MITF gene

MITF (Melanocyte Inducing Transcription Factor) is a protein coding gene located on chromosome 3p13. The protein encoded by this gene is a transcription factor that has both basic helix-loop-helix and leucine-zipper structural features. An important paralog of this gene is TFE3.

The gene codes for MITF (microphthalmia-associated transcription factor), a transcription factor that acts as the main regulator of melanocyte survival and differentiation as well as melanosome biogenesis. The encoded protein MITF regulates melanocyte development and is responsible for pigment cell-specific transcription of melanogenesis enzyme genes.

MITF is a basic-helix-loop-helix-leucine zipper (bHLHZip) factor that regulates the expression of tyrosinase and other melanocytic genes via a CATGTG promoter sequence and is involved in melanocyte differentiation.

Mutations of MITF in mice or humans with Waardenburg syndrome type 2 (WS2) often lead to severe disruption of the bHLHZip domain, indicating the importance of this structure (Takeda K et al. 2000).

MITF and β-catenin play a central role in the survival of melanocytes and melanoma cells (Genovese G et al. 2021). The transcriptional activity of MITF and β-catenin is inhibited by HITN-1. Stable, constitutive overexpression of the HINT1 protein in human melanoma cells significantly impaired cell proliferation in vitro and tumorigenesis in vivo (Genovese G et al. 2021).

MITF binds to M-boxes (5'-TCATGTG-3') and symmetrical DNA sequences (E-boxes) (5'-CACGTG-3') in the promoter of pigmentation genes such as tyrosinase (TYR) ((Takeda K et al. 2000; Amae S et al. 1998). The transcription factor is involved in the cellular response to amino acid availability by acting downstream of MTOR: in the presence of nutrients, MITF phosphorylation by MTOR promotes its inactivation (Nardone C et al. 2023). During starvation or lysosomal stress, inhibition of MTOR leads to dephosphorylation of MITF and thus to transcription factor activity (Nardone C et al. 2023). MITF plays an important role in melanocyte development by regulating the expression of tyrosinase (TYR) and tyrosinase-related protein 1 (TYRP1). Plays a crucial role in the differentiation of various cell types, such as melanocytes from the neural crest, mast cells, osteoclasts and pigment epithelial cells from the optic nerve head (Amae S et al. 1998).

Heterozygous mutations in this gene lead to auditory-pigmentary syndromes such as Waardenburg syndrome type 2 and Tietz syndrome.

In animals, mutations in this gene lead to leucism.

1. Amae S et al. (1998) Identification of a novel isoform of microphthalmia-associated transcription factor that is enriched in retinal pigment epithelium. Biochem Biophys Res Commun 247:710-715.
2. Genovese G et al. (2021) The tumor suppressor HINT1 regulates MITF and β-catenin transcriptional activity in melanoma cells. Cell Cycle 11:2206-2215.
3. Nardone C et al. (2023) A central role for regulated protein stability in the control of TFE3 and MITF by nutrients. Mol Cell 83:57-73.e9.
4. Takeda K et al. (2000) Ser298 of MITF, a mutation site in Waardenburg syndrome type 2, is a phosphorylation site with functional significance. Hum Mol Genet 9(:125-132.