All transcription factors are equal, but some are more equal than others. In the 25 yr since the gene encoding the microphthalmia-associated transcription factor (MITF) was first isolated, MITF has emerged as a key coordinator of many aspects of melanocyte and melanoma biology. Like all transcription factors, MITF binds to specific DNA sequences and up-regulates or down-regulates its target genes. What marks MITF as being remarkable among its peers is the sheer range of biological processes that it appears to coordinate. These include cell survival, differentiation, proliferation, invasion, senescence, metabolism, and DNA damage repair. In this article we present our current understanding of MITF's role and regulation in development and disease, as well as those of the MITF-related factors TFEB and TFE3, and highlight key areas where our knowledge of MITF regulation and function is limited.

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MITF—the first 25 years

Melanin is the main product of human melanocytes and functions to protect skin from ultraviolet (UV) radiation while conferring color to skin and hair. Tyrosinase is the rate-limiting enzyme for melanin synthesis along with tyrosinase-related protein (TRP)-1 and TRP-2. Microphthalmia-associated transcription factor regulates tyrosinase gene expression and is in turn regulated by extracellular signal-regulated kinase (ERK), phosphoinositide 3-kinase (PI3K)/AKT, and glycogen synthase kinase (GSK)3β signaling pathways. Pyruvic acid (PA) is an energy source for ATP synthesis in the tricarboxylic acid cycle that also acts as a reactive oxygen species (ROS) scavenger. As UV irradiation induces melanin synthesis and ROS generation, we speculated that PA or ethyl pyruvate (EP), a stable form of pyruvate, regulates melanogenesis. B16F10 melanoma cells served as a melanin synthesis model. Treatment with PA or EP suppressed melanin synthesis while increasing intracellular ROS levels, which was accompanied by increased ERK phosphorylation in the case of EP treatment. PA and EP induced GSK3β phosphorylation and activated PI3K/AKT signaling, leading to decreased melanin synthesis. These results indicate that PA and EP inhibit melanogenesis via PI3K/AKT and GSK3β signaling and targeting the ERK and GSK3β pathways, respectively. Thus, PA and EP can potentially be used for treatment of hyperpigmentation disorders.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/gtc.12654

Pyruvic acid/ethyl pyruvate inhibits melanogenesis in B16F10 melanoma cells through PI3K/AKT, GSK3β, and ROS-ERK signaling pathways.

Metabolic reprogramming contributes to the pathogenesis and heterogeneity of melanoma. It is driven both by oncogenic events and the constraints imposed by a nutrient- and oxygen-scarce microenvironment. Among the most prominent metabolic reprogramming features is an increased rate of lipid synthesis. Lipids serve as a source of energy and form the structural foundation of all membranes, but have also emerged as mediators that not only impact classical oncogenic signaling pathways, but also contribute to melanoma progression. Various alterations in fatty acid metabolism have been reported and can contribute to melanoma cell aggressiveness. Elevated expression of the key lipogenic fatty acid synthase is associated with tumor cell invasion and poor prognosis. Fatty acid uptake from the surrounding microenvironment, fatty acid β-oxidation and storage also appear to play an essential role in tumor cell migration. The aim of this review is (i) to focus on the major alterations affecting lipid storage organelles and lipid metabolism. A particular attention has been paid to glycerophospholipids, sphingolipids, sterols and eicosanoids, (ii) to discuss how these metabolic dysregulations contribute to the phenotype plasticity of melanoma cells and/or melanoma aggressiveness, and (iii) to highlight therapeutic approaches targeting lipid metabolism that could be applicable for melanoma treatment.

Lipid metabolic Reprogramming: Role in Melanoma Progression and Therapeutic Perspectives.

Summary Impaired human oligodendrocyte progenitor cell (hOPC) differentiation likely contributes to failed remyelination in multiple sclerosis. The characterization of molecular pathways that regulate hOPC differentiation will provide means to induce remyelination. In this study, we determined the gene expression profile of PDGFαR + hOPCs during initial oligodendrocyte commitment. Weighted gene coexpression network analysis was used to define progenitor and differentiation-specific gene expression modules and functionally important hub genes. These modules were compared with rodent OPC and oligodendrocyte data to determine the extent of species conservation. These analyses identified G-protein β 4 (GNB4), which was associated with hOPC commitment. Lentiviral GNB4 overexpression rapidly induced human oligodendrocyte differentiation. Following xenograft in hypomyelinating shiverer / rag2 mice, GNB4 overexpression augmented myelin synthesis and the ability of hOPCs to ensheath host axons, establishing GNB4 as functionally important in human myelination. As such, network analysis of hOPC gene expression accurately predicts genes that influence human oligodendrocyte differentiation in vivo .

Network-Based Genomic Analysis of Human Oligodendrocyte Progenitor Differentiation.

Inflammatory bowel disease (IBD) is a chronic and debilitating disorder that has few treatment options due to a lack of comprehensive understanding of its molecular pathogenesis. We used multiplexed mass spectrometry to collect high-content information on protein phosphorylation in two different mouse models of IBD. Because the biological function of the vast majority of phosphorylation sites remains unknown, we developed Substrate-based Kinase Activity Inference (SKAI), a methodology to infer kinase activity from phosphoproteomic data. This approach draws upon prior knowledge of kinase-substrate interactions to construct custom lists of kinases and their respective substrate sites, termed kinase-substrate sets that employ prior knowledge across organisms. This expansion as much as triples the amount of prior knowledge available. We then used these sets within the Gene Set Enrichment Analysis framework to infer kinase activity based on increased or decreased phosphorylation of its substrates in a dataset. When applied to the phosphoproteomic datasets from the two mouse models, SKAI predicted largely non-overlapping kinase activation profiles. These results suggest that chronic inflammation may arise through activation of largely divergent signaling networks. However, the one kinase inferred to be activated in both mouse models was mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2 or MK2), a serine/threonine kinase that functions downstream of p38 stress-activated mitogen-activated protein kinase. Treatment of mice with active colitis with ATI450, an orally bioavailable small molecule inhibitor of the MK2 pathway, reduced inflammatory signaling in the colon and alleviated the clinical and histological features of inflammation. These studies establish MK2 as a therapeutic target in IBD and identify ATI450 as a potential therapy for the disease.

Ying Wang

Papers

Phosphorylation of MITF by AKT affects its downstream targets and causes TP53-dependent cell senescence