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Subcellular localization and stability of MITF are modulated by the bHLH ‐Zip domain
Author(s) -
Fock Valerie,
Gudmundsson Sigurdur Runar,
Gunnlaugsson Hilmar Orn,
Stefansson Jon August,
Ionasz Vivien,
Schepsky Alexander,
Viarigi Jade,
Reynisson Indridi Einar,
Pogenberg Vivian,
Wilmanns Matthias,
Ogmundsdottir Margret Helga,
Steingrimsson Eirikur
Publication year - 2019
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/pcmr.12721
Subject(s) - microphthalmia associated transcription factor , leucine zipper , transcription factor , gene isoform , nuclear localization sequence , subcellular localization , basic helix loop helix leucine zipper transcription factors , microbiology and biotechnology , mutant , basic helix loop helix , biology , dna binding protein , chemistry , genetics , gene , cytoplasm
Summary Microphthalmia‐associated transcription factor ( MITF ) is a member of the basic helix–loop–helix leucine zipper ( bHLH ‐Zip) family and functions as the master regulator of the melanocytic lineage. MITF ‐M is the predominant isoform expressed in melanocytes and melanoma cells, and, unlike other MITF isoforms, it is constitutively nuclear. Mutational analysis revealed three karyophilic signals in the bHLH ‐Zip domain of MITF ‐M, spanning residues 197–206, 214–217, and 255–265. Structural characterization of the MITF protein showed that basic residues within these signals are exposed for interactions in the absence of DNA . Moreover, our data indicate that neither DNA binding nor dimerization of MITF ‐M are required for its nuclear localization. Finally, dimerization‐deficient MITF ‐M mutants exhibited a significantly reduced stability in melanoma cells when compared to the wild‐type protein. Taken together, we have shown that, in addition to its well‐established role in DNA binding and dimer formation, the bHLH ‐Zip domain of MITF modulates the transcription factor's subcellular localization and stability.