Subcellular localization and stability of MITF are modulated by the bHLH-Zip domain

被引：22

作者：

Fock, Valerie ^{[1
]}

Gudmundsson, Sigurdur Runar ^{[1
]}

Gunnlaugsson, Hilmar Orn ^{[1
]}

Stefansson, Jon August ^{[1
]}

Ionasz, Vivien ^{[1
]}

Schepsky, Alexander ^{[1
]}

Viarigi, Jade ^{[1
]}

Reynisson, Indridi Einar ^{[1
]}

Pogenberg, Vivian ^{[2
]}

Wilmanns, Matthias ^{[2
]}

Ogmundsdottir, Margret Helga ^{[1
]}

Steingrimsson, Eirikur ^{[1
]}

机构：

[1] Univ Iceland, Fac Med, Dept Biochem & Mol Biol, Biomed Ctr, Sturlugata 8, IS-101 Reykjavik, Iceland

[2] DESY, EMBL Hamburg, Hamburg, Germany

来源：

PIGMENT CELL & MELANOMA RESEARCH | 2019年 / 32卷 / 01期

基金：

奥地利科学基金会;

关键词：

bHLH-Zip; MITF; nuclear localization; stability; Waardenburg syndrome; MICROPHTHALMIA; MUTATIONS; WAARDENBURG; MELANOMA; GENE; PREDISPOSES; MECHANISM; AUTOPHAGY; LYSOSOME; MOUSE;

D O I：

10.1111/pcmr.12721

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：41 / 54

页数：14

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