Steroids and Retinoids

D.W.Tingley, Evolutions: Steroid-hormone receptor signalling (Bench Notes), Journal of NIH Research 8, April 1996, , pp. 81-84 & 87-88.
History TRANSPARENCY
Egyptians already knew that breast feeding delayed next pregnancy
Greek - silphion extract is contraceptive and aborttifacient (may bind estrogen receptors)
Eustachi - 1552 - drew adrenal glands
Addison - 1850 disease with deficiency of adrenal cortex hormones
Adrenalin isolated in 1901
Starling refers to adrenalin and secretin as hormones
1930's researchers isolated some steroids
1960's - explanation of estradiol-binding protein being in cytoplasm and nucleus
1972-1974 Ashburner shows that ecdysone induces puffs on Drosophila polytene chromosomes
Recent stuff drawn on main diagram
Steroid comes in. In cytoplasm-displaces Hsp proteins, functions as dimer in nucleus
Zinc finger aspect involved in DNA binding,
example is gene whose product inhibits Nuclear Factor (NF-kappaB)
TRANSPARENCY Figs 9-14 and 9-15 on p. 411 of Alberts et al.-
shows the structure of Zn-fingers in terms of amino acid sequence
and the binding of such a protein to DNA

TRANSPARENCY a transplantation experiment on limb bud from:
M. Hoffman, The embryo takes its vitamins (research news) Science 250, 372-373, 1990.
see also erratum on p. 1320 with the correct double bonds in retinoic acid
(this relates to the material on hedgehog)
retinoic acid is thought to be a morphogen
TRANSPARENCY showing transport, storage and binding proteins for retinoids from:
R. Blomhoff, et al., Transport and storage of vitamin A, Science 250, 399-403, 1990.
Note CM=chylomicrons involved in absorption of fats
There is conversion into and out of retinyl esters
in general, there is a "bucket-brigade" of binding proteins
TTR = transthyretin, a 55 kDa protein stuck on so that the carrier is too big for glomerular filtration

D.J.Mangelsdorf, The retinoid receptors (Chapter 8) in The Retinoids: Biology, Chemistry and Medicine 2nd edition Ed. by M.A. Sporn et al., Raven Press Ltd., New York, 1994.
in Xenopus embryo, all-trans retinoic acid reduces anterior structures - morphogenTRANSPARENCY formation or retinoic acid
TRANSPARENCY shows how hormone receptors are "nuclear receptors" (with and without ligand)
In this field, many receptors are called "orphan receptors" to denote that the ligand has not been found (yet)
bind to hormone response element
TRANSPARENCY shows all-trans- and 9-cis-retinoic acid
RXR is turned on preferentially by 9-cis, while RAR is equally sensitive to 9-cis and all-trans
TRANSPARENCY homology of RAR with vitamin D, glucocorticoid and thyroid hormone receptors
and RXR with the same and Drosophila ultraspiracle (usp)
TRANSPARENCY - shows conversions and receptor-response element interactions
note that there are cellular retinoid and retinoic acie binding proteins in cytoplasm
AGGTCA typically as direct repeats with 1,2,3,4 or 5 nucleotide separations
TRANSPARENCY shows dimerization and separations
TRANSPARENCY domain structure

S. M. Pemrick et al., The retinoid receptors (Review) Leukemia 8, 1994, 1797-1806
possibly receptors without hormones inhibit transcription
nuclear receptors bind as dimers - have dimerization interfaces in DNA and ligand binding domains
TRANSPARENCY depicts RXR bound to 9-cis RA and RAR bound to all-trans-RA
also shows binding to response elements with separation of 5 nucleotides
Figure 2 RAR & RXR alpha beta and gamma - these are about 450 amino acids (varies between types)
Domain structure, RAR: A-F, RXR: A-E
C is DNA binding domain and is highly conserved
E is ligand binding domain which is also highly conserved
TRANSPARENCY shows how direct regulation of one gene by retinoids can indirectly regulate another

W.A.Segraves, Something old, some things new: The steroid receptor superfamily in Drosophila (minireview), Cell 67, 225-225, 1991
Think about steroidal hormone signalling in, say, humans:
lots, adrenal cortex, gonads, (not to mention close relatives like thyroid)
in insects, ecdysone is the only one really known
TRANSPARENCY homology in members of steroid superfamily

A. Chawla et al., Nuclear receptors and lipid physiology: Opening the X-files, Science, 294, 1866-1870, 2001
48 members of this transcription factor family in human genome
receptors for steroids, thyroid hormones, vitamins A & D
Then there are orphan receptors where ligands etc. are (or were) not known
AF-1 a transcriptional activation function (ligand independent), AF-2 ligand dependent
Steroid receptors bind to DNA as homodimers
Others (orphans) function as heterodimers with RXR receptors

References

R. Blomhoff, et al., Transport and storage of vitamin A, Science 250, 399-403, 1990.

M. Hoffman, The embryo takes its vitamins (research news) Science 250, 372-373, 1990.
see also erratum on p. 1320 with the correct double bonds in retinoic acid

D.J.Mangelsdorf, The retinoid receptors (Chapter 8) in The Retinoids: Biology, Chemistry and Medicine 2nd edition Ed. by M.A. Sporn et al., Raven Press Ltd., New York, 1994.

S. M. Pemrick et al., The retinoid receptors (Review) Leukemia 8, 1994, 1797-1806

W.A.Segraves, Something old, some things new: The steroid receptor superfamily in Drosophila (minireview), Cell 67, 225-225, 1991

D.W.Tingley, Evolutions: Steroid-hormone receptor signalling (Bench Notes), Journal of NIH Research 8, April 1996, , pp. 81-84 & 87-88.

This page was last updated on Jan. 10, 2002

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