RaLP, a New Member of the Src Homology and Collagen Family, Regulates Cell Migration and Tumor Growth of Metastatic Melanomas

Fagiani, Ernesta; Giardina, Giuseppina; Luzi, Lucilla; Cesaroni, Matteo; Quarto, Micaela; Capra, Maria; Germano, Giovanni; Bono, Marı́a Rosa; Capillo, Manuela; Pelicci, PierGiuseppe; Lanfrancone, Luisa

doi:10.1158/0008-5472.can-06-2301

Cited by 65 publications

(83 citation statements)

References 41 publications

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“…The medium was changed three times a week, and cells were subcultured when approaching confluence by gentle tilting to avoid breaking the cell processes. 22 Normal keratinocytes were grown in serumfree medium. All cell lines were incubated at 37°C in a humidified atmosphere containing 5% CO 2 .…”

Section: Cell Culture and Growth Mediamentioning

confidence: 99%

Pirin Inhibits Cellular Senescence in Melanocytic Cells

Licciulli

Luise

Scafetta

et al. 2011

The American Journal of Pathology

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Cellular senescence has been widely recognized as a tumor suppressing mechanism that acts as a barrier to cancer development after oncogenic stimuli. A prominent in vivo model of the senescence barrier is represented by nevi, which are composed of melanocytes that, after an initial phase of proliferation induced by activated oncogenes (most commonly BRAF), are blocked in a state of cellular senescence. Transformation to melanoma occurs when genes involved in controlling senescence are mutated or silenced and cells reacquire the capacity to proliferate. Pirin (PIR) is a highly conserved nuclear protein that likely functions as a transcriptional regulator whose expression levels are altered in different types of tumors. We analyzed the expression pattern of PIR in adult human tissues and found that it is expressed in melanocytes and has a complex pattern of regulation in nevi and melanoma: it is rarely detected in mature nevi, but is expressed at high levels in a subset of melanomas. Loss of function and overexpression experiments in normal and transformed melanocytic cells revealed that PIR is involved in the negative control of cellular senescence and that its expression is necessary to overcome the senescence barrier. Our results suggest that PIR may have a relevant role in melanoma progression.

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Section: Cell Culture and Growth Mediamentioning

confidence: 99%

Pirin Inhibits Cellular Senescence in Melanocytic Cells

Licciulli

Luise

Scafetta

et al. 2011

The American Journal of Pathology

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“…GO analyses of the TCCS that was highly expressed in ACC showed significant enrichment in genes associated with the Notch and Wnt pathways ( Table 2) that have previously been associated with neuron differentiation and cancer. [31][32][33] Within TCCS, neural crest stem cell markers SOX10, 34 MAP2, 35 SALL2 36 and SLITRK6, 37 as well as melanoma markers SHC4 38 and MUM1 39 were also identified. Close co-expression of FGFR1 and EFNB3 with TrkC suggested possible co-function of these receptors in ACC.…”

Section: Introductionmentioning

confidence: 99%

TrkC signaling is activated in adenoid cystic carcinoma and requires NT-3 to stimulate invasive behavior

et al. 2012

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Treatment options for adenoid cystic carcinoma (ACC) of the salivary gland, a slowly growing tumor with propensity for neuroinvasion and late recurrence, are limited to surgery and radiotherapy. Based on expression analysis performed on clinical specimens of salivary cancers, we identified in ACC expression of the neurotrophin-3 receptor TrkC/NTRK3, neural crest marker SOX10, and other neurologic genes. Here, we characterize TrkC as a novel ACC marker, which was highly expressed in 17 out of 18 ACC primary-tumor specimens, but not in mucoepidermoid salivary carcinomas or head and neck squamous cell carcinoma. Expression of the TrkC ligand NT-3 and Tyr-phosphorylation of TrkC detected in our study suggested the existence of an autocrine signaling loop in ACC with potential therapeutic significance. NT-3 stimulation of U2OS cells with ectopic TrkC expression triggered TrkC phosphorylation and resulted in Ras, Erk 1/2 and Akt activation, as well as VEGFR1 phosphorylation. Without NT-3, TrkC remained unphosphorylated, stimulated accumulation of phospho-p53 and had opposite effects on p-Akt and p-Erk 1/2. NT-3 promoted motility, migration, invasion, soft-agar colony growth and cytoskeleton restructuring in TrkC-expressing U2OS cells. Immunohistochemical analysis demonstrated that TrkC-positive ACC specimens also show high expression of Bcl2, a Trk target regulated via Erk 1/2, in agreement with activation of the TrkC pathway in real tumors. In normal salivary gland tissue, both TrkC and Bcl2 were expressed in myoepithelial cells, suggesting a principal role for this cell lineage in the ACC origin and progression. Sub-micromolar concentrations of a novel potent Trk inhibitor AZD7451 completely blocked TrkC activation and associated tumorigenic behaviors. Pre-clinical studies on ACC tumors engrafted in mice showed efficacy and low toxicity of AZD7451, validating our in vitro data and stimulating more research into its clinical application. In summary, we describe in ACC a previously unrecognized pro-survival neurotrophin signaling pathway and link it with cancer progression.

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“…Research attention was focused on p66Shc because of the evidences that p66Shc null mice not only live the 30% longer [4] but they are resistant to a wide spectrum of age related pathologies including obesity [61,62], diabetes [63,64], atherosclerosis [65,66], and ischemic injury [67,68]. Even if the molecular mechanisms underlying p66Shc role in aging are, to date, only partially unrevealed [18], we demonstrated that p66Shc cooperates with p53 to negatively regulate the expression of a set of genes involved in cell cycle progression and physiologically downregulated in aging [23] Shc are the only class of proteins with a N-terminal PTB domain and a C-terminal SH2 domain and these proteins have likely a common ancestor (11): among Shc proteins we find at least eight proteins: p66/p52/p46Shc (ShcA), the brain-specific ShcB and ShcC, with two isoforms each [69,70], and ShcD, expressed, among adult tissues, only in melanomas [71].…”

Section: P66shc Is a Vertebrate Protein Conserved In Fishmentioning

confidence: 99%

Modelling the p53/p66Shc Aging Pathway in the Shortest Living Vertebrate Nothobranchius Furzeri

Priami¹,

Michele²,

Cotelli³

et al. 2015

Aging and disease

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Oxidative stress induced by reactive oxygen species (ROS) increases during lifespan and is involved in aging processes. The p66Shc adaptor protein is a master regulator of oxidative stress response in mammals. Ablation of p66Shc enhances oxidative stress resistance both in vitro and in vivo. Most importantly, it has been demonstrated that its deletion retards aging in mice. Recently, new insights in the molecular mechanisms involving p66Shc and the p53 tumor suppressor genes were given: a specific p66Shc/p53 transcriptional regulation pathway was uncovered as determinant in oxidative stress response and, likely, in aging. p53, in a p66Shc-dependent manner, negatively downregulates the expression of 200 genes which are involved in the G2/M transition of mitotic cell cycle and are downregulated during physiological aging. p66Shc modulates the response of p53 by activating a p53 isoform (p44/p53, also named Delta40p53). Based on these latest results, several developments are expected in the future, as the generation of animal models to study aging and the evaluation of the use of the p53/p66Shc target genes as biomarkers in aging related diseases. The aim of this review is to investigate the conservation of the p66Shc and p53 role in oxidative stress between fish and mammals. We propose to approach this study trough a new model organism, the annual fish Nothobranchius furzeri, that has been demonstrated to develop typical signs of aging, like in mammals, including senescence, neurodegeneration, metabolic disorders and cancer.

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RaLP, a New Member of the Src Homology and Collagen Family, Regulates Cell Migration and Tumor Growth of Metastatic Melanomas

Cited by 65 publications

References 41 publications

Pirin Inhibits Cellular Senescence in Melanocytic Cells

Pirin Inhibits Cellular Senescence in Melanocytic Cells

TrkC signaling is activated in adenoid cystic carcinoma and requires NT-3 to stimulate invasive behavior

Modelling the p53/p66Shc Aging Pathway in the Shortest Living Vertebrate Nothobranchius Furzeri

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