Constitutive Activation of the Mitogen-Activated Protein Kinase Signaling Pathway in Acral Melanomas

Takata, Minoru; Goto, Yasufumi; Ichii, Nami; Yamaura, Maki; Murata, Hiroshi; Koga, Hiroshi; Fujimoto, Akihide; Saida, Toshiaki

doi:10.1111/j.0022-202x.2005.23812.x

Cited by 57 publications

(59 citation statements)

References 22 publications

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“…One of the major signaling mediators of RTK is the MAP kinase pathway (ERK1/2), which has been most directly linked to its growth-promoting activities. Since self-sufficiency in growth signaling is a requisite capability acquired by all cancer cells (Hanahan and Weinberg 2000), hyperactive ERKs are common in many human cancers, including melanoma (Takata et al 2005;Zhuang et al 2005). Such a hyperactive state can theoretically be achieved by activating mutations of any signaling mediators upstream of ERKs, but there are clear tumor-type-specific patterns of mutational activation.…”

Section: Ras and Raf Activators Of Mitogen-activated Protein (Map) Kmentioning

confidence: 99%

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: Ras and Raf Activators Of Mitogen-activated Protein (Map) Kmentioning

confidence: 99%

Malignant melanoma: genetics and therapeutics in the genomic era

2006

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“…Gain of chromosome 7q is common in CMM suggesting that BRAF, located on 7q34, is a target for gene amplification (Tanami et al, 2004). Moreover, cyclin D1, a down-stream target of the MAPK pathway and p16INK4A antagonist, is amplified in acral-type CMM in which BRAF and NRAS mutations are infrequent (Takata et al, 2005). Finally, activation of the PIK3-pathway is essential and commonly pursued by inactivation of PTEN located on chromosome 10, a frequent deletion target in melanoma (Guldberg et al, 1997b).…”

Section: Introductionmentioning

confidence: 99%

Genomic profiling of malignant melanoma using tiling-resolution arrayCGH

et al. 2007

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Malignant melanoma is an aggressive, heterogeneous disease where new biomarkers for diagnosis and clinical outcome are needed. We searched for chromosomal aberrations that characterize its pathogenesis using 47 different melanoma cell lines and tiling-resolution bacterial artificial chromosome-arrays for comparative genomic hybridization. Major melanoma genes, including BRAF, NRAS, CDKN2A, TP53, CTNNB1, CDK4 and PTEN, were examined for mutations. Distinct copy number alterations were detected, including loss or gain of whole chromosomes but also minute amplifications and homozygous deletions. Most common overlapping regions with losses were mapped to 9p24.3-q13, 10 and 11q14.1-qter, whereas copy number gains were most frequent on chromosomes 1q, 7, 17q and 20q. Amplifications were delineated to oncogenes such as MITF (3p14), CCND1 (11q13), MDM2 (12q15), CCNE1 (19q12) and NOTCH2 (1p12). Frequent findings of homozygous deletions on 9p21 and 10q23 confirmed the importance of CDKN2A and PTEN. Pair-wise comparisons revealed distinct sets of alterations, for example, mutually exclusive mutations in BRAF and NRAS, mutual mutations in BRAF and PTEN, concomitant chromosome 7 gain and 10 loss and concomitant chromosome 15q22.2-q26.3 gain and 20 gain. Moreover, alterations of the various melanoma genes were associated with distinct chromosomal imbalances suggestive of specific genomic programs in melanoma development.

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“…Mitogen-activated protein/ERK kinase 1 (MEK1), when engineered to be constitutively active, can transform mammalian cells to a cancerous phenotype (Cowley et al 1994, Mansour et al 1994, Webb et al 1998, whereas inhibition of MAPK activity can inhibit the growth of Ras-transformed cells in vitro (Dudley et al 1995, Sebolt-Leopold et al 1999. In addition, the activated MAPK or increased levels of MAPK expression have been detected in a variety of human tumors (Oka et al 1995, Sivaraman et al 1997, Hoshino et al 1999, Kim et al 1999, Ahmed et al 2002, Satyamoorthy et al 2003, Liang et al 2005, Takata et al 2005. Thus, the MAPK signaling pathway is a potential target in cancer therapy (Duesbery et al 1999, Tecle et al 1999, Fang & Richardson 2005, Staehler et al 2005.…”

Section: Introductionmentioning

confidence: 99%

Calcitonin targets extracellular signal-regulated kinase signaling pathway in human cancers

Nakamura

Han

Nishishita

et al. 2007

Journal of Molecular Endocrinology

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The mitogen-activated protein kinases (MAPKs) signaling pathway is a potential target in cancer therapy. Constitutive phosphorylated extracellular signal-regulated kinase (ERK1/2), which is one of the MAPKs has been detected in a variety of tumors. Calcitonin (CT) is a polypeptide hormone secreted by the thyroid gland and has been used to treat the osteoporosis and humoral hypercalcemia of malignancy. We report that CT decreases ERK1/2 phosphorylation in cancer cells showing constitutive phosphorylated ERK1/2. In MDA-MB-231 cells, a breast cancer cell line showing constitutive phosphorylated ERK1/2, CT phosphorylated c-Raf at Ser 259 via the protein kinase A pathway, resulting in suppression of ERK1/2 phosphorylation. CT significantly reduced the tumor volume of MDA-MB-231 cells showing constitutive phosphorylated ERK1/2 compared with saline buffer. However, CT did not exert any significant effects on the proliferation of MCF-7 cells, a breast cancer cell line, showing non-constitutive phosphorylated ERK1/2. These novel findings indicate that CT may be used to target ERK in the treatment of cancer.

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Constitutive Activation of the Mitogen-Activated Protein Kinase Signaling Pathway in Acral Melanomas

Cited by 57 publications

References 22 publications

Malignant melanoma: genetics and therapeutics in the genomic era

Malignant melanoma: genetics and therapeutics in the genomic era

Genomic profiling of malignant melanoma using tiling-resolution arrayCGH

Calcitonin targets extracellular signal-regulated kinase signaling pathway in human cancers

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