251 research outputs found
MC1R functions, expression and implications for targeted therapy
Get PDFThe G protein-coupled MC1R is expressed in melanocytes and has a pivotal role in human skin pigmentation, with reduced function in human genetic variants exhibiting a red hair phenotype and increased melanoma predisposition. Beyond its role in pigmentation, MC1R is increasingly recognized as promoting UV-induced DNA damage repair. Consequently, there is mounting interest in targeting MC1R for therapeutic benefit. However, whether MC1R expression is restricted to melanocytes or is more widely expressed remains a matter of debate. In this paper, we review MC1R function and highlight that unbiased analysis suggests that its expression is restricted to melanocytes, granulocytes, and the brain
Leioscyta humeralis Goding
No full text<i>Leioscyta humeralis</i> Goding <p> <i>Leioscyta humeralis</i> Goding 1930a: 91; Metcalf and Wade, 1965a: 1317; McKamey, 1998a: 207. Original repository: MPSP.</p> <p> <b>Holotype male</b> from BRAZIL: <i>São Paulo</i>: São Paulo: " SÃO PAULO \ <i>Ipiranga</i> ", "[red label] Cotype", " <i>Leioscyta</i> \ <i>humeralis</i> \ <i>Goding</i> ", "Coleção \ PINTO DA \ FONSECA". Double-mounted on minuten, mesothoracic legs lacking tarsomeres; pronotum broken, lacking distal tip of posterior process.</p> <p> <b>Remarks.</b> Goding (1930) also designated three paratypes (one male and two females): one originally deposited at MPSP and two deposited in his personal collection. However, the author did not specify the sex of paratypes in each repository. One paratype (gender not specified) was not located in the collection.</p>Published as part of <i>Evangelista, Olivia, Santos, Guilherme Ide Marques Dos & Lamas, Carlos Einicker, 2014, An annotated catalogue of the Membracidae types in the Museu de Zoologia da Universidade de São Paulo, Brazil (Hemiptera: Auchenorrhyncha: Cicadomorpha), pp. 1-30 in Zootaxa 3895 (1)</i> on page 19, DOI: 10.11646/zootaxa.3895.1.1, <a href="http://zenodo.org/record/287608">http://zenodo.org/record/287608</a>
Fidicinoides distanti (Goding)
No full text<p> <i>Fidicinoides distanti</i> (Goding)</p> <p> – the FSCA has specimens from Rondonia 62 km S Ariquemes, linea C- 20, 7 km E B-65, 165m, Fazenda Rancho Grande, 10 o 32’S 62 o 48’W, 14-22-III- 1990; and Rondonia, 60 km S Ariquemes, 17-24-III-1989.</p> <p> The author received a specimen from C. Covell collected in Rondonia, Fazenda Rancho Grande, vicinityof Cacaulandia, 15-III-1991. The species has recently been transferred to <i>Fidicinoides</i> Boulard and Martinelli (Sanborn 2007a)</p> <p>and was reported previously only from Ecuador (Goding 1925) and Venezuela (Sanborn 2007a).</p>Published as part of <i>Sanborn, Allen F., 2008, New Records of Brazilian Cicadas Including the Description of a New Species (Hemiptera: Cicadoidea, Cicadidae), pp. 685-690 in Neotropical Entomology 37 (6)</i> on page 689, DOI: 10.1590/s1519-566x2008000600010, <a href="http://zenodo.org/record/3557762">http://zenodo.org/record/3557762</a>
The MITF regulatory network in melanoma
Get PDFBidirectional interactions between plastic tumor cells and the microenvironment critically impact tumor evolution and metastatic dissemination by enabling cancer cells to adapt to microenvironmental stresses by switching phenotype. In melanoma, a key determinant of phenotypic identity is the microphthalmia-associated transcription factor MITF that promotes proliferation, suppresses senescence, and anticorrelates with immune infiltration and therapy resistance. What determines whether MITF can activate or repress genes associated with specific phenotypes, or how signaling regulating MITF might impact immune infiltration is poorly understood. Here, we find that MITF binding to genes associated with high MITF is via classical E/M-box motifs, but genes downregulated when MITF is high contain FOS/JUN/AP1/ATF3 sites. Significantly, the repertoire of MITF-interacting factors identified here includes JUN and ATF3 as well as many previously unidentified interactors. As high AP1 activity is a hallmark of MITFLow, invasive, slow-cycling, therapy resistant cells, the ability of MITF to repress AP1-regulated genes provides an insight into how MITF establishes and maintains a pro-proliferative phenotype. Moreover, although β-catenin has been linked to immune exclusion, many Hallmark β-catenin signaling genes are associated with immune infiltration. Instead, low MITF together with Notch signaling is linked to immune infiltration in both mouse and human melanoma tumors
Role and regulation of MITF in melanocytes and melanoma
Get PDFOne key to understanding how cells integrate and how they respond to diverse stimuli in order to direct a transcriptional response is knowing how a transcription factor may be directed to an appropriate subset of its target genes. One mechanism with which this may be achieved is by modulation of the transcription factor’s post-translational modification status. The microphthalmia-associated transcription factor (MITF) is the master regulator of the melanocyte lineage, and it is also a lineage addiction gene in melanoma. Low or high levels of MITF expression induce a reversible cell cycle arrest. Invasive behaviour is characteristic of low MITF expression; differentiation a product of high MITF activity; and moderate levels of MITF expression promote proliferation. A major, unaddressed problem is how DNA binding by MITF may be differentially directed such that it regulates either a proliferation-associated or a differentiation-associated gene expression programme appropriate to the cellular microenvironment. This thesis explores the function and regulation of the signalling pathways controlling novel post-translational modifications of MITF. One such modification, in the DNA binding domain of MITF, defines a key switch that controls MITF’s DNA binding affinity and specificity. Moreover, a novel set of MITF target genes are revealed that extend its control beyond pigmentation and cell cycle regulation to implicate MITF as an overall regulator of cell behaviour in the melanocyte lineage
Regulation and role of TBX2 and TBX3 in tumour progression
Get PDFTBX2 and TBX3 belong to the T-box family of transcription factors and are im- portant in embryonic development and tumourigenesis. Overexpression of TBX2/3 has been observed in several types of cancer, promoting tumour proliferation, senescence bypass and invasiveness.
Given their important contribution to tumour progression, it might be of therapeutic benefit to pharmacologically inhibit their expression for cancer treatment. To identify novel regulators of TBX2/3, we carried out a high throughput screen for FDA-approved drugs that could affect TBX2/3 expression and/or subcellular localisation using melanoma cells ectopically expressing TBX2/3. We identified hit drugs from the initial imaging-base screen and confirmed the results of selected compounds targeting calcineurin.
In addition to the regulation of TBX2/3 protein, to further understand their role in tumour progression, we undertook genome-wide ChIP-seq and RNA-seq experiments to identify potential target genes and explore functional implications. As there is a lack of ChIP-grade TBX2/3 antibodies, we tagged the endogenous proteins with 3xHA using the CRISPR/Cas9 system. The generated cell lines produced high-quality ChIP-seq datasets of TBX2 and TBX3 and revealed the repertoire of binding sites genome-wide. Surprisingly, TBX2 binds to not only T-elements as expected, but also to a subset of E-box sequences bound by USF2. Integrative analysis of ChIP-seq and RNA-seq datasets identified E2F1 as a novel target gene of TBX2 that promotes cell growth.
Last, but not least, we also identified novel cofactors of TBX2, with preliminary data suggesting that TBX2 represses gene expression by interacting with polycomb repressive complex 1, and may be converted to a transactivator when interacting with basis helix-loop-helix transcription factor USF2
Transcriptional control of phenotype in melanoma
Get PDFMelanoma is the most aggressive and deadly type of skin cancer, mainly as a
consequence of its high metastatic capacity and refractoriness to treatment. Over recent
years increasing evidence suggests that the intra-tumour microenvironment can drive cells
to adopt invasive and drug-resistant phenotypes that play a key role in disease progression.
Understanding how phenotypic heterogeneity is generated, and the molecular mechanisms
underpinning the acquisition of invasive or drug-resistant states is key to the development
of more effective therapies. Current evidence suggests an important role for the
micropththalmia-associated transcription factor MITF in the development of phenotypic
heterogeneity in melanoma. Yet how MITF is regulated and how it controls melanoma
biology remains poorly characterised.
Here we show that activating transcription factor 4 (ATF4), whose expression is induced
via a translational switch that occurs under microenvironment stresses frequently found in
tumours such as nutrient deprivation or hypoxia, has the potential to directly supress MITF
expression and also directly target a repertoire of well-characterised and novel MITF target
genes. In addition, ATF4 also directly binds and has the potential to activate expression of
novel target genes linked to invasiveness/metastasis or with a cytoprotective role. Our
results therefore suggest that in response to a stressful intra-tumour microenvironment the
induction of ATF4 provides a potentially reversible mechanism for the generation of
phenotype heterogeneity in melanoma leading to the acquisition of metastatic and/or drugresistant
capacities in specific subpopulations of cells.</p
Post-translational regulation of transcription factor EB
Get PDFThe bHLH-LZ transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and autophagy, it also plays an important role in lipid and glucose metabolism, mitochondrial biogenesis, integrated stress response and immunity. Dysregulation of TFEB family is implicated in cancer as well as neurodegenerative diseases. TFEB subcellular localisation and transcriptional activity are regulated by cellular nutrient and energy status. Elucidating the mechanism of TFEB regulation is the key to understanding its role in maintaining cellular homeostasis as well as providing therapeutic insights. In this study we showed that TFEB subcellular localisation is regulated by both amino acids and glucose availability. Low glucose levels activate mTORC2-AKT signalling, leading to the inactivation of GSK3β, and GSK3β kinase activity is required for TFEB cytoplasmic localisation. We also demonstrated that GSK3β phosphorylates TFEB at S138 only after a priming phosphorylation event at S142. The sequential phosphorylation is required for CRM1-depedent nuclear export of TFEB via a novel nuclear export signal. This mechanism is important for the rapid cytoplasmic relocalisation and inactivation of TFEB upon nutrient replenishment. Additionally, we performed a high-throughput screen of 1,600 FDA-approved drugs and identified around 100 chemical modulators of TFEB and TFE3, of which around 50 % exhibited lysosomal biogenesis promoting potential. In particular, trifluoperazine, pimozide and loperamide induce TFEB nuclear translocation, lysosomal biogenesis and autophagy in an mTORC1- and AMPK- independent manner.</p
Post-translational modifications of BRAF and MITF
Get PDFMalignant melanoma is the deadliest and most aggressive form of skin cancer. Despite the development of targeted molecular therapies which specifically target oncogenic pathways in melanoma, melanoma remains highly refractory to treatment and prone to relapse. In order to develop more effective therapies, there is a need to investigate additional ways of manipulating aberrant molecular pathways in melanoma. To this end, we have identified novel sites of post-translational modifications in two oncogenic proteins that are known to play pivotal roles in driving melanoma tumorigenesis. We showed that BRAF, the most commonly mutated oncoprotein in melanoma, can be acetylated at K473 and K475 by the p300/CBP acetyltransferases. Importantly, acetylation of BRAF reduced its activity regardless of its mutational status at the commonly mutated V600 residue. We also identified a novel phosphorylation site targeted by GSK3 in microphthalmia-associated transcription factor (MITF), the melanocyte master regulator. GSK3 phosphorylation of S69, together with ERK-mediated phosphorylation of the nearby S73 residue, was found to promote MITF nuclear export via a previously undescribed nuclear export signal comprising of the S69, S73, M75, L78 and L80 residues. Importantly, phosphorylation-induced nuclear export was associated with reduced MITF activity, which may have important functional implications for melanocyte development and melanoma oncogenesis. In addition, we showed that the cyclin-dependent kinases CDK1 and CDK2 can also phosphorylate MITF at S73
Diversity of pigmentation in cultured human melanocytes is due to differences in the type as well as quantity of melanin
No full textCultured human melanocytes differ tremendously in visual pigmentation, and recapitulate the pigmentary phenotype of the donor's skin. This diversity arises from variation in type as well as quantity of melanin produced. Here, we measured contents of eumelanin (EM) and pheomelanin (PM) in 60 primary human melanocyte cultures (51 neonatal and nine adults), and correlated some of these values with the respective activity and protein levels of tyrosinase, and the melanocortin-1 receptor (MC1R) genotype. Melanocytes were classified into four phenotypes (L, L+, D, D+) as depicted by visual pigmentation using light microscopy, and by the pigmentary phenotype of the donor's skin. There were large differences in total melanin (TM) and EM, which increased progressively for L, L+, D and D+ melanocytes. TM content, the sum of EM and PM, showed a good correlation with TM measured spectrophotometrically, and with the activity and protein levels of tyrosinase. Log EM/PM ratio did not correlate with MC1R genotype. We conclude that: (i) EM consistently correlates with the visual phenotype; (ii) lighter melanocytes tend to be more pheomelanic in composition than darker melanocytes; (iii) in adult melanocyte cultures, EM correlates with the ethnic background of the donors (African-American > Indian > Caucasian); and (iv) MC1R loss-of-function mutations do not necessarily alter the phenotype of cultured melanocytes
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