Various environmental and genetic factors affect the development and progression of skin cancers including melanoma. Melanoma development is initially triggered by environmental factors including ultraviolet (UV) light, and then genetic/epigenetic alterations occur in skin melanocytes. These first triggers alter the conditions of numerous genes and proteins, and they induce and/or reduce gene expression and activate and/or repress protein stability and activity, resulting in melanoma progression. Microphthalmia-associated transcription factor (MITF) is a master regulator gene of melanocyte development and differentiation and is also associated with melanoma development and progression. To find better approaches to molecular-based therapies for patients, understanding MITF function in skin melanoma development and progression is important. Here, we review the molecular networks associated with MITF in skin melanoma development and progression.
1. Introduction
Much evidence that environmental factors are correlated with various diseases has been accumulating. The environmental factors can be classified into physical [1–4], chemical [5–8], and biological [9, 10] factors. In addition to the environmental factors, genetic factors also have a great influence on the development and pathogenesis of various diseases [2, 11, 12]. Skin is a representative organ that directly suffers from environmental factors. There is much evidence showing that sunlight and ultraviolet light induce various skin cancers with modulation of the signaling of cell proliferation and DNA damage [13–16]. Therefore, roles of skin cancer-related molecules should be discussed with consideration of the effects of environmental factors. Moreover, the incidence of skin melanoma has recently been increasing at a greater rate than that of any other cancer [17]. In the USA, 68,130 cases of invasive melanoma and at least 48,000 cases of melanoma in-situ were diagnosed in a year [18]. Since melanoma is the most aggressive skin cancers [17, 18], we focus on skin melanoma in this paper.
Not only studies on humans including epidemiological research but also animal models can be useful for analyzing melanomagenesis [19–23]. For example, exposure of skin to oxygen might regulate development of benign melanocytic tumors with modulation of tumor immunity in animal models [19]. Ultraviolet (UV) light is correlated with malignant transformation from benign melanocytic tumors and melanoma [15, 24]. In addition to these environmental factors, various kinds of genetic factors have been reported as crucial factors of melanoma. For example, tyrosine kinases are important for the development and pathogenesis of melanoma in mice and humans [19, 21–23, 25–27]. Various membrane trafficking-associated molecules have also been reported to be involved in melanoma pathogenesis [28–30]. Moreover, some acidic glycosphingolipids have been reported to be expressed at high levels in melanomas and promote their malignant properties by activating cell growth and adhesion signals in melanoma cells [31–33].
Microphthalmia-associated transcription factor (MITF) is believed to be one of the master molecules to regulate melanomagenesis among the many previously reported melanoma-associated molecules. Therefore, we selected MITF as a cancer-associated molecule in melanoma and introduce recent findings regarding MITF in this paper.
2. Results
Melanocytes, melanin-producing cells that are widely distributed in several tissues from fungi to primates on the long evolutionary process, have multifunctionality for survival strategy [34–41]. Melanocytes are also present in skin surfaces and protect them from UV that damages DNA, thereby causing genotoxic mutations or skin cancers [42, 43], but once they transform, they can result in the development of one of the most serious cancers, melanoma.
The MITF gene, encoding a basic-helix-loop-helix-leucine zipper transcription factor, is expressed in melanocytes, retinal pigmented epithelium, mast cells, osteoclasts, and melanoma [36, 37, 40–42, 44–49]. MITF protein forms dimers and binds to specific consensus DNA sequences in the promoter regions of various target genes to regulate several events including differentiation, proliferation, migration, invasion, and tumorigenesis (Figure 1) [50].
MITF-centered schematic scheme of cellular signaling on melanoma development and progression. Open arrows indicate direct transcriptional targets of MITF. The amount of transcripts of these targets is regulated by direct MITF binding to cis-elements in their promoter sequence. Black arrows or lines indicate signal cascades associated with melanoma development and progression. Arrows or lines toward MITF mean direct association by binding to the MITF promoter region or MITF protein. αMSH: melanocyte-stimulating hormone; BCL2: B-cell leukemia/lymphoma 2; BRN2: brain-2; CDK2/CDK4: cyclin-dependent kinase 2/4; CREB: cAMP-responsive element-binding protein; DCT: dopachrome tautomerase; DIA1: diaphanous homolog 1; FZD: frizzled; GSK3β: glycogen synthase kinase 3 beta; HGF: hepatocyte growth factor; HIF1α: hypoxia inducible factor 1, alpha subunit; MC1R: melanocortin 1 receptor; MDM2: transformed mouse 3T3 cell double minute 2; PMEL17: premelanosome protein; RB1: retinoblastoma 1; SCF: stem cell factor; SNAI2: snail homolog 2; SOX10: Sry-related HMG box 10; TYR: tyrosinase, WNT: wingless-related MMTV integration site.
2.2. Regulation of MITF Expression and Activity
Several transcription factors directly control MITF gene transcription to regulate melanocyte and melanoma development. Paired box 3 (PAX3) and Sry-related HMG box 10 (SOX10), highly correlated with melanocyte development and melanomagenesis [51–53], positively regulate MITF expression by directly binding to MITF promoter regions [54–57]. Activation of melanocortin 1 receptor (MC1R) by binding of alpha-melanocyte stimulating hormone (α-MSH) induces cAMP production via activation of adenylyl cyclase and phosphorylates cAMP response element-binding protein (CREB). Phosphorylated CREB directly binds to the MITF promoter region and stimulates MITF transcription [58, 59]. Wingless-type (WNT) signaling is often activated in human melanoma [60–63]. Activation of Frizzled receptors by binding of WNT molecules enhances interaction of β-catenin with TCF/LEF transcription factors, resulting in stimulation of MITF promoter activity [64–66].
Furthermore, MITF protein is modified by several factors after translation. Phosphorylation at Ser 301 of MITF is induced by UV through p38 stress-activated kinase [67], and Ser 298 of the protein is phosphorylated by GSK3β [65], resulting in stimulation of MITF transcriptional activity. The c-KIT receptor activated by stem cell factor (SCF, c-KIT ligand) phosphorylates Ser 73 and thereby increases MITF transcriptional activity followed by immediate degradation of MITF [59, 68], whereas sumoylation at Lys 182 and Lys 316 increases MITF transcriptional activity [69, 70].
2.3. Transcriptional Targets of MITF
MITF is associated with cellular senescence, apoptosis, proliferation, migration/invasion, and differentiation through regulating transcription of target genes.
Overcoming cellular senescence, acquisition of anti-apoptotic activity, and promotion of proliferation are critical cellular events for the initiation of tumorigenesis [50, 71–75]. CDKN2A and WAF1 genes encode senescence mediator proteins, p16INK4A and p14ARF , and p21Cip1 , respectively, and are the well-known familial melanoma locus [71, 73, 76]. Copy number of CyclinD1 (CCND1) gene, a cell cycle mediator, is amplified in 25% of human melanomas [77]. MITF directly binds to the promoter regions of p16Ink4a , p21Cip1 , and CyclinD1 and positively regulates their transcription [78–80]. T-Box transcription factor 2 (TBX2) is highly expressed in melanoma cell lines and represses p19ARF and p21Cip1 , both of which are implicated as effectors of senescence, promotes proliferation, and suppresses senescence in melanoma [81, 82]. TBX2 has also been described as one of the MITF target genes [81]. These reports indicate that MITF is linked to melanoma development as a transcriptional activator of senescence-/proliferation-associated genes.
Antiapoptotic effect is a key process for melanoma development. B-cell leukemia/lymphoma 2 (BCL2) is an antiapoptotic gene and is widely expressed in human melanomas [83–85]. BCL2 is an MITF target gene and is activated at the transcription level [86]. Baculoviral IAP repeat containing 7/melanoma inhibitor of apoptosis (BIRC7/ML-IAP), which is an antiapoptotic regulator, is highly expressed in human melanomas [87] and provides resistance to apoptosis-based chemotherapeutic treatments [88]. BIRC7 transcription is also directly activated by MITF, and overexpression of BIRC7 rescued melanoma from apoptosis in MITF-depleted melanoma cells [87]. Antioxidative stress activity is important for melanocyte survival and melanoma development. Oxidative stress from environmental factors such as solar UV causes DNA damage and apoptosis. Recently, apurinic/apyrimidinic endonuclease1/redox factor-1 (APEX1/Ref1) has been identified as a MITF target gene and has been shown to be partially rescued from oxidative stress-induced apoptosis in MITF-depleted cells [89]. Hypoxia-inducible factor 1 α (HIF1α) has also been demonstrated to be activated at the transcription level by direct MITF binding to the HIF1α promoter region and acts as an antiapoptotic factor in melanoma cells [90]. Antiapoptotic activity and resistance to chemotherapy of melanoma are under the control of MITF activity.
Angiogenesis and invasion are critical steps for tumor progression, and these activities are enhanced in melanoma. MITF depletion in melanoma cells represses not only transcription of HIF1α but also that of vascular endothelial growth factor (VEGF), which is a target of HIF1α and has been demonstrated to be a major contributor to angiogenesis [90]. The c-MET protooncogene, which encodes hepatocyte growth factor receptor (HGFR), is highly expressed in human melanomas and linked to metastatic potential in melanomas. c-MET transcription is directly regulated by MITF [91]. SNAI2 has been reported to be a key player for epithelial-mesenchymal transition (EMT), which is a crucial phenomenon during invasion, metastasis of melanoma, by repressing E-cadherin transcription and stimulating fibronectin expression, and MITF directly activates the transcription level of SNAI2 [92–94]. On the other hand, MITF directly binds to the promoter region of diaphanous homolog 1 (DIAPH1, DIA1) gene and activates its transcription, resulting in inhibiting the invasiveness of melanoma by activation of actin polymerization [95].
MITF is also well known as a master regulator of melanin production. Melanin pigment is synthesized from tyrosine via an enzymatic process. This process is catalyzed by tyrosinase family proteins, tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1), and DCT (dopachrome tautomerase). After melanin production, melanin pigment is stored in melanosomes, which are organelles containing melanin, and is transported to the skin for UV protection. MART1 and PMEL17 are localized in melanosomes and contribute to melanosome maturation [96–99]. Direct regulation of melanin synthesis-associated genes at transcription levels by MITF stimulates melanin production. [100–103].
2.4. “Two-Faced” Function of Mitf in Melanoma Development and Progression
MITF is expressed in most human melanomas, and stability of its expression is essential for melanoma cell proliferation and survival [104]. In addition, amplification of the MITF locus was observed in human metastatic melanomas [105]. However, the expression level of MITF in melanomas is significantly lower than that in normal melanocytes, and higher expression level of MITF in melanoma represses cell proliferation even in the presence of oncogenic BRAF [106]. Most likely, MITF plays both cancer-promoting and cancer-inhibiting roles alternated by the expression level and/or activity. A low level of MITF expression promotes proliferation in melanoma, whereas a high level of MITF expression promotes differentiation through induction of cellular senescence and melanin production [107–109]. MITF has the ability to upregulate transcription of melanoma-promoting genes (e.g., CyclinD1, BCL2, c-MET) and also that of melanoma-repressing genes (e.g., p16Ink4a , p21Cip1 , DIAHP1). Taken together, MITF has two-faced functions in melanoma development and progression, and strict regulation of MITF in its expression and/or activity is likely to switch melanocytes to melanoma cells.
3. Concluding Remarks
Skin melanoma is an aggressive tumor of the skin, and patients have a poor prognosis. Analysis of the expression profile and function of MITF and identification of its target genes are important to better understand the complex system of melanoma development and progression. Expression patterns, functions, and many target genes of MITF have been reported by a number of groups, though the complicated functions of MITF in skin melanoma development and progression are still not well understood. Extensive analyses of MITF will lead to a better understanding of melanoma development and progression and to the establishment of more effective therapeutics.
Ida-EtoM.OhgamiN.IidaM.Partial requirement of endothelin receptor B in spiral ganglion neurons for postnatal development of hearing2011286342962129626OhgamiN.Ida-EtoM.SakashitaN.Partial impairment of c-Ret at tyrosine 1062 accelerates age-related hearing loss in miceNeurobiology of Aging. In pressWefstaedtP.ScheperV.RiegerH.LenarzT.StöverT.Neurotrophic factors of the GDNF family and their receptors are detectable in spiral ganglion cells of normal hearing as well as of deafened rats200685118028082-s2.0-3375152165010.1055/s-2006-925287YlikoskiJ.PirvolaU.MoshnyakovM.PalgiJ.ArumaeU.SaarmaM.Expression patterns of neurotrophin and their receptor mRNAs in the rat inner ear1993651-269782-s2.0-002753561010.1016/0378-5955(93)90202-CHossainK.AkhandA. A.KatoM.DuJ.TakedaK.WuJ.TakeuchiK.LiuW.SuzukiH.NakashimaI.Arsenite induces apoptosis of murine T lymphocytes through membrane raft-linked signaling for activation of c-Jun amino-terminal kinase20001658429042972-s2.0-0034668012KatoM.katomasa@isc.chubu.ac.jpKumasakaM. Y.TakedaK.HossainK.IidaM.YajimaI.GotoY.OhgamiN.L-cysteine as a regulator for arsenic-mediated cancer-promoting and anti-cancer effects201125362362910.1016/j.tiv.2010.12.012KatoM.OnumaS.KatoY.ThangN. D.YajimaI.HoqueM. Z.ShekharH. U.Toxic elements in well water from Malaysia2010929160916122-s2.0-7795669942410.1080/02772241003707454KatoM.TakedaK.HossainK.ThangN. D.KanekoY.KumasakaM.YamanoshitaO.UemuraN.TakahashiM.OhgamiN.KawamotoY.A redox-linked novel pathway for arsenic-mediated RET tyrosine kinase activation201011023994072-s2.0-7795207394210.1002/jcb.22550KatoM.HattoriT.IkedaR.YamamotoJ.YamashitaT.YanagitaN.NakashimaI.Amount of pollen has an effect on the systemic and local levels of soluble ICAM-1 in patients with seasonal allergic rhinitis19965121281322-s2.0-0030009920KatoM.HattoriT.KatoY.MatsumotoY.YamashitaT.NakashimaI.Elevated soluble tumor necrosis factor receptor levels in seasonal allergic rhinitis patients19995432782822-s2.0-003301296410.1034/j.1398-9995.1999.00942.xKatoM.TakedaK.KawamotoY.IwashitaT.AkhandA. A.SengaT.YamamotoM.SobueG.HamaguchiM.TakahashiM.NakashimaI.Repair by Src kinase of function-impaired RET with multiple endocrine neoplasia type 2A mutation with substitutions of tyrosines in the COOH-terminal kinase domain for phenylalanine2002628241424222-s2.0-0037089461OhgamiN.Ida-EtoM.ShimotakeT.SakashitaN.SoneM.NakashimaT.TabuchiK.HoshinoT.ShimadaA.TsuzukiT.YamamotoM.SobueG.JijiwaM.AsaiN.HaraA.TakahashiM.KatoM.c-Ret-mediated hearing loss in mice with Hirschsprung disease20101072913051130562-s2.0-7795564968210.1073/pnas.1004520107KatoM.katomasa@isc.chubu.ac.jpIidaM.GotoY.KondoT.YajimaI.Sunlight exposure-mediated DNA damage in young adults20112081622162810.1158/1055-9965.EPI-11-0228KatoM.IwashitaT.AkhandA. A.LiuW.TakedaK.TakeuchiK.YoshiharaM.HossainK.WuJ.DuJ.OhC.KawamotoY.SuzukiH.TakahashiM.NakashimaI.Molecular mechanism of activation and superactivation of Ret tyrosine kinases by ultraviolet light irradiation2000248418492-s2.0-0034534534KatoM.IwashitaT.TakedaK.AkhandA. A.LiuW.YoshiharaM.AsaiN.SuzukiH.TakahashiM.NakashimaI.Ultraviolet light induces redox reaction-mediated dimerization and superactivation of oncogenic Ret tyrosine kinases2000111931012-s2.0-0033973130KatoM.OhgamiN.KawamotoY.TsuzukiT.HossainK.YanagishitaT.OhshimaY.TsuboiH.YamanoshitaO.MatsumotoY.TakahashiM.NakashimaI.Protective effect of hyperpigmented skin on UV-mediated cutaneous cancer development20071275124412492-s2.0-3424724989310.1038/sj.jid.5700659HusseinM. R.HaemelA. K.SodilovskyO.WoodG. S.Genomic instability in radial growth phase melanoma cell lines after ultraviolet irradiation20055843893962-s2.0-1714439768110.1136/jcp.2004.021519RigelD. S.darrell.rigel@gmail.comEpidemiology of melanoma201029420420910.1016/j.sder.2010.10.005KatoM.LiuW.AkhandA. A.DaiY.OhbayashiM.TuzukiT.SuzukiH.IsobeK. I.TakahashiM.NakashimaI.Linkage between melanocytic tumor development and early burst of Ret protein expression for tolerance induction in metallothionein-I/ret transgenic mouse lines19991838378422-s2.0-003359062510.1038/sj.onc.1202329KatoM.LiuW.YiH.AsaiN.HayakawaA.KozakiK. I.TakahashiM.NakashimaI.The herbal medicine Sho-saiko-to inhibits growth and metastasis of malignant melanoma primarily developed in ret-transgenic mice199811146406442-s2.0-003166436210.1046/j.1523-1747.1998.00341.xKatoM.TakedaK.KawamotoY.TsuzukiT.DaiY.NakayamaS.ToriyamaK.TamadaY.TakahashiM.NakashimaI.RET tyrosine kinase enhances hair growth in association with promotion of melanogenesis20012051753675412-s2.0-003582974210.1038/sj.onc.1204918KatoM.TakedaK.KawamotoY.TsuzukiT.HossainK.TamakoshiA.KunisadaT.KambayashiY.OginoK.SuzukiH.TakahashiM.NakashimaI.c-kit-targeting immunotherapy for hereditary melanoma in a mouse model20046438018062-s2.0-1074423228010.1158/0008-5472.CAN-03-2532KumasakaM. Y.YajimaI.HossainK.IidaM.TsuzukiT.OhnoT.TakahashiM.YanagisawaM.KatoM.A novel mouse model for de novo melanoma201070124292-s2.0-7514912905110.1158/0008-5472.CAN-09-2838KatoM.LiuW.AkhandA. A.HossainK.TakedaK.TakahashiM.NakashimaI.Ultraviolet radiation induces both full activation of Ret kinase and malignant melanocytic tumor promotion in RFP-RET-transgenic mice20001156115711582-s2.0-003451823910.1046/j.1523-1747.2000.0202a-2.xIwamotoT.TakahashiM.ItoM.HamataniK.OhbayashiM.WajjwalkuW.IsobeK.NakashimaI.Aberrant melanogenesis and melanocytic tumour development in transgenic mice that carry a metallothionein/ret fusion gene19911011316731752-s2.0-0026048502KatoM.TakahashiM.AkhandA. A.LiuW.DaiY.ShimizuS.IwamotoT.SuzukiH.NakashimaI.Transgenic mouse model for skin malignant melanoma19981714188518882-s2.0-0032497642OhshimaY.YajimaI.TakedaK.IidaM.KumasakaM.MatsumotoY.KatoM.c-RET molecule in malignant melanoma from oncogenic RET-carrying transgenic mice and human cell lines2010542-s2.0-7795535023010.1371/journal.pone.0010279e10279KatoM.WicknerW.Ergosterol is required for the Sec18/ATP-dependent priming step of homotypic vacuole fusion20012015403540402-s2.0-003542311610.1093/emboj/20.15.4035KatoM.WicknerW.Vam10p defines a Sec18p-independent step of priming that allows yeast vacuole tethering200310011639864032-s2.0-003831308910.1073/pnas.1132162100RichmondA.GuoH. F.DhawanP.YangJ.How do chemokine/chemokine receptor activations affect tumorigenesis?200425674892-s2.0-2142827810HamamuraK.FurukawaK.HayashiT.HattoriT.NakanoJ.NakashimaH.OkudaT.MizutaniH.HattoriH.UedaM.UranoT.LloydK. O.FurukawaK.Ganglioside GD3 promotes cell growth and invasion through p130Cas and paxillin in malignant melanoma cells20051023111041110462-s2.0-2334444859810.1073/pnas.0503658102OhkawaY.MiyazakiS.HamamuraK.KambeM.MiyataM.TajimaO.OhmiY.YamauchiY.FurukawaK.FurukawaK.Ganglioside GD3 enhances adhesion signals and augments malignant properties of melanoma cells by recruiting integrins to glycolipid-enriched microdomains20102853527213272232-s2.0-7795624595110.1074/jbc.M109.087791YamauchiY.FurukawaK.HamamuraK.FurukawaK.koichi@med.nagoya-u.ac.jpPositive feedback loop between PI3K-Akt-mTORC1 signaling and the lipogenic pathway boosts Akt signaling: induction of the lipogenic pathway by a melanoma antigen201171144989499710.1158/0008-5472.CAN-10-4108BloisM. S.Vitamin D, sunlight, and natural selection19681598156522-s2.0-0014407224KameiS.YajimaI.YamamotoH.KobayashiA.MakabeK. W.YamazakiH.HayashiS. I.KunisadaT.Characterization of a novel member of the FGFR family, HrFGFR, in Halocynthia roretzi200027525035082-s2.0-003472667710.1006/bbrc.2000.3334KumasakaM.SatoS.YajimaI.GodingC. R.YamamotoH.Regulation of melanoblast and retinal pigment epithelium development by Xenopus laevis Mitf200523435235342-s2.0-2744444080610.1002/dvdy.20505KumasakaM.SatoS.YajimaI.YamamotoH.Isolation and developmental expression of tyrosinase family genes in Xenopus laevis20031654554622-s2.0-004233713410.1034/j.1600-0749.2003.00064.xPuigI.YajimaI.BonaventureJ.DelmasV.LarueL.The tyrosinase promoter is active in a subset of vagal neural crest cells during early development in mice20092233313342-s2.0-6554911388810.1111/j.1755-148X.2009.00546.xSatoS.ToyodaR.KatsuyamaY.SaigaH.NumakunaiT.IkeoK.GojoboriT.YajimaI.YamamotoH.Structure and developmental expression of the ascidian TRP gene: insights into the evolution of pigment cell-specific gene expression199921532252372-s2.0-003299567110.1002/(SICI)1097-0177(199907)215:3<225::AID-AJA5>3.0.CO;2-SYajimaI.EndoK.SatoS.ToyodaR.WadaH.ShibaharaS.NumakunaiT.IkeoK.GojoboriT.GodingC. R.YamamotoH.Cloning and functional analysis of ascidian Mitf in vivo: insights into the origin of vertebrate pigment cells200312012148915042-s2.0-034570767310.1016/j.mod.2003.08.009YajimaI.LarueL.The location of heart melanocytes is specified and the level of pigmentation in the heart may correlate with coat color20082144714762-s2.0-4724913510110.1111/j.1755-148X.2008.00483.xGodingC. R.Melanocytes: the new black20073922752792-s2.0-3384519587310.1016/j.biocel.2006.10.003RobinsA.1991New York, NY, USACambridge University PressHemesathT. J.SteingrimssonE.McGillG.HansenM. J.VaughtJ.HodgkinsonC. A.ArnheiterH.CopelandN. G.JenkinsN. A.FisherD. E.Microphthalmia, a critical factor in melanocyte development, defines a discrete transcription factor family1994822277027802-s2.0-0028062014HodgkinsonC. A.MooreK. J.NakayamaA.SteingrimssonE.CopelandN. G.JenkinsN. A.ArnheiterH.Mutations at the mouse Microphthalmia locus are associated with defects in a gene encoding a novel basic-helix-loop-helix-zipper protein19937423954042-s2.0-002720414910.1016/0092-8674(93)90429-TSteingrímssonE.CopelandN. G.JenkinsN. A.Melanocytes and the Microphthalmia transcription factor network2004383654112-s2.0-1094423456010.1146/annurev.genet.38.072902.092717WidlundH. R.FisherD. E.Microphthalamia-associated transcription factor: a critical regulator of pigment cell development and survival20032220303530412-s2.0-003845755610.1038/sj.onc.1206443YajimaI.SatoS.KimuraT.YasumotoK. I.ShibaharaS.GodingC. R.YamamotoH.An L1 element intronic insertion in the black-eyed white (Mitf(mi-bw)) gene: the loss of a single Mitf isoform responsible for the pigmentary defect and inner ear deafness199988143114412-s2.0-003281596410.1093/hmg/8.8.1431YasumotoK. I.AmaeS.UdonoT.FuseN.TakedaK.ShibaharaS.A big gene linked to small eyes encodes multiple Mitf isoforms: many promoters make light work19981163293362-s2.0-0032248265CheliY.OhannaM.BallottiR.BertolottoC.Fifteen-year quest for Microphthalmia-associated transcription factor target genes201023127402-s2.0-7434911917610.1111/j.1755-148X.2009.00653.xKhongH. T.RosenbergS. A.The Waardenburg syndrome type 4 gene, SOX10, is a novel tumor-associated antigen identified in a patient with a dramatic response to immunotherapy20026211302030232-s2.0-0036605973MascarenhasJ. B.LittlejohnE. L.WolskyR. J.YoungK. P.NelsonM.SalgiaR.LangD.PAX3 and SOX10 activate MET receptor expression in melanoma20102322252372-s2.0-7794937146910.1111/j.1755-148X.2010.00667.xPlummerR. S.SheaC. R.NelsonM.PowellS. K.FreemanD. M.DanC. P.LangD.PAX3 expression in primary melanomas and nevi20082155255302-s2.0-4254917101110.1038/modpathol.3801019BondurandN.PingaultV.GoerichD. E.LemortN.SockE.Le CaignecC.WegnerM.GoossensM.Interaction among SOX10, PAX3 and MITF, three genes altered in Waardenburg syndrome2000913190719172-s2.0-0034641596LeeM.GoodallJ.VerasteguiC.BallottiR.GodingC. R.Direct regulation of the Microphthalmia promoter by Sox10 links Waardenburg-Shah syndrome (WS4)-associated hypopigmentation and deafness to WS220002754837978379832-s2.0-003453633810.1074/jbc.M003816200PotterfS. B.FurumuraM.DunnK. J.ArnheiterH.PavanW. J.Transcription factor hierarchy in Waardenburg syndrome: regulation of MITF expression by SOX10 and PAX320001071162-s2.0-003390646810.1007/s004390050001VerasteguiC.BilleK.OrtonneJ. P.BallottiR.Regulation of the Microphthalmia-associated transcription factor gene by the Waardenburg syndrome type 4 gene, SOX1020002754030757307602-s2.0-0034613374BertolottoC.AbbeP.HemesathT. J.BilleK.FisherD. E.OrtonneJ. P.BallottiR.Microphthalmia gene product as a signal transducer in cAMP-induced differentiation of melanocytes199814238278352-s2.0-003182800310.1083/jcb.142.3.827PriceE. R.DingH. F.BadalianT.BhattacharyaS.TakemotoC.YaoT. P.HemesathT. J.FisherD. E.Lineage-specific signaling in melanocytes. C-Kit stimulation recruits p300/CBP to Microphthalmia19982732917983179862-s2.0-003254106810.1074/jbc.273.29.17983DelmasV.BeermannF.MartinozziS.CarreiraS.AckermannJ.KumasakaM.DenatL.GoodallJ.LucianiF.VirosA.DemirkanN.BastianB. C.GodingC. R.LarueL.β-Catenin induces immortalization of melanocytes by suppressing p16INK4a expression and cooperates with N-Ras in melanoma development20072122292329352-s2.0-3624902652810.1101/gad.450107GilesR. H.van EsJ. H.CleversH.Caught up in a Wnt storm: Wnt signaling in cancer2003165311242-s2.0-003835935310.1016/S0304-419X(03)00005-2OmholtK.PlatzA.RingborgU.HanssonJ.Cytoplasmic and nuclear accumulation of β-catenin is rarely caused by CTNNB1 exon 3 mutations in cutaneous malignant melanoma20019268398422-s2.0-003587711510.1002/ijc.1270RimmD. L.CacaK.HuG.HarrisonF. B.FearonE. R.Frequent nuclear/cytoplasmic localization of β-catenin without exon 3 mutations in malignant melanoma199915423253292-s2.0-0032937232DorskyR. I.RaibleD. W.MoonR. T.Direct regulation of nacre, a zebrafish MITF homolog required for pigment cell formation, by the Wnt pathway20001421581622-s2.0-0034650485TakedaK.TakemotoC.KobayashiI.WatanabeA.NobukuniY.FisherD. E.TachibanaM.Ser298 of MITF, a mutation site in Waardenburg syndrome type 2, is a phosphorylation site with functional significance2000911251322-s2.0-0034110297WidlundH. R.HorstmannM. A.PriceE. R.CuiJ.LessnickS. L.WuM.HeX.FisherD. E.β-Catenin-induced melanoma growth requires the downstream target Microphthalmia-associated transcription factor20021586107910872-s2.0-003711994810.1083/jcb.200202049ManskyK. C.SankarU.HanJ.OstrowskiM. C.Microphthalmia transcription factor is a target of the p38 MAPK pathway in response to receptor activator of NF-κB ligand signaling20022771311077110832-s2.0-003719278410.1074/jbc.M111696200WuM.HemesathT. J.TakemotoC. M.HorstmannM. A.WellsA. G.PriceE. R.FisherD. Z.FisherD. E.c-Kit triggers dual phosphorylations, which couple activation and degradation of the essential melanocyte factor Mi20001433013122-s2.0-0034142326MillerA. J.LevyC.DavisI. J.RazinE.FisherD. E.Sumoylation of MITF and its related family members TFE3 and TFEB200528011461552-s2.0-1284426857410.1074/jbc.M411757200MurakamiH.ArnheiterH.Sumoylation modulates transcriptional activity of MITF in a promoter-specific manner20051842652772-s2.0-2274445039710.1111/j.1600-0749.2005.00234.xBennettD. C.How to make a melanoma: what do we know of the primary clonal events?200821127382-s2.0-4104911474710.1111/j.1755-148X.2007.00433.xColladoM.GilJ.EfeyanA.GuerraC.SchuhmacherA. J.BarradasM.BenguríaA.ZaballosA.FloresJ. M.BarbacidM.BeachD.SerranoM.Tumour biology: senescence in premalignant tumours200543670516422-s2.0-2324444789310.1038/436642aGray-SchopferV. C.CheongS. C.ChongH.ChowJ.MossT.Abdel-MalekZ. A.MaraisR.Wynford-ThomasD.BennettD. C.Cellular senescence in naevi and immortalisation in melanoma: a role for p16?20069544965052-s2.0-3374719283310.1038/sj.bjc.6603283MichaloglouC.VredeveldL. C. W.SoengasM. S.DenoyelleC.KuilmanT.van der HorstC. M. A. M.MajoorD. M.ShayJ. W.MooiW. J.PeeperD. S.BRAFE600-associated senescence-like cell cycle arrest of human naevi200543670517207242-s2.0-2324444703710.1038/nature03890MooiW. J.PeeperD. S.Oncogene-induced cell senescence—halting on the road to cancer200635510103710462-s2.0-3374842207910.1056/NEJMra062285VidalM. J.LoganzoF.Jr.de OliveiraA. R.HaywardN. K.AlbinoA. P.Mutations and defective expression of the WAF1 p21 tumour-suppressor gene in malignant melanomas1995542432502-s2.0-0028997764SauterE. R.YeoU. C.von StemmA.ZhuW.LitwinS.TichanskyD. S.PistrittoG.NesbitM.PinkelD.HerlynM.BastianB. C.Cyclin D1 is a candidate oncogene in cutaneous melanoma20026211320032062-s2.0-0036605974CarreiraS.GoodallJ.AksanI.La RoccaS. A.GalibertM. D.DenatL.LarueL.GodingC. R.Mitf cooperates with Rb1 and activates p21Cip1 expression to regulate cell cycle progression200543370277647692-s2.0-1394427376710.1038/nature03269DuJ.WidlundH. R.HorstmannM. A.RamaswamyS.RossK.HuberW. E.NishimuraE. K.GolubT. R.FisherD. E.Critical role of CDK2 for melanoma growth linked to its melanocyte-specific transcriptional regulation by MITF2004665655762-s2.0-1094422876410.1016/j.ccr.2004.10.014LoercherA. E.TankE. M. H.DelstonR. B.HarbourJ. W.MITF links differentiation with cell cycle arrest in melanocytes by transcriptional activation of INK4A2005168135402-s2.0-1214425403410.1083/jcb.200410115CarreiraS.LiuB.GodingC. R.The gene encoding the T-box factor Tbx2 is a target for the Microphthalmia-associated transcription factor in melanocytes20002752921920219272-s2.0-003469814110.1074/jbc.M000035200VanceK. W.CarreiraS.BroschG.GodingC. M.Tbx2 is overexpressed and plays an important role in maintaining proliferation and suppression of senescence in melanomas2005656226022682-s2.0-1684438709710.1158/0008-5472.CAN-04-3045CerroniL.SoyerH. P.KerlH.bcl-2 protein expression in cutaneous malignant melanoma and benign melanocytic nevi19951717112-s2.0-0028894034RamsayJ. A.FromL.KahnH. J.bcl-2 protein expression in melanocytic neoplasms of the skin1995821501542-s2.0-0028905806SelzerE.Schlagbauer-WadlH.OkamotoI.PehambergerH.PötterR.JansenB.Expression of Bcl-2 family members in human melanocytes, in melanoma metastases and in melanoma cell lines1998831972032-s2.0-003183896710.1097/00008390-199806000-00001McGillG. G.HorstmannM.WidlundH. R.DuJ.MotyckovaG.NishimuraE. K.LinY. L.RamaswamyS.AveryW.DingH. F.JordanS. A.JacksonI. J.KorsmeyerS. J.GolubT. R.FisherD. E.Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability200210967077182-s2.0-1844441879710.1016/S0092-8674(02)00762-6VucicD.StennickeH. R.PisabarroM. T.SalvesenG. S.DixitV. M.ML-IAP, a novel inhibitor of apoptosis that is preferentially expressed in human melanomas20001021135913662-s2.0-003459763010.1016/S0960-9822(00)00781-8ChangH.SchimmerA. D.Livin/melanoma inhibitor of apoptosis protein as a potential therapeutic target for the treatment of malignancy20076124302-s2.0-3384682693810.1158/1535-7163.MCT-06-0443LiuF.FuY.MeyskensF. L.MiTF regulates cellular response to reactive oxygen species through transcriptional regulation of APE-1/Ref-1200912924224312-s2.0-5854909146310.1038/jid.2008.255BuscàR.BerraE.GaggioliC.KhaledM.BilleK.MarchettiB.ThyssR.FitsialosG.LarribèreL.BertolottoC.VirolleT.BarbryP.PouysségurJ.PonzioG.BallottiR.Hypoxia-inducible factor 1α is a new target of Microphthalmia- associated transcription factor (MITF) in melanoma cells2005170149592-s2.0-2224446740910.1083/jcb.200501067McGillG. G.HaqR.NishimuraE. K.FisherD. E.c-Met expression is regulated by Mitf in the melanocyte lineage20062811510365103732-s2.0-3374453115410.1074/jbc.M513094200ManiS. A.GuoW.LiaoM. J.EatonE. N.AyyananA.ZhouA. Y.BrooksM.ReinhardF.ZhangC. C.ShipitsinM.CampbellL. L.PolyakK.BriskenC.YangJ.WeinbergR. A.The epithelial-mesenchymal transition generates cells with properties of stem cells200813347047152-s2.0-4304916545310.1016/j.cell.2008.03.027NietoM. A.The snail superfamily of zinc-finger transcription factors2002331551662-s2.0-003651362610.1038/nrm757Sánchez-MartínM.Rodríguez-GarcíaA.Pérez-LosadaJ.SagreraA.ReadA. P.Sánchez-GarcíaI.isg@usal.esSLUG (SNA12) deletions in patients with Waardenburg disease2002112532313236CarreiraS.GoodallJ.DenatL.RodriguezM.NuciforoP.HoekK. S.TestoriA.LarueL.GodingC. R.Mitf regulation of Dia1 controls melanoma proliferation and invasiveness20062024342634392-s2.0-3384571116610.1101/gad.406406BersonJ. F.HarperD. C.TenzaD.RaposoG.MarksM. S.Pmel17 initiates premelanosome morphogenesis within multivesicular bodies20011211345134642-s2.0-0035200704HoashiT.WatabeH.MullerJ.YamaguchiY.VieiraW. D.HearingV. J.MART-1 is required for the function of the melanosomal matrix protein PMEL17/GP100 and the maturation of melanosomes20052801414006140162-s2.0-1714437966010.1074/jbc.M413692200RaposoG.TenzaD.MurphyD. M.BersonJ. F.MarksM. S.Distinct protein sorting and localization to premelanosomes, melanosomes, and lysosomes in pigmented melanocytic cells200115248098242-s2.0-003591114610.1083/jcb.152.4.809WasmeierC.HumeA. N.BolascoG.SeabraM. C.Melanosomes at a glance2008121, part 24399539992-s2.0-5934911575310.1242/jcs.040667BertolottoC.BuscàR.AbbeP.BilleK.AberdamE.OrtonneJ. P.BallottiR.Different cis-acting elements are involved in the regulation of TRP1 and TRP2 promoter activities by cyclic AMP: pivotal role of M boxes (GTCATGTGCT) and of Microphthalmia19981826947022-s2.0-0031907728DuJ.MillerA. J.WidlundH. R.HorstmannM. A.RamaswamyS.FisherD. E.MLANA/MART1 and SILV/PMEL17/GP100 are transcriptionally regulated by MITF in melanocytes and melanoma200316313333432-s2.0-0037968710YasumotoK. I.YokoyamaK.TakahashiK.TomitaY.ShibaharaS.Functional analysis of Microphthalmia-associated transcription factor in pigment cell-specific transcription of the human tyrosinase family genes199727215035092-s2.0-003103260110.1074/jbc.272.1.503YavuzerU.KeenanE.LowingsP.VachtenheimJ.CurrieG.GodingC. R.The Microphthalmia gene product interacts with the retinoblastoma protein in vitro and is a target for deregulation of melanocyte-specific transcription19951011231342-s2.0-0028816090LevyC.KhaledM.FisherD. E.MITF: master regulator of melanocyte development and melanoma oncogene20061294064142-s2.0-3374788266110.1016/j.molmed.2006.07.008GarrawayL. A.WidlundH. R.RubinM. A.GetzG.BergerA. J.RamaswamyS.BeroukhimR.MilnerD. A.GranterS. R.DuJ.LeeC.WagnerS. N.LiC.GolubT. R.RimmD. L.MeyersonM. L.FisherD. E.SellersW. R.Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma200543670471171222-s2.0-2184447874710.1038/nature03664WellbrockC.MaraisR.Elevated expression of MITF counteracts B-RAF-stimulated melanocyte and melanoma cell proliferation200517057037082-s2.0-2414447794710.1083/jcb.200505059GodingC.MeyskensF. L.Jr.Microphthalmic-associated transcription factor integrates melanocyte biology and melanoma progression2006124106910732-s2.0-3364478594210.1158/1078-0432.CCR-05-2648Gray-SchopferV.WellbrockC.MaraisR.Melanoma biology and new targeted therapy200744571308518572-s2.0-3384722036410.1038/nature05661HoekK. S.GodingC. R.Cancer stem cells versus phenotype-switching in melanoma20102367467592-s2.0-7804923740510.1111/j.1755-148X.2010.00757.x