Trends in Molecular Medicine
Volume 12, Issue 9, September 2006, Pages 406-414
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Review
MITF: master regulator of melanocyte development and melanoma oncogene

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Microphthalmia-associated transcription factor (MITF) acts as a master regulator of melanocyte development, function and survival by modulating various differentiation and cell-cycle progression genes. It has been demonstrated that MITF is an amplified oncogene in a fraction of human melanomas and that it also has an oncogenic role in human clear cell sarcoma. However, MITF also modulates the state of melanocyte differentiation. Several closely related transcription factors also function as translocated oncogenes in various human malignancies. These data place MITF between instructing melanocytes towards terminal differentiation and/or pigmentation and, alternatively, promoting malignant behavior. In this review, we survey the roles of MITF as a master lineage regulator in melanocyte development and its emerging activities in malignancy. Understanding the molecular function of MITF and its associated pathways will hopefully shed light on strategies for improving therapeutic approaches for these diseases.

Section snippets

Microphthalmia-associated transcription factor

Microphthalmia-associated transcription factor (MITF) is a tissue restricted, basic helix–loop–helix leucine zipper (b-HLH-Zip), dimeric transcription factor. It is encoded by the Mitf locus in mice [1] and, when mutated, leads to defects in melanocytes, the retinal pigmented epithelium, mast cells and osteoclasts 1, 2, 3.

Functionally, MITF binds to the canonical E-box promoter sequence CACGTG and the non-palindromic sequence CACATG 4, 5, 6. MITF binds to DNA as a dimer, involving a parallel

Transcriptional and post-translational MITF regulation

The MITF gene has a multi-promoter organization in which at least nine distinct promoter–exon units direct the initiation of specific MITF isoforms that differ in their first one or two exons, which are spliced onto the common downstream exons [12] (Figure 1). The promoter that is located most proximal to the common downstream exons is known as the M promoter and seems to be selectively expressed in melanocytes [13]. The melanocyte-specific exon adds only a small number of amino acids that are

Mutation of the Mitf locus

In humans, mutation of MITF causes Waardenburg syndrome (WS) type IIA [34]. This autosomal dominant inherited condition [35] arises from melanocytic deficiencies in the eye, forelock and inner ear. The most serious consequence of MITF mutation in affected individuals is sensorineural hearing impairment (ranging from mild to severe). Although their precise actions are uncertain, melanocytes reside within the stria vascularis of the cochlea (inner ear) where their presence is thought to

Mutations and genetic models of melanoma

Melanoma, a neoplasm of melanocytic origin, is the most severe human skin cancer and is highly resistant to treatment. During the past ten years, the incidence and annual mortality of melanoma has increased more rapidly than any other cancer. Although progress has been made in deciphering the molecular underpinnings of melanoma, successful treatment for metastatic melanoma remains frustratingly uncommon [48].

The increased incidence of melanoma correlates with discordance between human skin

MITF in melanoma progression

Evidence that MITF is an oncogene in human melanoma came from studies investigating chromosomal alterations in human cancer cell lines using high-density single nucleotide polymorphism (SNP) arrays [65]. These studies identified copy gains at the MITF locus in melanoma lines, and corroborated those findings by fluorescence in situ hybridization. Using primary melanoma tissue microarrays, MITF was found to be amplified in 10–20% of cases, with a higher incidence among advanced (metastatic)

Transcriptional target genes of MITF

Because MITF seems to have a pivotal role in melanocyte development and melanoma, it is crucial to examine the transcriptional target genes of MITF. Although it is probably an oversimplification, the growing number of MITF target genes can be classified into two groups: differentiation or growth and/or survival genes (Figure 3).

MITF regulates the transcription of three major pigmentation enzymes: TYR, TYRP1 and DCT. The promoters of these genes contain the MITF consensus E-box sequence and they

MiT family cancers

In addition to the identification of MITF as an amplified oncogene in melanoma, the human TFE3 and TFEB genes have also been implicated in human cancer. Translocations involving fusions of pediatric renal-cell carcinoma (PRCC), non-POU domain-containing octamer-binding protein (NONO, also known as p54nrb), PSF, regulator of chromosome condensation 1 (RCC1) and alveolar soft-part sarcoma (ASPL) to TFE3 have been identified in renal-cell carcinomas and in alveolar soft-part sarcomas 93, 94, 95, 96

Concluding remarks

Unlike most normal cellular precursors of specific cancers in humans, melanocytes have a specifically important role in protecting humans from UV-induced skin cancers. For this reason, additional understanding of pigment biology and its regulation might impact cancer through the development of novel prevention strategies. Conversely, MITF oncogenic activities are still poorly understood, although directly implicated in melanoma oncogenesis (Box 1). The discovery of the roles of MITF in melanoma

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