BMC Seminar Thursday 16th of November at 12:00 in room 343 Læknagarður
Speaker: Josué Ballesteros, PhD student at Eiríkur Steingrímsson´s lab, Faculty of Medicine, Sturlugata 8
Title: MITF, TFEB and TFE3 in melanoma – Regulation and interaction
Abstract: The MITF, TFEB, TFE3 and TFEC (MiT-TFE) proteins belong to a larger family of basic helix-loop-helix leucine zipper transcription factors that are able to bind to E and M boxes. MITF is crucial for melanocyte development and has been called a lineage specific oncogene in melanoma whereas its relatives, TFEB and TFE3, are involved in the biogenesis and function of lysosomes and autophagosomes, regulating cellular clearance pathways.
We have investigated the interaction, cross-regulatory relationship and nuclear localization of MITF, TFE3 and TFEB in melanoma cells. Like MITF, the TFEB and TFE3 genes are expressed in melanoma cells and tissues. Using co-immunoprecipitation studies, we demonstrate that MITF, TFEB and TFE3 interact in melanoma cells forming heterodimers. However, they are not able to interact with other members of the bHLH family such as MAX. We have identified a three amino acid region that is responsible for dimerization specificity. Through mutagenesis, we are constructing a version of MITF that only forms homodimers and will determine its effects on gene expression. Reporter gene and ChIP assays show that the three factors are able to bind and activate expression of genes involved in autophagy, as well as in lysosomal and melanosomal biogenesis. Interestingly, some genes are exclusively regulated by one of the factors.
The relationship between MITF, TFEB and TFE3 is complex and involves regulation of gene expression, protein-protein interactions and complementary functions. It is important to unravel further this relationship in melanoma in order to better understand the cross-regulatory mechanisms. This requires the characterization of common and unique targets of these factors and their ability to form homo- and heterodimers.