Induction of Melanocyte-specific Microphthalmia-associated Transcription Factor by Wnt-3a

Takeda, Kazuhisa; Yasumoto, Ken Ichi; Takada, Ritsuko; Takada, Shinji; Watanabe, Ken Ichi; Udono, Tetsuo; Saitō, Hideo; Takahashi, Kazuhiro; Shibahara, Shigeki

doi:10.1074/jbc.c000113200

Cited by 296 publications

(248 citation statements)

References 37 publications

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“…Importantly, the investigators found that enforced Mitf expression was able to measurably rescue melanoblast survival in Wntdeficient embryos, providing functional evidence that Mitf is a developmentally essential Wnt target. Additional studies identified similar biochemical relationships between Wnt effectors (␤-catenin, TCF/LEF) and Mitf expression in murine and human melanocytes and melanoma cells (Takeda et al 2000b;Widlund et al 2002). Interactions have also been observed between LEF-1 and MITF, suggesting that MITF may function as an alternative coactivator of certain Wnt-signaling targets (independent of ␤-catenin) (Yasumoto et al 2002).…”

Section: Wnt Signalingmentioning

confidence: 78%

Malignant melanoma: genetics and therapeutics in the genomic era

2006

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Cell for cell, probably no human cancer is as aggressive as melanoma. It is among a handful of cancers whose dimensions are reported in millimeters. Tumor thickness approaching 4 mm presents a high risk of metastasis, and a diagnosis of metastatic melanoma carries with it an abysmal median survival of 6-9 mo. What features of this malignancy account for such aggressive behavior? Is it the migratory history of its cell of origin or the programmed adaptation of its differentiated progeny to environmental stress, particularly ultraviolet radiation? While the answers to these questions are far from complete, major strides have been made in our understanding of the cellular, molecular, and genetic underpinnings of melanoma. More importantly, these discoveries carry profound implications for the development of therapies focused directly at the molecular engines driving melanoma, suggesting that we may have reached the brink of an unprecedented opportunity to translate basic science into clinical advances. In this review, we attempt to summarize our current understanding of the genetics and biology of this disease, drawing from expanding genomic information and lessons from development and genetically engineered mouse models. In addition, we look forward toward how these new insights will impact on therapeutic options for metastatic melanoma in the near future. The diseaseMelanomas most often arise within epidermal melanocytes of the skin, although they can also derive from noncutaneous melanocytes such as those lining the choroidal layer of the eye, GI and GU mucosal surfaces, or the meninges. Melanoma is also among the more common causes of "metastatic cancer of unknown primary," which may reflect either a propensity to arise in unexpected sites along the neural crest migratory route, or rapid growth of poorly differentiated lesions arising from indolent or unrecognized cutaneous primary lesions. Clinical staging for primary cutaneous melanoma employs measurements of thickness (in millimeters), presence of ulceration, penetration through cutaneous layers, mitotic rate, evidence of "in transit" metastasis, tumor spread to draining lymph nodes, and evidence of distant metastasis. Management issues in melanoma can be classified in terms of prevention, diagnosis, local disease management, and treatment of metastatic disease.In view of the epidemiological and emerging experimental evidence linking melanoma incidence to UV exposure and skin phototype, prevention and screening strategies represent key areas for reduction of disease incidence and severity. For most cutaneous melanomas in the so-called radial growth phase (e.g., thin melanomas), surgical removal affords curative treatment. In contrast, a significant fraction of patients diagnosed with intermediate-thickness (2-4 mm) cutaneous melanoma eventually succumb to recurrence at regional or distant sites.Critical biological questions facing the melanoma research community include: (1) What genetic and environmental factors contribute to and/or modulate risk of melanom...

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Section: Wnt Signalingmentioning

confidence: 78%

Malignant melanoma: genetics and therapeutics in the genomic era

2006

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“…Recent evidence has revealed that low levels of Mitf activity can promote proliferation (Carreira et al 2006) while high levels inhibit cell division (Carreira et al 2005;Loercher et al 2005;Wellbrock and Marais 2005). Since ␤-catenin can directly activate the Mitf-M promoter via a LEF/Tcf-binding site (Takeda et al 2000), any activation of ␤-catenin would either promote or inhibit proliferation depending on the basal level of Mitf activity in the cell. Thus, activated ␤-catenin can potentially act both positively and negatively on melanocyte proliferation, though clearly in vivo the net result of the expression of activated ␤-catenin was the reduction of melanoblast number.…”

Section: Discussionmentioning

confidence: 99%

β-Catenin induces immortalization of melanocytes by suppressing p16^INK4a expression and cooperates with N-Ras in melanoma development

Delmas¹,

Beermann²,

Martinozzi³

et al. 2007

Genes Dev.

292

280

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Tumor progression is a multistep process in which proproliferation mutations must be accompanied by suppression of senescence. In melanoma, proproliferative signals are provided by activating mutations in NRAS and BRAF, whereas senescence is bypassed by inactivation of the p16 Ink4a gene. Melanomas also frequently exhibit constitutive activation of the Wnt/␤-catenin pathway that is presumed to induce proliferation, as it does in carcinomas. We show here that, contrary to expectations, stabilized ␤-catenin reduces the number of melanoblasts in vivo and immortalizes primary skin melanocytes by silencing the p16 Ink4a promoter. Significantly, in a novel mouse model for melanoma, stabilized ␤-catenin bypasses the requirement for p16 Ink4a mutations and, together with an activated N-Ras oncogene, leads to melanoma with high penetrance and short latency. The results reveal that synergy between the Wnt and mitogen-activated protein (MAP) kinase pathways may represent an important mechanism underpinning the genesis of melanoma, a highly aggressive and increasingly common disease.[Keywords: Mitf; Wnt; senescence; development; tumor suppressor; oncogene] Supplemental material is available at http://www.genesdev.org.

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“…The PAX3 and SOX10 genes (Watanabe et al, 1998;Bondurand et al, 2000;Lee et al, 2000;Potterf et al, 2000;Verastegui et al, 2000) as well the Wnt-signaling pathway (Dorsky et al, 2000;Takeda et al, 2000b) potently activate the MITF-M promoter. These factors transactivate the MITF-M promoter/enhancer in a manner that may involve formation of coordinated transcriptional complexes, although the nature of such interactions is incompletely understood (Figure 2).…”

Section: Mitf-m Is Critical For the Melanocyte Fate In The Neural Crementioning

confidence: 99%

Microphthalamia-associated transcription factor: a critical regulator of pigment cell development and survival

2003

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The microphthalamia-associated transcription factor (MITF) is an integral transcriptional regulator in melanocyte, the lineage from which melanoma cells originate. This basic-helix-loop-helix-leucine-zipper (bHLHzip) protein is critical for melanocyte cell-fate choice during commitment from pluripotent precursor cells in the neural crest. Its role in differentiation pathways has been highlighted by its potent transcriptional and lineage-specific regulation of the three major pigment enzymes: tyrosinase, Tyrp1, and Dct as well as other pigmentation factors. However, the cellular functions of MITF seem to be wider than differentiation and cell-fate pathways alone, since melanocytes and melanoma cells appear to require an expression of this factor. Here, we discuss the transcriptional networks in which MITF is thought to reside and describe signaling pathways in the cell which impinge on MITF. Accumulating evidence supports the notion that MITF is involved in survival pathways during normal development as well as during neoplastic growth of melanoma.

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Induction of Melanocyte-specific Microphthalmia-associated Transcription Factor by Wnt-3a

Cited by 296 publications

References 37 publications

Malignant melanoma: genetics and therapeutics in the genomic era

Malignant melanoma: genetics and therapeutics in the genomic era

β-Catenin induces immortalization of melanocytes by suppressing p16^INK4a expression and cooperates with N-Ras in melanoma development

Microphthalamia-associated transcription factor: a critical regulator of pigment cell development and survival

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Induction of Melanocyte-specific Microphthalmia-associated Transcription Factor by Wnt-3a

Cited by 296 publications

References 37 publications

Malignant melanoma: genetics and therapeutics in the genomic era

Malignant melanoma: genetics and therapeutics in the genomic era

β-Catenin induces immortalization of melanocytes by suppressing p16INK4a expression and cooperates with N-Ras in melanoma development

Microphthalamia-associated transcription factor: a critical regulator of pigment cell development and survival

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β-Catenin induces immortalization of melanocytes by suppressing p16^INK4a expression and cooperates with N-Ras in melanoma development