Anton M. Jetten, Ph.D.
Immunity, Inflammation, and Disease Laboratory / Cell Biology Group
Building 101, Room D240
111 T.W. Alexander Drive
Research Triangle Park, NC 27709
Action and functions of retinoic acid-related orphan receptors (RORs)
Retinoic acid-related orphan receptors (RORs) play a critical role in embryonic development as well as in several other physiological processes. RORA and RORC are essential for normal thymopoiesis and Th17 cell differentiation and regulate both innate and adaptive immune responses. RORC-deficient mice exhibited a greatly reduced susceptibility to various autoimmune diseases and allergen-induced lung inflammation. RORC is also essential for lymph node development, while RORA regulates cerebellar development and bone formation. Moreover, RORA and RORC play an important role in the regulation of various metabolic pathways and energy homeostasis. Deficiency in RORA greatly decreases the susceptibility to age- and diet-induced obesity and the development of hepatosteatosis, adipose tissue-associated inflammation, and insulin resistance. RORC-deficient mice also exhibit a greater glucose tolerance. The RORs nuclear receptors function as ligand dependent transcription factors and therefore may provide a novel therapeutic target in the management of obesity and associated metabolic diseases as well as several autoimmune diseases. Our objective is to obtain greater insights in the mechanisms by which these proteins regulate these physiological processes and understand their roles in these diseases.
Physiological functions of GLI-similar (GLIS) transcription factors and roles in disease
The GLIS1-3 proteins constitute a subfamily of Krüppel-like zinc finger transcription factors identified by the Jetten laboratory. These proteins play a critical role in a number of physiological functions and have been implicated in a variety of pathologies. Deficiency in GLIS3 gene in mice and humans leads to the development of neonatal diabetes, hypothyroidism, congenital glaucoma, hepatic fibrosis, polycystic kidneys, osteopenia, as well as developmental delay and facial dysmorphism. Moreover, single nucleotide polymorphisms in GLIS3 have been associated with an increased risk of type 1 and 2 diabetes. GLIS3 plays a critical role in the generation of pancreatic β-cell and in the regulation of insulin gene expression. These findings indicate that GLIS3 might be a therapeutic target for diabetes. Loss of GLIS2 expression leads to nephronophthisis, the most frequent genetic cause of end-stage renal disease among young adults. It is characterized by the development of renal fibrosis, inflammation, tubular atrophy, and ultimately renal failure. The induction of renal fibrosis in GLIS2 deficiency involves epithelial-mesenchymal transition (EMT) of tubule epithelial cells. Our goal is to study the molecular mechanism by which these proteins regulate gene transcription and understand their roles in disease.
Dr. Anton Jetten received his Ph.D in Microbiology from the University Nijmegen, The Netherlands. Following postdoctoral fellowships at the Massachusetts Institute of Technology and the Roche Institute of Molecular Biology, Dr. Jetten joined the NCI in 1980 and the NIEHS in 1982 as principal investigator. He became Acting Chief in 2009 and Chief of the Laboratory of Pulmonary Biology in 2011. His research has been focusing on the study of the mechanism of action and the physiological functions of the retinoic acid-related orphan receptors (RORs) and GLI-similar (GLIS) transcription factor subfamilies as well as their roles in disease, particularly lung inflammation, autoimmune disease, obesity and diabetes. Dr. Jetten has published over 260 papers, to date, in scientific journals.
Kang HS, Okamoto K, Kim YS, Takeda Y, Bortner CD, Dang H, Wada T, Xie W, Yang XP, Liao G, Jetten AM. Nuclear orphan receptor TAK1/TR4-deficient mice are protected against obesity-linked inflammation, hepatic steatosis, and insulin resistance. Diabetes. 2011;60(1):177-88.
ZeRuth GT, Yang XP, Jetten AM. Modulation of the transactivation function and stability of Krüppel-like zinc finger protein Gli-similar 3 (Glis3) by Suppressor of Fused. J Biol Chem. 2011;286(25):22077-89.
Wang X, Zhang Y, Yang XO, Nurieva RI, Chang SH, Ojeda SS, Kang HS, Schluns KS, Gui J, Jetten AM, Dong C. Transcription of Il17 and Il17f is controlled by conserved noncoding sequence 2. Immunity. 2012;36(1):23-31.
Purwar R, Schlapbach C, Xiao S, Kang HS, Elyaman W, Jiang X, Jetten AM, Khoury SJ, Fuhlbrigge RC, Kuchroo VK, Clark RA, Kupper TS. Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells. Nat Med. 2012.
Takeda Y, Jothi R, Birault V, Jetten AM. RORγ directly regulates the circadian expression of clock genes and downstream targets in vivo. Nucleic Acids Res. 2012;40(17):8519-35.