MITF-the first 25 years

Abstract

All transcription factors are equal, but some are more equal than others. In the 25 yr since the gene encoding the microphthalmia-associated transcription factor (MITF) was first isolated, MITF has emerged as a key coordinator of many aspects of melanocyte and melanoma biology. Like all transcription factors, MITF binds to specific DNA sequences and up-regulates or down-regulates its target genes. What marks MITF as being remarkable among its peers is the sheer range of biological processes that it appears to coordinate. These include cell survival, differentiation, proliferation, invasion, senescence, metabolism, and DNA damage repair. In this article we present our current understanding of MITF's role and regulation in development and disease, as well as those of the MITF-related factors TFEB and TFE3, and highlight key areas where our knowledge of MITF regulation and function is limited.

Keywords: MITF; MiT family; melanocytes; melanoma; transcription factor.

Figure 1.

Phenotypes associated with MITF mutations in mice and humans. (A) Microphthalmia and white coat seen in a mouse homozygous for the Mitf^mi-vga9 mutation (due to the insertion of a transgene). (B) COMMAD (coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness) syndrome, here due to compound heterozygosity for K206N/R217Del based on the (+) MITF-M sequence or K307N/R318Del based on the (−) MITF-A sequence as published by George et al. (2016). (Note, however, that based on the deletion of one of three AGA codons in a row, it is impossible to determine which of the three corresponding arginines R215-R217 is deleted.) (Photograph courtesy of the Withrow family.)

Figure 2.

Schematic representation of the human MITF gene and protein isoforms. Exon/intron distribution and protein isoforms differing at their N termini are shown. Note that exon 1MC is based on similarity with the mouse sequence. For detailed annotated sequences, see Supplemental Figures S1 (for human MITF) and S2 (for mouse Mitf).

Figure 3.

Structure of mouse MITF cocrystalized with dsDNA. Protein: Ribbon view of a dimer of two monomeric bHLH-LZ domains of MITF, comprised of 118 residues each (protein database: 4ATI). DNA: cartoon view of a 16-nt dsDNA comprising an M-box motif with flanking sequences (Pogenberg et al. 2012). The left part of the figure schematically represents the different parts of the bHLH-LZ domain of the cocrystal structure of MITF.

Figure 4.

Representative spontaneous, ENU-induced and engineered mouse Mitf mutations (top panel) and selected symptomatic human MITF mutations (bottom panel). (For detailed references for mouse mutations, see Mouse Genome Informatics, http://www.informatics.jax.org/phenotypes.shtml; for human mutations, see Leiden Open Variable Database, https://databases.lovd.nl/shared/genes/MITF.)

Figure 5.

Schematic representation of MITF posttranslational modifications relevant to pigment cells or osteoclasts and resulting from activation of the indicated signaling pathways. (CD) Conserved domain; (AD) activation domain.

Figure 6.

Schematic diagram of transcription factors regulating the MITF-M promoter positively or negatively and their response to signaling pathways. Transcription factor binding sites, as far as identified, are indicated in Supplemental Figures S1 and S2. Note that the precise binding sites for DEC1 and ALX3 (aristaless-like homeobox 3) are not known. Also, ATF4 (activating transcription factor 4) may repress Mitf-M transcription by directly competing with CREB (cyclic AMP regulatory element-binding protein)-binding (Ferguson et al. 2017).

Figure 7.

Schematic view of the translational control of MITF. Nutrient limitation, inflammation, and ER stress all lead to eIF2α phosphorylation, in turn leading to global inhibition of translation, including that of MITF, but an increase in translation of ATF4, which, as shown in Figure 6, inhibits Mitf-M transcription.

Figure 8.

Schematic view of MITF ChIP-binding peaks over a portion of human chromosome 12 comprising the CDK2 and PMEL genes. The majority of MITF-bound sites are CACGTG E-box motifs flanked by A and/or T, with a minority being equally flanked CATGTG “M-box” motifs present mostly in differentiation-associated genes such as pMEL. The flanking sequences enable discrimination between MITF- and MYC-binding sites.

Figure 9.

MITF interaction partners. Schematic showing some of the well-characterized MITF interaction partners. The NURF and pBAF/BRG complexes facilitate chromatin remodeling by MITF and may include alternative subunits. p300 and CBP are highly related lysine acetyl transferases. β-Catenin facilitates transcription activation of some differentiation-associated genes by MITF, while HINT (histidine triad nucleotide-binding protein) is a negative regulator of MITF function. Other interacting partners (not shown) have been identified, but their function in association with MITF is poorly understood.

Figure 10.

Schematic diagram of target gene regulation by different activity levels of MITF. The selected target genes are associated with the major biological functions of MITF as indicated at the right and in Figure 11. The model, known as the “rheostat model,” shows that high MITF activity levels are associated with cell differentiation and reduced proliferation and that progressively decreasing MITF activity levels are associated with proliferation, dedifferentiation/invasion (as shown for melanoma cells), senescence, and eventually cell death. Note, however, that this schematic integrated view does not reflect the relative induction levels of each target gene. In fact, it is likely that the different “activity levels” of MITF, brought about by absolute protein levels in conjunction with posttranslational modifications and the availability of interacting proteins, are associated with differential regulation, for instance, of proliferation- and differentiation-linked target genes. Furthermore, target gene regulation need not necessarily be directly or indirectly proportional to MITF activity levels and may well be biphasic or multiphasic.

Figure 11.

Summary view of the hallmarks of the biological functions of MITF.