BBB seminar: Katarina Gradin
Gene regulation in hypoxic cells - a complex molecular switch
Department of Molecular and Cellular Biology, Karolinska Institute, Stockholm, Sweden
Alteration of gene expression is a crucial component of adaptive responses to hypoxia. These responses are mediated by hypoxia-inducible transcription factors (HIFs). HIFs belong to the basic helix-loop-helix/Per-Arnt-Sim-domain (bHLH/PAS) family of transcription factors. This family of factors also includes the dioxin receptor, which functions as a ligand-dependent transcription factor that is activated by a broad spectrum of xenobiotic chemicals. Thus, certain bHLH/PAS factors are seemingly designed to respond to environmental cues, defining a novel group of stress-inducible transcription factors. Recently, we have shown that the inhibitory PAS (Per/Arnt/Sim) domain protein, IPAS, functions as a dominant negative regulator of HIF-mediated control of gene expression. We have also observed that IPAS is predominantly expressed in mice in the corneal epithelium of the eye where it appears to play a role in negative regulation of angiogenesis and maintenance of an avascular phenotype. In similarity to IPAS, an inhibitor of the dioxin receptor has been detected. Unlike IPAS, however, the Ah-receptor repressor (AhRR) can bind to cognate response elements, thereby functioning as a negative regulator of the dioxin receptor function.
Dr. Gradin has a long-standing interest in the molecular switches mediated by the helix-loop-helix group of transcriptional regulators. Her initial work focused on the role of induction of cytochrome P450 enzymes in response to dioxin in tumour development. For the last years, Dr. Gradin has been studying the hypoxia-inducible transcription factors (HIFs) and how gene expression is altered in responses to hypoxia.
Dr. Gradin will present recent data on the inhibitory PAS (Per/Arnt/Sim) domain protein, IPAS, demonstrating its functions as a dominant negative regulator of HIF-mediated control of gene expression and angiogenesis. Furthermore, Dr. Gradin will present the work that led to the identification of an inhibitor of the dioxin receptor. The Ah-receptor repressor (AhRR) can bind to cognate response elements, thereby functioning as a negative regulator of the dioxin receptor function.