endocrine signalling

Question 1

what do nuclear receptors do

Answer 1

promote transcription

Question 2

nuclear receptor positions in cells

Answer 2

steroid receptors - found in cytoplasm bound to chaperones and function as homodimers

non-steroid receptors - found in nucleus, function as heterodimers

Question 3

generic structure of nuclear receptors

Answer 3

ligand binding domain
DNA binding domain
unique N-terminal domain
hinge region

Question 4

hormone response element

Answer 4

region of DNA to which NR binds
will be close to gene that is to be transcribed

sequence of HRE can influence NR - whether it activates or represses transcription

Question 5

NR superfamily can be divided into 4 classes depending on..

Answer 5

interaction with HRE,
classification based on sequence of HRE

5’ - AGAACA - 3’ class one receptors
5’ - AGGTCA - 3’ all other receptors

Question 6

bipartite structure of the response element

Answer 6

one half is consensus site while other half more divergent

consensus half is recognised first by one DBD leading to conformational change in receptor, supporting dimerisation interface enabling co-operative binding of second DBD to less conserved half site

Question 7

core elements eukaryotic promoter

Answer 7

TATA box
initiator element
downstream promoter element

Question 8

how to nuclear receptors promote transcription

Answer 8

basal TFs: activate transcription above basal level using RNA pol II machinery of the basal promoter

chromatin

Question 9

NRs promote formation of stable pre-initiation complex by

Answer 9

making direct contact with components of basal transcription machinery

recruiting co-activators which promote PIC assembly

Question 10

chromatin and NRs

Answer 10

NRs can recruit co-activators that add acetylene groups to histones to open them out

or can recruit co-repressors to chop away acetyl groups

Question 11

shutting off the system

Answer 11

chaperone proteins can promote removal of NRs and RNA pol II from DNA

Question 12

gene repression by NRs

Answer 12

blocks action of other transcription factors

non-steroid hormone receptors

stay bound to HRE even when not bound to ligand. when bound with ligand they activate trnascription. when bound without ligand they repress

Question 13

anti-hormones

Answer 13

pharmaceutical agents used against hormone dependent tumours

inhibits binding of co-activators and promotes binding of co-repressors

Question 14

negative response elements

Answer 14

in absence of hormone now activates transcription and vice versa

Question 15

cross talk between pathways

Answer 15

NRs can work w/o binding to HRE by interfering with signalling pathways

e.g. Jun and Fos - transcription factors

Question 16

NRs and disease: acute promyelocytic leukaemia

Answer 16

w/o ligand, retinoic acid receptor has repressor function which allows normal proliferation of myeloid cells
with retinoic acid binds, proliferation is turned off and myeloid differentiation occurs

there is mutation causing hybrid gene

repressor function still works, but normal levels of retinoic acid will not make switch to differentiation –> uncontrolled proliferation