• Abstract and Figures
• Public Full-text

Review article Microphthalmia-associated transcription factor (MITF) – from Waardenburg syndrome genetics to melanoma therapy Ivan Šamija, Josip Lukač, Zvonko Kusić Department of Oncology and Nuclear Medicine, Microphthalmia-associated transcription factor (MITF) was University Hospital “Sestre milosrdnice”, first discovered as protein coded by gene whose mutations Zagreb, Croatia are associated with Waardenburg syndrome. Later, MITF was shown to be key transcription factor regulating melanogen- esis. Further studies have shown that in addition to regulat- ing melanogenesis MITF also plays central role in regulation Corresponding author: of melanocyte development and survival. MITF gene is am- Ivan Šamija plified in a proportion of melanomas and ectopic MITF ex- Department of oncology and Nuclear Medicine pression can transform melanocytes so MITF can function University Hospital “Sestre milosrdnice” as melanoma “lineage survival” oncogene. Different studies Vinogradska cesta 29 have further revealed MITF’s important but complex role in 10000 Zagreb tumorigenesis and progression of melanoma. As expected Croatia from its important role in melanocytes and melanoma MITF [email protected] is intricately regulated on all the levels from transcription to Tel.: + 385 1 3787647 post-translational modifications. Although complex mecha- nisms of MITF functioning are still being revealed, MITF already has a valuable role in managing melanoma patients. Immunohistochemical analysis of MITF has shown both di- agnostic and prognostic value in patients with melanoma. MITF is also a valuable specific marker for detection of circu- lating melanoma cells by reverse-transcription – polymerase chain reaction. MITF has recently been investigated as a po- tential target for melanoma therapy. Key words: Microphthalmia-associated transcription fac- Received: 28 September 2010 tor, Melanoma, Melanocytes, Biological tumor markers, Accepted: 31 October 2010 Waardenburg’s syndrome. Introduction has also an important role in melanoma tumorigenesis and progression. The role of Microphthalmia-associated transcription MITF in both normal melanocytes and mel- factor (MITF) was first discovered as a anoma is complex and depends on intricate protein associated with Waardenburg syn- system of regulation on different levels, from drome. Further studies have revealed MITF MITF transcription to post-translational as a master regulator of melanocyte func- modifications. That system, all components tion, development and survival. As expected of which are still being discovered, enables from its role in normal melanocytes, MITF MITF to adjust behaviour of melanocytes 175 Acta Medica Academica 2010;39:175-193 and melanoma cells to various signals com- ed on a non-mutated allele of MITF gene ing from within the cell and from the envi- can’t reach the intracellular concentration ronment of the cell. Although all the com- necessary for its normal function (7). The ponents of MITF’s functioning are still un- symptoms of Waardenburg syndrome type known, MITF already has a valuable role in 2 (white patches of the skin, altered iris pig- managing patients with melanoma as diag- mentation and loss of hearing associated nostic and prognostic marker. Also, several with absence of melanocytes in stria vas- therapeutic approaches to melanoma target- cularis of the cochlea) can be explained as ing MITF are being explored. In addition a consequence of the melanocyte depletion to its role in melanocytes and melanoma, (3). Mutations in MITF gene have also been MITF also plays important role in several associated with Tietz syndrome, which is a other cell types, like osteoclasts and mast rare hereditary auditory-pigmentary dis- cells, but the focus of this review will be on order (8). The symptoms characteristic for a complex role of MITF in melanocytes and Tietz syndrome are similar to the ones as- melanoma, and on application of MITF in sociated with Waardenburg syndrome type managing melanoma patients. 2 but are present in a more severe form (8). Mice with mutations in microphthalmia (mi) locus which is responsible for the syn- MITF and Waardenburg syndrome thesis of Mitf, a mouse homologue of MITF, MITF was discovered as a protein coded on have following disorders: loss of pigmenta- a gene locus associated with Waardenburg tion, reduced eye size (microphthalmia), re- syndrome in humans (1, 2). Waardenburg duced number of mast cells, osteoporosis as a syndrome is a hereditary autosomal domi- consequence of disturbed osteoclast function, nant disorder characterized by heterochro- and hearing impairment (9). These disorders mia iridis, patchy abnormal pigmentation of implicate a role of Mitf in the development the hair and skin and sensorineural deafness and function of melanocytes, mast cells, reti- (3). Clinically Waardenburg syndrome is nal pigment epithelial cells and osteoclasts. classified in four types. Waardenburg syn- drome type 1 and Waardenburg syndrome MITF isoforms type 3 have been associated with mutations in PAX3 gene (4). Waardenburg syndrome Gene MITF is located on a third human type 4 also known as Waardenburg-Shah chromosome in a region 3p12.3-3p14.1 and syndrome has been associated with muta- is responsible for the synthesis of nine so tions in three genes, SOX10, gene for endo- far described isoforms: MITF-M, MITF-A, thelin 3, and gene for endothelin receptor B MITF-H, MITF-B, MITF-C, MITF-D, MITF- (EDNRB) (5). Mc, MITF-E and MITF-J (2, 10-16) (Figure Waardenburg syndrome type 2 has been 1.). Protein MITF contains a basic domain associated with mutations in one allele of required for DNA binding and helix-loop- MITF gene (6, 7). It has been shown that helix and leucine zipper domains required for mutations in one allele of MITF gene do not dimer formation (bHLH-LZ structure) (1-2). influence the activity of protein coded on MITF is similar in amino acid sequence to the other (non-mutated) copy of MITF gene other transcription factors that share the same (7). Therefore the dominant inheritance of bHLH-LZ structure: TFE3, TFEB and TFEC Waardenburd syndrome type 2 has been (17-19). MITF can bind DNA as a homodi- explained as a result of haploinsufficiency, mer or as a heterodimer with transcription mechanism by which a MITF protein cod- factors TFE3, TFEB and TFEC (17). 176 Ivan Šamija et al .: Microphthalmia-associated transcription factor All the isoforms of MITF protein have in comparison to normal melanocytes (23). a common C-terminal region containing a MITF-M is specifically expressed in mela- domain required for transcription activa- nocytes originating from neural crest and in tion and bHLH-LZ structure but each iso- melanoma cells (10, 11, 24, 25). The malano- form has a distinct N-terminal region (20, cyte-restricted promoter region from which 21) (Figure 1). The shortest isoform MITF- MITF-M isoform is transcribed is respon- M consists of 419 amino acids and contains sible for such a specific expression of this a unique N-terminal domain M (amino acid isoform (26). A splice variant of MITF-M sequence: MLEMLEYNHY) and a six amino named MITF-Mdel containing two in frame acids insert (ACIFPT) close to the basic re- deletions, 56 amino acids deletion in exon gion of the protein (18). It has been shown 2 (from V32 to E87) and 6 amino acids de- that also the MITF-M protein without this letion in exon 6 (from A187 to T192), has six amino acids insert is synthesized (18). been identified (27). Like MITF-M, MITF- Bismuth et al have shown that MITF-M iso- Mdel is also specifically expressed in mela- form containing six amino acids insert can nocytes and melanoma cells (27). inhibit cell proliferation unlike the isoform Isoforms MITF-A, MITF-H, MITF-B, without six amino acids insert (22). In accor- MITF-C, MITF-Mc and MITF-J have a com- dance to this finding substantially increased mon B1b domain of 83 amino acid residues proportion of isoform without six amino ac- and each its unique N-terminal domain (A, H, ids insert was found in metastatic melanoma B1a, C, Mc and J) (13-16, 18, 20) (Figure 1). Figure 1 Structures of MITF isoforms . Schematic representations of all described isoforms of MITF protein (MITF-M, MITF-A, MITF-H, MITF-B, MITF-C, MITF-D; MITF-Mc, MITF-E and MITF-J) are shown . An activation region (AR), basic helix-loop-helix leucine-zipper region (bHLH-LZ), serine-rich region (S) and N-terminal regions encodedy b isoform-specific exons (A, B1a, B1b, C, H, Mc and M) are indicated for each isoform . Corresponding exons of MITF gene (1A, 1B1a, 1B1b, 1C, 1D, 1E, 1H, 1J, 1Mc, 1M, 2, 3, 4, 5, 6, 7, 8 and 9) are indicated under the schematic representation of each isoform . 177 Acta Medica Academica 2010;39:175-193 Domain A consists of 35 amino acid resi- are encoded by ten exons. Each isoform is dues, domain H of 19, domain B1a of 10, transcribed from its own unique promoter, and domain C of 34 amino acid residues (12, suggesting the functional diversity of these 20). Unlike the other isoforms, the transla- isoforms in different tissues (12). The amino tion of MITF-E and MITF-D, and probably acid sequences of homologues of human also MITF-J isoform, does not start from the MITF protein have been determined in mice first exon, because it does not contain a code (1), rats (28), chicken (29), hamsters (30), for methionine, but it starts from within quails (31) and zebrafish (Danio rerio) (32). B1b region (Figure 1.). Therefore the protein All of these sequences are highly homolo- products for these three isoforms (MITF-E, gous with the one of human MITF protein. MITF-D and MITF-J) are the same (13, 14, Analysis of publicly available genomic se- 16) (Figure 1). quence data indicates the existence of genes Isoforms MITF-A and MITF-H are ex- homologous to human MITF gene also in pressed in different cell types, including me- other vertebrate as well as invertebrate spe- lanocytes and melanoma cells, with varying cies (33).

Load more

  19

Copy Link