3 Flashcards
How is cholesterol converted to Oestrogen?
Using aromatase enzymes as Oestegen have an aromatic ring.
How do steroid hormones have an effect on the cell?
- The hormone diffuses across the phospholipid bilayer.
- Some meet a receptor in the cytosol; others have a receptor in the nucleus.
- A receptor-ligand complex is formed.
- This complex is then able to bind to DNA. Nuclear receptors have the ability to directly bind to DNA and regulate the expression of adjacent genes, hence these receptors are classified as transcription factors.
What regions in DNA can regulate transcription? Where are these located?
25bp upstream of the start of transcription are core promoter elements. Here various core transcription factors bind and form a complex where RNA polymerase II can bind.
1-3kb upstream of the start of transcription are enhancers and silencers involved in tissue specific regulated transcription. Some of these elements are the site where steroid hormones or thyroid hormones bind.
What is the structure of nuclear hormone receptor?
At the amino terminus there is the transcription regulation domain. Other transcription factors can bind and interact with etc hormone.
Downstream of this domain is the DNA binding domain. Formed from loops of protein designed to bind to DNA. Have Zinc atoms and in the case of steroid hormone receptors there are cysteine which coordinate to the Zinc and hold it in place. This is known as a Zinc Finger.
The dimerisation domain follows.
A hormone-binding domain is found downstream at the carboxyl terminus. Recognises either the steroid hormone or the thyroid hormone to start tarnscription.
What is the purpose of the dimerisation domain?
It results in two of the binding of the protein receptors - which act as transcription factors - joining together in the middle forming a dimeric structure.
What is a palindrome with respect to DNA?
A palindromic sequence is a sequence made up of nucleic acids within double helix of DNA and/or RNA that is the same when read from 5’ to 3’ on one strand and 5’ to 3’ on the other, complementary, strand. Essentially, if you rotated the DNA by 180 degrees, it would read the same.
What is a hormone response element?
A hormone response element (HRE) is a short sequence of DNA within the promoter of a gene that is able to bind to a specific hormone receptor complex and therefore regulate transcription
How can the Oestrogen-Receptor comped bring about a change in the cell? How is it able to do so?
The Oestrogen response element is a palindrome made up of two subdomains. The steroid hormone receptors - particularly oestrogen receptors - dimerise in opposite directions.
One half of the dimerised receptor is recognising half on the palindrome facing in one direction. The other half is recognising the other domain facing in the opposite direction. Together transcription factor (being the receptor) can recognise the whole oestrogen response element. The
How do oestrogen binding receptors contribute to breast cancer?
Healthly breast tissue normally expresses more ERβ than ERα. ER being the oestrogen receptor. in some types of breast cancer, more ERα is expresses. Oestrogen promotes growth; Oestrogen therefore binds to these receptors and so promotes growth.
How does Tamoxifen work?
It blocks the ERα. Tamoxifen gets converted to an active form called 4-hydroxy tamoxifen. The active drug binds to the receptor; this means the receptor cannot under go a shape change and so cannot bind to its co-activators and so the action of oestrogen is stopped, inhibiting growth the tumour. Tamoxifen treatment however can result in tumours acquiring mutations and so generating receptor that are not longer responsive to Tamoxifen.
How is T4 produced? How is it converted to T3?
Thyroglobulin is a protein that has tyrosine molecules in critical regions. The tyrosine molecules have iodine added onto them via the enzyme Thyroid peroxidase. The iodine crosslinks; one of the tyrosine residues is take off and stuck onto the other. The molecule is then cleaved off. This releases the active hormone known as T4.
One of the Iodine molecules is lost to form T3. T3 is the more active form.
What is the difference between the location of thyroid hormones receptors and steroid hormones receptors?
Thyroid hormone receptors are always bound to DNA. A conformational change in the complex enables the complex to act as a transcription factor. Steroid hormone receptors pick up their steroid hormone and bind to DNA.
Thyroid hormone receptor bind to others can pair with each other or with other nuclear factors. This that instead of there being two thyroid hormone receptors bound next to each other in DNA, they can bind to something else. It is a hetero-dimer.
Steroid hormone receptors go in pairs with the same steroid hormone receptor.. It is usually a homo-dimer.
What is bound to thyroid hormone receptors in the active form and inactive form?
In the absence of hormones, the thyroid hormone receptors have picked up repressor molecules and so transcription does not occur.
In the presence of the hormone, the repressor disappears, an activator take its place and transcription starts.
How do we know that thyroid hormone response elements have transcription factors?
Some retroviruses when integrating its DNA within the host DNA can cause the DNA of the host to rearrange. The virus then picks up a gene from its host in addition to its genes required to make the virus. A virus of chickens known as v-erbA gave chickens a form of leukaemia. The virus picked up an oncogene. The erbA gene was a mutated gene for one of the thyroid hormone receptors. The thyroid hormone receptor is used in the transcription of tumour-suppressor genes.
v-erbA binds to the thyroid hormone receptor. It however cannot transcribe the genes. There is no longer the production of the tumour suppressor and so the chickens are liable to get cancer. This is a dominant negative effect.
Without the action of thyroid hormones, tumour suppressor genes are not translated.
