Endocrinology, lecture on Hormone Synthesis
VIII. Mechanisms of Action - Hormone Synthesis
A. Hormones affect protein synthesis via HREs by
stimulating transcription and enzyme activation
1. some of the proteins synthesized are hormones
a. some are enzymes which are important in steroid,
monoamine, or thyroid hormone synthesis
(1) peptides too
B. Transcription activation
1. RNA Polymerase activity
a. á enzyme (polymerase) molecule number
i. mediated by transcription and translation
b. activating existing enzyme (not phosphorylation)
i. basal transcription factors
2. mRNA stability
a. mRNA accumulation follows RNA polymerase activation
b. hormones may á mRNA half-life (eg. E2, F, T3)
i. á effective translation
(1) glucagon ¯ mRNA half-life
3. Specificity - Template activity
a. Which genes are transcribed - HREs present
b. DNA sensitivity
i. condensed DNA is less sensitive to DNAse
ii. unwound DNA necessary for transcription
(1) specific genes are made available for receptor binding
(a) Hormone/receptor complex may unwind DNA
by sliding along or by configurational change
due to binding to HRE
iii. once available, 2nd transcription induction may occur
more quickly = memory effect
(1) 2nd hormone (eg. E2) dose more effective than the first
(a) also by up-regulating receptor
c. DNA Methylation (CH3 = methyl group)
i. methylation of cytosine at the 5 position
may repress gene activation
(1) methylation enhances DNA curvature
ii. hormones may actively demethylate specific genes
(1) helps unwind DNA
iii. hormones or other transcription factors bound
to active genes prevent methylation
(1) after hormone withdrawl the demethylated site
is not immediately remethylated
® involved in the memory effect
C. RNA processing and translation
1. the gene coding for the hormone includes exons (coding
for amino acid sequences) intersperced with introns
2. introns are removed from the primary transcript so mRNA
includes only codes for peptide and signal sequence
3. translation begins on a free ribosome and transferred
to the endoplasmic reticulum (rER)
a. signal sequence interacts with signal recognition particle
b. SRP binds to SRP receptor on the ER
4. translated peptide + signal sequence = preprohormone
a. moved into the ER lumen by chaperonins/foldases or hsp
i. signal peptide cleaved from the N-terminal by protease
on cisternal (inside) membrane surface
(1) prohormone
(a) half-life of preprohormone is short
b. steroid production is also stimulated by protein synthesis:
enzymes which have their effect in mitochondria and sER
5. ER is transitional to Golgi
a. prohormone packaged into vesicle
i. prohormone cleaved to hormone by protease
(1) if necessary
6. hormone released by exocytosis (vesicle fuses to cell membrane)
a. Ca++ dependent