GROUP LEADER: Prof. Ann Louw
Office: A119 JC Smuts Building
PhD, University of Stellenbosch, Biochemistry, 1998
NRF C2-rating (2013-2018)
Golden Key International Honour Society Award for Best lecturer in Science Faculty (2008)
Steroid receptor signal transduction, Steroid-binding globulins, Phytoestrogens, Dissociated glucocorticoids, Interplay of stress and immune function.
Our research focus is on steroid hormone binding proteins, specifically the steroid hormone transport proteins in serum and intracellular steroid hormone receptors. The interplay between these two categories of steroid hormone binding proteins, whether elicited by drugs or physiological conditions, has been neglected in an era of specialization despite the obvious physiological relevance.
We aim to study the effects of specific compounds, such as Compound A and phytoestrogens, or physiological conditions, such as stress, on steroid hormone signal transduction via cognate receptors, such as the glucocorticoid receptor (GR) and oestrogen receptor (ER). This is complemented by investigating effects on the high affinity steroid binding globulins, specifically corticosteroid binding globulin (CBG) and sex hormone binding globulin (SHBG).
Molecular mechanism of action of GR – focus on implications of dimerization
Glucocorticoids remain the most effective treatment for inflammatory diseases. However, side-effects limit their usefulness. Dissociated glucocorticoids, which discriminate between transactivation and transrepression, have recently been hailed as drugs that retain potent anti-inflammatory action while displaying reduced side-effects. Compound A, synthesized in our department, is such a dissociated glucocorticoid and may exert its dissociated activity through abrogation of GR dimerization. We are currently investigating the implications of a gain or loss of dimerization potential on the biological action of GR.
Phytoestrogenic activity of Cyclopia (honeybush)
Alternatives for hormone replacement therapy are avidly sought and phytoestrogens have been hailed as a viable alternative with fewer side-effects. We have established that Cyclopia contains phytoestrogens and that an extract from Cyclopia can compete with commercial preparations in terms of potency and efficacy. Recent work suggests that a Cyclopia extract displays three desirable estrogenic attributes, antagonism of ERα, agonist behaviour through ERβ, and attenuation of oestrogen induced breast cancer proliferation. We have now embarked on characterizing the molecular mechanism of action of Cyclopia by focusing on breast cancer and SHGB, the high affinity carrier of sex steroids in plasma that determines the biological availability of steroids and phytoestrogens.
Interplay of pro-inflammatory cytokines and GR-ligands in the liver
Although the repression of inflammatory cytokines by glucocorticoids is well studied as being the basis of the anti-inflammatory action of glucocorticoids the effect of inflammatory cytokines on glucocorticoid action, especially in the periphery, is less well studied. Having shown in vivo that IL-6 antagonizes the effect of glucocorticoids in the liver we expanded the study in tissue culture and found that glucocorticoids and pro-inflammatory cytokines generally have divergent effects on the GR levels and metabolic enzymes, while their functions are convergent on the acute phase proteins. Further work on the interaction between the stress and inflammatory system is focussing on corticosteroid binding globulin (CBG), which is both a negative acute phase protein synthesised in the liver and the plasma binding protein involved in the transport of glucocorticoids.
Nicolette Verhoog, Fatima Allie-Reid, Wim Vanden Berghe, Carine Smith, Guy Haegeman, Janet Hapgood, Ann Louw (2014) Inhibition of Corticosteroid-Binding Globulin Gene Expression by Glucocorticoids Involves C/EBPβ. PLoS ONE 9(10): e110702.
Visser, K, Mortimer, M, Louw, A. (2013) Cyclopia extracts act as ERα antagonists and ERβ agonists, in vitro and in vivo. PLoS ONE 8(11):e79223.
Ann Louw, Elizabeth Joubert and Koch Visser (2013) Phytoestrogenic potential of Cyclopia extracts and polyphenols. Planta Medica 79: 580–590.
Steven Robertson, Johann M. Rohwer, Janet P. Hapgood and Ann Louw (2013) Impact of Glucocorticoid Receptor Density on Ligand-independent Dimerization, Cooperative Ligand-binding and Basal Priming of Transactivation: A cell culture model. PLoS ONE 8(5): e64831.
Steven Robertson, Janet P. Hapgood and Ann Louw (2013) Glucocorticoid Receptor Concentration and the Ability to Dimerize Influence Nuclear Translocation and Distribution. Steroids 78, 182–194.
K. Visser, C. Smith and A. Louw (2010) Interplay of the inflammatory and stress systems in a hepatic cell line: Interactions between glucocorticoid receptor agonists and interleukin-6. Endocrinology 151, 5279-93.
S. Robertson, F. Allie-Reid, W. Vanden Berghe, K. Visser, A. Binder, D. Africander, M. Vismer, K. De Bosscher, J. Hapgood, G. Haegeman and A. Louw (2010) Abrogation of glucocorticoid receptor dimerization correlates with dissociated glucocorticoid behaviour of Compound A. Journal of Biological Chemistry 285, 8061–8075
C Mfenyana, E. Joubert, and A. Louw (2008) Selective extraction of Cyclopia for enhanced in vitro phytoestrogenicity and benchmarking against commercial phytoestrogen extracts. J Steroid Biochemistry and Molecular Biology, 112, 74-86
NJD Verhoog, E Joubert and A. Louw (2007) Evaluation of the phytoestrogenic activity of Cyclopia genistoides (honeybush) methanol extracts and relevant polyphenols. Journal of Agricultural and Food Chemistry 55, 4371-4381.
C Smith, NW Wilson, A Louw, KH Myburgh (2007) Illuminating the interrelated immune and endocrine adaptations after multiple exposures to short immobilisation stress by in vivo blocking of IL-6. Am J Physiol Regulatory Integrative Comp Physiol 292:1439-1447.
K. De Bosscher , W. Vanden Berghe, I.M.E. Beck, Wim Van Molle, Nathalie Hennuyer, Janet Hapgood, Claude Libert, Bart Staels, A. Louw and G. Haegeman (2005) A novel plant-derived, fully dissociated compound for the specific repression of NF-kappaB-driven inflammatory genes. PNAS 102, 15827-15832.
A. Louw, P. Swart, and F. Allie (2000) Influence of an aziridine precursor on the in vitro binding parameters of rat and ovine corticosteroid-binding globulin (CBG), Biochemical Pharmacology, 59, 167-175.
A. Louw and P. Swart (1999) Salsola tuberculatiformis Botschantzev and an aziridine precursor analog mediate the in vivo increase in free corticosterone and decrease in corticosteroid-binding globulin in female Wistar rats, Endocrinology 140, 2044-2053.