UVB radiation suppresses Dicer expression through β-catenin.

Ultraviolet (UV) rays prompt a natural response in epidermal cells, particularly within melanocytes. The changes in gene expression and related signaling pathways in melanocytes following exposure to UV radiation are still not entirely understood. Our findings reveal that UVB irradiation suppresses the expression of Dicer (also known as Dicer1).

Loss of Dicer in Newborn Melanocytes Leads to Premature Hair Graying and Changes in Integrin Expression.

Premature hair graying occurs owing to the depletion of melanocyte stem cells in the hair follicle, which can be accelerated by stress caused by genetic or environmental factors. However, the connection between stress and melanocyte stem cell loss is not fully understood. MicroRNAs are molecules that control gene expression by regulating mRNA stability and translation and are produced by the enzyme Dicer, which is repressed under stress.

Derivation and Use of Cell Lines from Mouse Models of Melanoma.

The establishment of consistent genetically modified mouse melanoma models and cell lines is of paramount importance for prevention and treatment. In this study, we review the different mouse melanoma cell lines that have been established. After careful molecular characterization of the established mouse melanoma cell lines, modification of the genome, microenvironment, or even the environment using appropriate in cellulo and in vivo assays may reveal novel genetic and nongenetic changes.

Targeting GPCRs and Their Signaling as a Therapeutic Option in Melanoma.

G-protein-coupled receptors (GPCRs) serve prominent roles in melanocyte lineage physiology, with an impact at all stages of development, as well as on mature melanocyte functions. GPCR ligands are present in the skin and regulate melanocyte homeostasis, including pigmentation. The role of GPCRs in the regulation of pigmentation and, consequently, protection against external aggression, such as ultraviolet radiation, has long been established.

Stabilization of β-catenin promotes melanocyte specification at the expense of the Schwann cell lineage.

The canonical Wnt/β-catenin pathway governs a multitude of developmental processes in various cell lineages, including the melanocyte lineage. Indeed, β-catenin regulates transcription of Mitf-M, the master regulator of this lineage. The first wave of melanocytes to colonize the skin is directly derived from neural crest cells, whereas the second wave of melanocytes is derived from Schwann cell precursors (SCPs).

BRN2 is a non-canonical melanoma tumor-suppressor.

While the major drivers of melanoma initiation, including activation of NRAS/BRAF and loss of PTEN or CDKN2A, have been identified, the role of key transcription factors that impose altered transcriptional states in response to deregulated signaling is not well understood. The POU domain transcription factor BRN2 is a key regulator of melanoma invasion, yet its role in melanoma initiation remains unknown. Here, in a Braf Pten context, we show that BRN2 haplo-insufficiency promotes melanoma initiation and metastasis.

A role for Dynlt3 in melanosome movement, distribution, acidity and transfer.

Skin pigmentation is dependent on cellular processes including melanosome biogenesis, transport, maturation and transfer to keratinocytes. However, how the cells finely control these processes in space and time to ensure proper pigmentation remains unclear. Here, we show that a component of the cytoplasmic dynein complex, Dynlt3, is required for efficient melanosome transport, acidity and transfer.

Sequencing two Tyr::CreER transgenic mouse lines.

The Cre/loxP system is a powerful tool that has allowed the study of the effects of specific genes of interest in various biological settings. The Tyr::CreER system allows for the targeted expression and activity of the Cre enzyme in the melanocyte lineage following treatment with tamoxifen, thus providing spatial and temporal control of the expression of specific target genes. Two independent transgenic mouse models, each containing a Tyr::CreER transgene, have been generated and are widely used to study melanocyte transformation.

Simulation of melanoblast displacements reveals new features of developmental migration.

To distribute and establish the melanocyte lineage throughout the skin and other developing organs, melanoblasts undergo several rounds of proliferation, accompanied by migration through complex environments and differentiation. Melanoblast migration requires interaction with extracellular matrix of the epidermal basement membrane and with surrounding keratinocytes in the developing skin. Migration has been characterized by measuring speed, trajectory and directionality of movement, but there are many unanswered questions about what motivates and defines melanoblast migration.

A histopathological classification system of Tyr::NRAS murine melanocytic lesions: A reproducible simplified classification.

Genetically engineered mouse models offer essential opportunities to investigate the mechanisms of initiation and progression in melanoma. Here, we report a new simplified histopathology classification of mouse melanocytic lesions in Tyr::NRAS derived models, using an interactive decision tree that produces homogeneous categories. Reproducibility for this classification system was evaluated on a panel of representative cases of murine melanocytic lesions by pathologists and basic scientists.

Beyond cell-cell adhesion: Plakoglobin and the regulation of tumorigenesis and metastasis.

Plakoglobin (also known as γ-catenin) is a member of the Armadillo family of proteins and a paralog of β-catenin. Plakoglobin is a component of both the adherens junctions and desmosomes, and therefore plays a vital role in the regulation of cell-cell adhesion. Similar to β-catenin, plakoglobin is capable of participating in cell signaling in addition to its role in cell-cell adhesion.

The WNT-less wonder: WNT-independent β-catenin signaling.

β-catenin is known as an Armadillo protein that regulates gene expression following WNT pathway activation. However, WNT-independent pathways also activate β-catenin. During the establishment of the melanocyte lineage, β-catenin plays an important role.

A caveolin-dependent and PI3K/AKT-independent role of PTEN in β-catenin transcriptional activity.

Loss of the tumour suppressor PTEN is frequent in human melanoma, results in MAPK activation, suppresses senescence and mediates metastatic behaviour. How PTEN loss mediates these effects is unknown. Here we show that loss of PTEN in epithelial and melanocytic cell lines induces the nuclear localization and transcriptional activation of β-catenin independent of the PI3K-AKT-GSK3β axis.

Plakoglobin represses SATB1 expression and decreases in vitro proliferation, migration and invasion.

Plakoglobin (γ-catenin) is a homolog of β-catenin with dual adhesive and signaling functions. Plakoglobin participates in cell-cell adhesion as a component of the adherens junction and desmosomes whereas its signaling function is mediated by its interactions with various intracellular protein partners. To determine the role of plakoglobin during tumorigenesis and metastasis, we expressed plakoglobin in the human tongue squamous cell carcinoma (SCC9) cells and compared the mRNA profiles of parental SCC9 cells and their plakoglobin-expressing transfectants (SCC9-PG).

Plakoglobin interacts with the transcription factor p53 and regulates the expression of 14-3-3σ.

Plakoglobin (γ-catenin), a constituent of the adherens junction and desmosomes, has signaling capabilities typically associated with tumor/metastasis suppression through mechanisms that remain undefined. To determine the role of plakoglobin during tumorigenesis and metastasis, we expressed plakoglobin in human tongue squamous cell carcinoma (SCC9) cells and compared the mRNA profiles of parental SCC9 cells and their plakoglobin-expressing transfectants (SCC9-PG). We detected several p53-target genes whose levels were altered upon plakoglobin expression.

Plakoglobin: role in tumorigenesis and metastasis.

Plakoglobin (γ-catenin) is a member of the Armadillo family of proteins and a homolog of β-catenin. As a component of both the adherens junctions and desmosomes, plakoglobin plays a pivotal role in the regulation of cell-cell adhesion. Furthermore, similar to β-catenin, plakoglobin is capable of participating in cell signaling.

Learning to predict relapse in invasive ductal carcinomas based on the subcellular localization of junctional proteins.

The complexity of breast cancer biology makes it challenging to analyze large datasets of clinicopathologic and molecular attributes, toward identifying the key prognostic features and producing systems capable of predicting which patients are likely to relapse. We applied machine-learning techniques to analyze a set of well-characterized primary breast cancers, which specified the abundance and localization of various junctional proteins. We hypothesized that disruption of junctional complexes would lead to the cytoplasmic/nuclear redistribution of the protein components and their potential interactions with growth-regulating molecules, which would promote relapse, and that machine-learning techniques could use the subcellular locations of these proteins, together with standard clinicopathological data, to produce an efficient prognostic classifier.

Tamoxifen and ICI 182,780 increase Bcl-2 levels and inhibit growth of breast carcinoma cells by modulating PI3K/AKT, ERK and IGF-1R pathways independent of ERalpha.

We recently showed that estrogen withdrawal from the ERalpha(+), high Bcl-2-expressing breast carcinoma cells (MCF-7B) reduced Bcl-2 protein levels while increasing cell-cell adhesion, and junction formation. Here we compared these cells with the ERalpha(+) and low Bcl-2-expressing MCF-7 cells and with the normal mammary epithelial cell line MCF-10-2A not expressing ERalpha or Bcl-2. All cell lines expressed normal HER2.