Biology and Biochemistry Department
Many of the body's hormones, including sex hormones and corticosteroids have to get right into the nuclei of their target cells to be able to have their effect. The receptors (or receivers) for these hormones are molecules in the cell nucleus, and are therefore called nuclear receptors. The receptor has a shape into which the hormone molecule fits. The hormone slides into a cavity in the receptor. In the next stage, the cavity closes and changes take place on the surface of the receptor molecule. The surface structure that is formed depends on which hormone has bound to the receptor.
The surface structure is recognized by other proteins which then attach to the surface. A long chain reaction, a "signaling relay" involving many molecules has started. The result is that the hormone-controlled gene in the genetic material is read off so that the protein for which the gene constitutes the blueprint can be produced.
Hormone-controlled processes are important for the normal functions of most of the body's organs. So it is not surprising that such processes have major significance in many diseases too. In many cases therefore, the ability to affect hormone-controlled mechanisms is an effective way to treat diseases. This makes hormone nuclear receptors into interesting targets for drugs. The fact is that receptors can be "fooled" and molecules other than hormones can fit into the cavity and bind to the receptor. By creating molecules with this capability, it is possible to artificially stimulate or block the activity of the receptor. Stimulating substances are called agonists and blocking ones are called antagonists.
A number of the world's leading pharmaceutical companies are now investing major resources into the development of substances which are agonists or antagonists for nuclear receptors in various parts of the body and which can relieve or cure serious diseases. The research results from Gustafsson and his co-workers have provided important contributions to the knowledge base from which pharmaceutical companies are proceeding.
The research group's greatest discovery to date was made in the mid 1990s. The group worked with so-called orphan receptors. These are nuclear receptors which we know exist, but do not know which hormones they are receptors for. In their search for a new receptor for male sex hormone, the research group studied orphan receptors in the prostate gland.
"To our great amazement, we found instead a previously unknown receptor for the female sex hormone, estrogen," explains Gustafsson.
Up to this point, science was only aware of one type of estrogen receptor. That was discovered in 1958. When, at a researchers' symposium in the US in 1996, Jan-Åke Gustafsson's research group presented their discovery of a new estrogen receptor, it caused a great stir and was hailed as the biggest news there.
So as to distinguish the two estrogen receptors, the first one to be discovered was called ER-alpha, and the second one which Gustafsson's group found was called ER-beta (ER stands for oestrogen receptor). Whilst ER-alpha's activity is chiefly aimed at regulating fertility and conception, ER-beta has a broader profile. Far from just being present in the reproductive organs (both men´s and women's) ER-beta also plays a vital role in a wide range of other organs including the brain, lungs and immune system.
The two estrogen receptors are very similar to each other. ER-alpha has an activating function and speeds up various processes in the body, including cell division. ER-beta has the opposite effect, suppressing things like cell division and stimulating cell death or apoptosis.
An ER-beta agonist is being produced against prostate cancer and there is much to indicate that this type of drug will also be able to work on breast cancer and colon cancer among others. Other diseases against which ER-beta agonists are under development are rheumatoid arthritis, inflammatory bowel diseases, benign prostate enlargement and ovulation disorders. Gustafsson also sees many other possibilities, such as an ER-beta agonist being a good alternative to estrogen therapy in depression associated with the menopause.
Another interesting aspect of ER-beta concerns diet. There is research indicating that certain cancerous diseases can be prevented with the aid of a diet containing a lot of fruit and vegetables. Other research indicates that a vegetarian diet can ease the symptoms of rheumatoid arthritis. Jan-Åke Gustafsson believes the explanation for these effects is connected with the phyto-estrogen content in certain plants. Phyto-oestrogens bind around one hundred times better to ER-beta in the body than ER-alpha and can thereby stimulate the effect of ER-beta.
The research group is continuing its work on the ER-beta receptor, its effects in the body and the mechanisms it controls in the cell. Genetically manipulated mouse models are an important tool.
Another of the group's projects aims to correspondingly investigate the nuclear liver X receptor or LXR, first discovered in the liver. The receptor was found simultaneously by Gustafsson´s team and other researchers at the start of the 1990s. This receptor also appears in an alpha and a beta form. The liver X receptor is very important for the metabolism of cholesterol in the body. When the receptor is not working normally it can lead to a harmful accumulation of cholesterol. The consequences of this depend on how the accumulation takes place. If the central nervous system is affected, it can lead to nerve cell death, and these mechanisms may be part of the profile in dementia diseases such as Alzheimer's. Gustafsson is convinced that the liver X research may also lead to new drugs.
"This project is as fascinating as the work with ER-beta and there are probably major possibilities in future of the results being of medical benefit."
Z. Weihua, S. Mäkelä, L. C. Andersson, S. Salmi, S. Saji, J. I. Webster, E. V. Jensen, S. Nilsson, M. Warner, and J.-Å. Gustafsson: A role for estrogen receptor in the regulation of growth of the ventral prostate. Proc.Natl.Acad.Sci. USA, 98, 6330-6335, 2001.
DISCOVERY OF THE REGULATORY ROLE OF ERß IN THE GROWTH OF THE PROSTATE
A.M. Brzozowski, A.C.W. Pike, Z. Dauter, R.E. Hubbard, T. Bonn, O. Engström, L. Öhman, G.L. Greene, J.-Å. Gustafsson and M. Carlquist: Insights into the molecular basis of agonism and antagonism in the oestrogen receptor as revealed by complexes with 17ß-oestradiol and raloxifene. Nature, 389, 753-758, 1997. DISCOVERY OF THE MOLECULAR MECHANISM OF ANTAGONISM (HELIX 12 PERTURBATION) WITHIN NUCLEAR RECEPTORS
G.G.J.M. Kuiper, E. Enmark, M. Pelto-Huikko, S. Nilsson, and J.-Å. Gustafsson: Cloning of a novel estrogen receptor expressed in rat prostate and ovary. Proc.Natl.Acad.Sci. USA, 93, 5925-5930, 1996. DISCOVERY OF THE 2ND ESTROGEN RECEPTOR, ERß, CAUSING A PARADIGM SHIFT IN OUR UNDERSTANDING OF ESTROGEN SIGNALING
M. Teboul, E. Enmark, Q. Li, A.C. Wikström, M. Pelto-Huikko, and J.-Å. Gustafsson: OR-1, a member of the nuclear receptor superfamily that interacts with the 9-cis-retinoic acid receptor. Proc. Natl. Acad. Sci. USA, 92, 2096-2100, 1995. DISCOVERY OF LXRß
M. Göttlicher, E. Widmark, Q. Li, and J.-Å. Gustafsson: Fatty acids activate a chimera of the clofibric acid-activated receptor and the glucocorticoid receptor. Proc.Natl.Acad.Sci. USA, 89, 4653-4657, 1992. FIRST DESCRIBED ACTIVATORS OF AN ORPHAN NUCLEAR RECEPTOR (FATTY ACIDS FOR PPARa)
T. Härd, E. Kellenbach, R. Boelens, B. A. Maler, K. Dahlman, L. P. Freedman, J. Carlstedt-Duke, K. R. Yamamoto, J.-Å. Gustafsson, and R. Kaptein: Solution structure of the glucocorticoid receptor DNA-binding domain. Science, 249, 157-160, 1990. FIRST 3-D STRUCTURE OF A NUCLEAR RECEPTOR DOMAIN (THE DBD)
R. Miesfeld, S. Okret, A.-C. Wikström, Ö. Wrange, J.-Å. Gustafsson and K. Yamamoto: Characterization of a steroid receptor gene and mRNA in wild-type and mutant cells. Nature 312, 779-781, 1984. FIRST CLONING OF A NUCLEAR RECEPTOR cDNA
F. Payvar, Ö. Wrange, J. Carlstedt-Duke, S. Okret, J.-Å. Gustafsson and K.R. Yamamoto: Purified glucocorticoid receptors bind selectively in vitro to a cloned DNA fragment whose transcription is regulated by glucocorticoids in vivo. Proc. Natl. Acad. Sci. USA 78, 6628-6632, 1981. FIRST DEMONSTRATION OF SPECIFIC BINDING OF A NUCLEAR RECEPTOR TO DNA
Ö. Wrange, J. Carlstedt-Duke and J.-Å. Gustafsson: Purification of the glucocorticoid receptor from rat liver cytosol. J. Biol. Chem. 254, 9284-9290, 1979. FIRST PURIFICATION OF A NUCLEAR RECEPTOR TO HOMOGENEITY
Ö. Wrange and J.-Å. Gustafsson: Separation of the hormone- and DNA-binding sites of the hepatic glucocorticoid receptor by means of proteolysis. J. Biol. Chem. 253, 856-865, 1978. FIRST DEMONSTRATION OF DOMAIN STRUCTURE OF A NUCLEAR RECEPTOR