Professor at Faculty of Medicine, Shool of Health Sciences, University of Iceland
Member of the European Molecular Biology Organization (EMBO)
1985, BS, University of Iceland.
1992, PhD, University of California, Los Angeles (UCLA).
1993-1997, Postdoctoral research at the National Cancer Institute in Frederick, Maryland.
1997-present, Professor at the University of Iceland, Faculty of Medicine.
The Steingrimsson group aims to characterize the transcription factor MITF and to understand its role in melanocyte development, pigmentation and melanoma.
The color of our eyes, skin and hair is determined by special cells called melanocytes. Aside from making pigment, melanocytes have many other interesting properties. They originate in the neural crest as melanoblasts and migrate to their destination in the skin, eye, hairbulb and other regions of the body. In the hairbulb, the melanoblasts reach a split road. One leads to the matrix of the hair where they end up as pigment-producing melanocytes. The other leads to the bulge-region where they become melanocyte stem cells. As the hair undergoes cycles of hair renewal, the stem cells are ready to replenish the melanocyte population making sure that the new hair is correctly pigmented . When they have reached their final destination, melanocytes produce the pigment melanin which is deposited into cellular organelles called melanosomes. These organelles are delivered to neighboring cells, shielding their DNA from UV radiation by forming a protective cap over the nucleus.
The transcription factor MITF has been shown to be essential for all steps in melanocyte development and differentiation, including stem cell maintenance. It has thus been termed the master regulator of melanocytes. MITF has also been shown to be important in melanoma, a deadly type of skin cancer, formed from melanocytes. In melanoma, MITF is a key regulator mediating a switch between multiplying tumor cells and dormant migrating cells. How this single transcription factor can mediate multiple events during melanocyte development on one hand and melanomagenesis on the other hand, is a critical question. How this master regulator is controlled and which signalling processes regulate its expression and activity are the major questions that the members of the laboratory are trying to answer.
MITF has a central role in melanoma, melanocyte development and pigmentation. It is crucial, therefore, to fully understand its range of target genes, how it is regulated by signaling pathways and how it interacts with other transcription factors to determine its multiple roles in the cell. At present, little is known about how MITF influences tumor formation. Similarly, it is not clear which genes MITF regulates during normal pigmentation in humans or those with various pigmentation phenotypes.
Our future aims in characterizing and understanding the functions of MITF are threefold:
- To identify human pigmentation genes and determine their role in melanocytes and melanoma and their regulation by MITF. This is being performed in collaboration with Decode genetics.
- To determine how MITF interacts with other transcription factors, including IRF4 and TFEB. We have shown that IRF4 is important for human pigmentation where it interacts with MITF to mediate pigmentation. In collaboration with Matthias Willmanns’group at EMBL, we have recently solved the crystal structure (add link) of the MITF protein, an important step in understanding its specificity in selecting partner proteins. TFEB can interact with MITF and form DNA-binding heterodimers. More importantly, TFEB is a master regulator of lysosomes. As lysosomes and melanosomes are related organelles, it is important to understand the interaction of these proteins.
- To analyze how MITF is regulated by signaling. It is known that MITF activity and stability are affected by signaling pathways. In collaboration with Lars Rönnstrand at Lund University, we are characterizing the phosphorylation pattern of MITF, determining which signaling pathways are involved and analyzing their functional consequences. As activating mutations are found in BRAF in about 50% of all melanoma it is important to understand whether this leads to effects on MITF activity.
We are always looking for new people to join our lab. Feel free to contact us with any further questions.
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