Our group`s research focuses on the molecular and cell biology of lipid activated transcription factors, so called nuclear receptors. Nuclear hormone receptors are ligand activated transcription factors participating in the regulation of cellular proliferation, differentiation and homeostasis. Members of this receptor superfamily, such as the estrogen receptor, progesterone receptor or the retinoic acid and thyroid hormone receptor are classical endocrine regulators.

The ligand-induced switch

We are interested in the molecular details of hormone action. Lipid soluble hormones such as oestrogens and retinoids act via small protein molecules (receptors)which bind to and regulate the expression of certain genes. This is how they affect the function and fate of cells and tissues. To positively or negatively regulate gene expression they need to communicate with other protein molecules. The specific protein molecules interacting with the receptors were recently identified. It is critical to understand how the small lipid soluble molecules (hormones) regulate these interactions. We try to understand the details and molecular determinants of these interactions using molecular and cell biological approaches.

References:

Nuclear receptor repression mediated by a complex containing SMRT, mSin3A and histone deacetylase
Nagy, L., Kao, H-Y., Chakravarti, D., Lin, R.J., Hassig, C.A., Ayer, D.E., Schreiber, S.L. and Evans, R.M.
Cell 89 (3): 373-380 (1997)

Nuclear receptor co-activator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300
Chen, H., Lin, R., Schiltz, L., Chakravarti, D., Nash, A., Nagy, L., Privalsky, M.L., Nakatani, Y. and Evans, R.M.
Cell 90 (3): 569-580 (1997)

Role of the histone deacetylase complex in Acute Promyelocytic Leukemia
Lin, J.R., Nagy, L., Satoshi, I., Shao, W., Miller, W., and Evans, R.M.
Nature 391:811-814 (1998)

Mechanism of co-repressor binding and release from nuclear hormone receptors
Nagy, L., Kao H-Y., Love, JD, Li, C., Banayo, E., Gooch, JT., Chatterjee, VKK, Evans,
RM and Schwabe, JWR
Genes and Development 13(24): 3209-3216 (1999)

The structural basis for the specificity of retinoid-X-receptor selective agonists: new insights into the role of helix H12.
Love, J.D., Gooch, J.T., Benkő, S., Nagy, L., Chatterjee, V.K.K., Evans,, R.M. and Schwabe, J.W.R.
Journal of Biological Chemistry 277(13):11385-11391 (2002)

Molecular determinants of the balance between co-repressor and co-activator recruitment to the retinoic acid receptor
Benkő, S., Love, J.D., Béládi, M., Schwabe, J.W.R. and Nagy, L.,
Journal of Biological Chemistry 278: 43797-43806 (2003)

The mechanism of nuclear receptor molecular switch
Nagy, L. and Schwabe J.W.R.
Trends in Biochemical Sciences 29(6):317-324 (2004)

Roles for nuclear receptors in myeloid cell differentiation and function

We are also interested in the biological function of certain newly discovered receptors of the nuclear hormone receptor superfamily. There is an emerging group of receptors such as PPARs, LXR,SXR which do not appear to have high affinity endogenous ligands (hormones) but rather several low affinity, highly abundant activators (metabolites)were identified for these receptors. It is our hypothesis that these receptors act as sensors of metabolic state and translate it directly to the level of transcription. We decided to study these processes in white blood cells (monocytes/macrophages). We try to understand how these receptors modulate macrophage function, which genes/gene networks get activated by them and what is their contribution to disease states such as diabetes, obesity, inflammation and atherosclerosis. For these studies we use molecular and cell biology approaches, global (DNA chip technology) and quantitative (Q PCR) expression profiling and animal (mouse) models of diseases.

References:

Oxidized LDL regulates macrophage gene expression through ligand activation of PPARg
Nagy, L., Tontonoz, P., Alvarez, JGA., Chen, H. and Evans, RM.
Cell 93(2): 229 -240 (1998)

PPARg promotes monocyte/macrophage differentiation and uptake of oxidized LDL
Tontonoz, P., Nagy, L., Alvarez, JGA., Thomazy, VA. and Evans, RM.
Cell 93(2): 241 - 252 (1998)

A role for PPARa in oxidized phospholipid induced synthesis of MCP-1 and IL-8 by endothelial cells
Lee, H, Shi, W, Tontonoz, P, Wang, S, Subbanagounder, G., Hedrick, L., Hama, S., Borromeo,C., Evans, RM., Berliner, JA and Nagy, L.
Circulation Research 87: 516-521 (2000)

A PPARg-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis
Chawla, A, Boisvert, W.A., Lee, C-H., Laffitte, B., Barak, Y., Joseph, S.B., Nagy, L., Liao, D., Edwards, P.A., Curtiss, L.K., Evans, R.M., and Tontonoz , P.
Molecular Cell 7: 161-171 (2001)

PPARg dependent and independent effects on macrophage gene expression in lipid metabolism and inflammation
Chawla, A., Barak, Y., Nagy, L., Liao, D. Tontonoz, P., and Evans, RM
Nature Medicine 7(1):48-53 (2001)

Activation of PPARg specifies a dendritic cell subtype capable of enhanced induction of iNKT cell expansion
Szatmári, I., Gogolak, P., Im s.,, J., Dezso, B., Rajnavolgyi, E. and Nagy, L.
Immunity 21:95-106 (2004)

Transcriptional regulation of human CYP27 integrates retinoid, PPAR and LXR signaling
Szántó, A., Benkő, S., Szatmári, I., Bálint, L.B., Fürtös, I., Rühl, R., Molnar, S., Csiba, L., Garuti, R., Calandra, S., Larsson, H., Diczfalusy, U. and Nagy, L.
Molecular and Cellular Biology 24(18):8154-8166 (2004)