Lecture 34 How hormones act within the cell

Question 1

what is oestradiol

Answer 1

= an oestrogen

Question 2

what is tamoxifen

Answer 2

= an anti-oestrogen

Question 3

steroid hormones are derived from…

Answer 3

cholesterol

Question 4

thyroid hormones are derived from…

Answer 4

tyrosine, within the protein thyroglobulin

Question 5

example of an androgen

Answer 5

testosterone (male sex hormone)

Question 6

aromatase enzyme

Answer 6

catalyses conversion of testosterone (an androgen) to oestradiol (an oestrogen). Introduces aromatic ring by getting rid of -CH3 group

Question 7

aromatase inhibitors

Answer 7

target for drugs - given to people with tumours who are producing too much oestrogen

Question 8

steroid hormones

Answer 8

testosterone and oestradiol

Question 9

steroid hormones are

Answer 9

hydrophobic

Question 10

hydrophobic hormones can

Answer 10

diffuse across phospholipid bilayer

Question 11

thyroid hormones are

Answer 11

hydrophobic

Question 12

steroid hormones can cross the plasma membrane

Answer 12

true

Question 13

steroid hormone crosses bilayer and either

Answer 13

• bind to free receptor in cytosol and go to nucleus

- bind to receptor found in nucleus

Question 14

what does the hormone receptor complex act as

Answer 14

transcription factor as complex binds to DNA in nucleus and starts transcription, mRNA is produced

Question 15

distal promoter elements are often controlled by

Answer 15

steroid and thyroid hormones

Question 16

how far away are distal promoter elements upstream from transcription site

Answer 16

1-3kb

Question 17

what are distal elements involved in

Answer 17

tissue-specific and regulated gene expression

Question 18

what do steroid and thyroid hormones bind to

Answer 18

nuclear hormone receptors which ligand activated proteins

Question 19

what are the four domains of the nuclear hormone receptors

Answer 19

1. Amino terminus = transcription regulation domain
2. Dna binding domain
3. Dimerization domain
4. Carboxyl terminus = hormone binding domain

Question 20

transcription regulation domain

Answer 20

interacts with other proteins that regulate transcription

Question 21

Dna binding domain

Answer 21

zinc fingers involving Zn 2+ ions that bind to the DNA helix

Question 22

steroid hormone receptors zinc fingers

Answer 22

Loops of protein that contain a Zn 2+ ion that forms a complex and coordinately bonds with 4 cysteine residues

Question 23

dimerization domain

Answer 23

nuclear receptors go round in pairs and will pair up through the dimerization domain facing in opposite directions

Question 24

Vitellogenin is a …

Answer 24

protein found in egg yolk, has some regions of homology to ApoB

Question 25

what are ERa/ERb

Answer 25

two closely related oestrogen receptors

Question 26

why is vitellogenin important

Answer 26

its production (transcription) is regulated by oestrogen - steroid hormone

Question 27

what oestrogen receptor does healthy tissue express more

Answer 27

ERb

Question 28

what oestrogen receptor do some tumour express strongly

Answer 28

ERa

Question 29

what does oestrogen promote

Answer 29

rapid division of ERa positive breast cancer cells

Question 30

what colour are ERa positive cells stained using anitbody test (antibodies against the oestrogen receptor)

Answer 30

brown

Question 31

what does tamoxifen (inactive) get converted to (active)

Answer 31

4-hydroxy tamoxifen

Question 32

tamoxifen is a pro drug, what is a pro-drug?

Answer 32

biologically inactive compound that can be metabolised in the body to produce a drug

Question 33

how does tamoxifen work

Answer 33

tamoxifen binds to oestrogen receptor, doesn't activate receptor so no shape change so receptor cannot bind to co-activators

Question 34

inactive thyroid hormone

Answer 34

T4

Question 35

active thyroid hormone

Answer 35

T3

Question 36

thyroxine = T4

Answer 36

the main hormone secreted into the bloodstream

Question 37

T4 = thyroxine

Answer 37

tetra-iodothyronine, thyroxine

Question 38

T3

Answer 38

tri-iodothyronine

Question 39

how is T4 produced

Answer 39

1. tyrosine molecules on thyroglobulin protein are iodinated by the enzyme of thyroid peroxide = diiodotyrosine 2. the diiodotyrosine molecules in thyroglobulin are cross linked 3. thyroxine (T4) molecule is cut out of thyroglobulin and released as a free hormone

Question 40

conversion of T4 to T3

Answer 40

deiodination of T4 where one iodine molecule is removed from T4

Question 41

TRE

Answer 41

thyroid hormone response element = section of DNA

Question 42

(TR) thyroid hormone receptors = there are two separate genes for thyroid hormone receptors - the receptors have slightly different actions

Answer 42

thyroid hormone receptors (TR) are bound to thyroid hormone response element (TRE) in nucleus both in absence and presence of hormone

Question 43

where is recognition sequence (TRE) located

Answer 43

in front of various genes of energy metabolism and heart function that are switched on by thyroid hormones

Question 44

difference between steroid and thyroid receptors

Answer 44

thyroid receptors are always bound to the TRE DNA sequence whereas steroid receptors bind to hormone and then bind to the DNA

Question 45

TR

Answer 45

thyroid receptor

Question 46

absence of hormone, TR bind to

Answer 46

co-repressor molecules

Question 47

what do corepressor molecules do

Answer 47

switch off transcription

Question 48

TR and TRE

Answer 48

TR (thyroid receptors) bind to TRE (thyroid hormone response elements) in the DNA

Question 49

presence of hormone, TR binds to

Answer 49

the co-repressor unbinds from TR, and a coactivator binds to the receptor and transcription starts

Question 50

homodimer

Answer 50

TR binds with another nuclear receptor molecule = another TR (same)

Question 51

heterodimer

Answer 51

TR binds with a different nuclear receptor molecule

Question 52

can retroviruses sometimes incorporate a section of host DNA into their viral DNA

Answer 52

Yes - occasionally host DNA from the cell they have infected can rearrange and be inserted into the viral DNA which changes the sequence of viral DNA as a new gene has been inserted

Question 53

v-erbA

Answer 53

``` v = virus erb = erthyroblastosis ```

Question 54

what is v-erbA

Answer 54

a highly mutated version of thyroid hormone receptor (protein) and is therefore encoded for by an oncogene (a gene that causes cancer)

Question 55

v-erbA and chickens

Answer 55

naturally occuring virus in which this oncogene was incorporated = causes leukaemia in chickens, also causes cancer in mice when inserted (transgenic mice)

Question 56

normal situation in presence of hormone T3

Answer 56

T3 binds to receptor and transcription of several genes occurs = one gene is a tumour supressor gene

Question 57

abnormal situation involving v-erbA

Answer 57

V-erbA binds to the TRE and so prevents binding of TR and so cannot activate transcription = hence blocks thyroid hormone action

Question 58

what is the action of v-erbA binding

Answer 58

= dominant negative

Question 59

human cancers in which TR mutations have been detected

Answer 59

liver, kidney, breast, pituitary, thyroid