Subcellular localization and stability of MITF are modulated by the bHLH-Zip domain
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Subcellular localization and stability of MITF are modulated by the bHLH-Zip domain. / 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.
in: PIGM CELL MELANOMA R, Jahrgang 32, Nr. 1, 01.2019, S. 41-54.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Subcellular localization and stability of MITF are modulated by the bHLH-Zip domain
AU - Fock, Valerie
AU - Gudmundsson, Sigurdur Runar
AU - Gunnlaugsson, Hilmar Orn
AU - Stefansson, Jon August
AU - Ionasz, Vivien
AU - Schepsky, Alexander
AU - Viarigi, Jade
AU - Reynisson, Indridi Einar
AU - Pogenberg, Vivian
AU - Wilmanns, Matthias
AU - Ogmundsdottir, Margret Helga
AU - Steingrimsson, Eirikur
N1 - © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
PY - 2019/1
Y1 - 2019/1
N2 - 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.
AB - 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.
KW - Amino Acid Sequence
KW - Arginine/metabolism
KW - Cell Line
KW - Cell Nucleus/metabolism
KW - Helix-Loop-Helix Motifs
KW - Humans
KW - Microphthalmia-Associated Transcription Factor/chemistry
KW - Protein Domains
KW - Protein Multimerization
KW - Protein Stability
KW - Protein Transport
KW - Subcellular Fractions/metabolism
U2 - 10.1111/pcmr.12721
DO - 10.1111/pcmr.12721
M3 - SCORING: Journal article
C2 - 29938923
VL - 32
SP - 41
EP - 54
JO - PIGM CELL MELANOMA R
JF - PIGM CELL MELANOMA R
SN - 1755-1471
IS - 1
ER -