Málstofa Lífvísinaseturs: Novel mechanisms of MITF regulation identified

Málstofa Lífvísindaseturs fimmtudaginn 31. október kl. 12:00 í Árnagarði, stofu 201

Fyrirlesari: Dr. Nhung Hong Vu, nýdoktor á rannsóknastofu Eiríks Steingrímssonar, Læknadeild, Háskóla Íslands

Titill: Novel mechanisms of MITF regulation identified in a mouse suppressor screen

Ágrip: MITF, a basic-Helix-Loop-Helix Zipper (bHLHZip) transcription factor, plays vital roles in melanocyte development and functions as an oncogene. We performed a genetic screen for suppressors of the Mitf-associated pigmentation phenotype in mice and identified an intragenic Mitf mutation that terminates MITF at the K316 SUMOylation site leading to loss of the C-end intrinsically disordered region (IDR). The resulting protein is more nuclear but less stable than wild-type MITF and retains DNA-binding ability. Interestingly, as a dimer, it can translocate wild-type and mutant MITF partners into the nucleus, improving its own stability thus ensuring nuclear MITF supply. Interactions between K316 SUMOylation and S409 phosphorylation sites across monomers largely explain the observed effects. Notably, the recurrent melanoma-associated E318K mutation in MITF, which affects K316 SUMOylation, also alters protein activity in concert with S409, inducing the expression of AXL and BRN2, genes implicated in melanoma metastasis and resistance. Suppressor screens in the mouse can unravel novel regulatory mechanism with unexpected disease insights. 

Heimild: 10.1038/s44319-024-00225-3