Subcellular localization and stability of <scp>MITF</scp> are modulated by the <scp>bHLH</scp>‐Zip domain

Fock, Valerie; Guðmundsson, Sigurður; Gunnlaugsson, Hilmar Orn; Stefansson, Jon August; Ionasz, Vivien; Schepsky, Alexander; Viarigi, Jade; Reynisson, Indriði Einar; Pogenberg, Vivian; Wilmanns, Matthias; Ögmundsdóttir, Margrét H.; Steingrı́msson, Eirı́kur

doi:10.1111/pcmr.12721

Cited by 30 publications

(24 citation statements)

References 37 publications

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“…Although there are no published reports of MITF being acetylated, there are several lysine residues upstream of the basic helix loop helix domain that are predicted to be acetylation sites [65]. These are in regions of MITF that modulate its localization to the nucleus [65,66]. Moreover, MITF like MYOD in myocytes, interacts with the histone acetyl transferase, CBP, which can affect DNA binding and activity [67,68].…”

Section: Discussionmentioning

confidence: 99%

Bromodomain and extra-terminal domain (BET) proteins regulate melanocyte differentiation

Trivedi

Mehrotra

Baum

et al. 2020

Epigenetics & Chromatin

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Background: Pharmacologic inhibition of bromodomain and extra-terminal (BET) proteins is currently being explored as a new therapeutic approach in cancer. Some studies have also implicated BET proteins as regulators of cell identity and differentiation through their interactions with lineage-specific factors. However, the role of BET proteins has not yet been investigated in melanocyte differentiation. Melanocyte inducing transcription factor (MITF) is the master regulator of melanocyte differentiation, essential for pigmentation and melanocyte survival. In this study, we tested the hypothesis that BET proteins regulate melanocyte differentiation through interactions with MITF. Results: Here we show that chemical inhibition of BET proteins prevents differentiation of unpigmented melanoblasts into pigmented melanocytes and results in de-pigmentation of differentiated melanocytes. BET inhibition also slowed cell growth, without causing cell death, increasing the number of cells in G1. Transcriptional profiling revealed that BET inhibition resulted in decreased expression of pigment-specific genes, including many MITF targets. The expression of pigment-specific genes was also down-regulated in melanoma cells, but to a lesser extent. We found that RNAi depletion of the BET family members, bromodomain-containing protein 4 (BRD4) and bromodomaincontaining protein 2 (BRD2) inhibited expression of two melanin synthesis enzymes, TYR and TYRP1. Both BRD4 and BRD2 were detected on melanocyte promoters surrounding MITF-binding sites, were associated with open chromatin structure, and promoted MITF binding to these sites. Furthermore, BRD4 and BRD2 physically interacted with MITF. Conclusion: These findings indicate a requirement for BET proteins in the regulation of pigmentation and melanocyte differentiation. We identified changes in pigmentation specific gene expression that occur upon BET inhibition in melanoblasts, melanocytes, and melanoma cells.

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Section: Discussionmentioning

confidence: 99%

Bromodomain and extra-terminal domain (BET) proteins regulate melanocyte differentiation

Trivedi

Mehrotra

Baum

et al. 2020

Epigenetics & Chromatin

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“…Since GSK3 is inhibited by both WNT and PI3K signaling, the MITF export signal is responsive to two key signaling pathways downstream from receptor tyrosine kinases, which are also deregulated in melanoma. Under normal conditions, however, MITF-M is predominantly nuclear owing to a constitutive nuclear localization signal within its basic region (Takebayashi et al 1996;Fock et al 2018) and the absence of a domain that mediates cytoplasmic retention of exon 1B-containing isoforms (Martina and Puertollano 2013;Ngeow et al 2018). Flux through the nuclear import-export cycle regulated by both GSK3 and ERK and their associated signaling pathways is likely to play a key role in MITF function.…”

Section: Mitf Posttranslational Regulationmentioning

confidence: 99%

MITF—the first 25 years

2019

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“…The MITF-M cDNA was cloned into the p3xFlag-CMV14 vector using EcoRI and BamHI restriction sites. The four arginines in the basic domain were mutated to alanines by in situ mutagenesis to generate the construct MITF-B4RA (Fock et al, 2019). The human TYR promoter in pGL3 Basic Luciferase Reporter vector was used for co-transfection assays.…”

Section: Plasmidsmentioning

confidence: 99%

Mitf Links Neuronal Activity and Long-Term Homeostatic Intrinsic Plasticity

Atacho¹,

Reynisson²,

Pétursdóttir³

et al. 2020

eNeuro

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Neuroplasticity forms the basis for neuronal circuit complexity and differences between otherwise similar circuits. We show that the microphthalmia-associated transcription factor (Mitf) plays a central role in intrinsic plasticity of olfactory bulb (OB) projection neurons. Mitral and tufted (M/T) neurons from Mitf mutant mice are hyperexcitable, have a reduced A-type potassium current (I A) and exhibit reduced expression of Kcnd3, which encodes a potassium voltage-gated channel subunit (Kv4.3) important for generating the I A. Furthermore, expression of the Mitf and Kcnd3 genes is activity dependent in OB projection neurons and the MITF protein activates expression from Kcnd3 regulatory elements. Moreover, Mitf mutant mice have changes in olfactory habituation and have increased habituation for an odorant following long-term exposure, indicating that regulation of Kcnd3 is pivotal for long-term olfactory adaptation. Our findings show that Mitf acts as a direct regulator of intrinsic homeostatic feedback and links neuronal activity, transcriptional changes and neuronal function.

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

Cited by 30 publications

References 37 publications

Bromodomain and extra-terminal domain (BET) proteins regulate melanocyte differentiation

Bromodomain and extra-terminal domain (BET) proteins regulate melanocyte differentiation

MITF—the first 25 years

Mitf Links Neuronal Activity and Long-Term Homeostatic Intrinsic Plasticity

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