Dorothy C Bennett

Publications (59)545.99 Total impact

• Source

  Available from: Michal J Besser

  Article: MicroRNA-mediated loss of ADAR1 in metastatic melanoma promotes tumor growth.

  Yael Nemlich, Eyal Greenberg, Rona Ortenberg, Michal J Besser, Iris Barshack, Jasmine Jacob-Hirsch, Elad Jacoby, Eran Eyal, Ludmila Rivkin, Victor G Prieto, Nitin Chakravarti, Lyn M Duncan, David M Kallenberg, Eitan Galun, Dorothy C Bennett, Ninette Amariglio, Menashe Bar-Eli, Jacob Schachter, Gideon Rechavi, Gal Markel
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  ABSTRACT: Some solid tumors have reduced posttranscriptional RNA editing by adenosine deaminase acting on RNA (ADAR) enzymes, but the functional significance of this alteration has been unclear. Here, we found the primary RNA-editing enzyme ADAR1 is frequently reduced in metastatic melanomas. In situ analysis of melanoma samples using progression tissue microarrays indicated a substantial downregulation of ADAR1 during the metastatic transition. Further, ADAR1 knockdown altered cell morphology, promoted in vitro proliferation, and markedly enhanced the tumorigenicity in vivo. A comparative whole genome expression microarray analysis revealed that ADAR1 controls the expression of more than 100 microRNAs (miRNAs) that regulate many genes associated with the observed phenotypes. Importantly, we discovered that ADAR1 fundamentally regulates miRNA processing in an RNA binding-dependent, yet RNA editing-independent manner by regulating Dicer expression at the translational level via let-7. In addition, ADAR1 formed a complex with DGCR8 that was mutually exclusive with the DGCR8-Drosha complex that processes pri-miRNAs in the nucleus. We found that cancer cells silence ADAR1 by overexpressing miR-17 and miR-432, which both directly target the ADAR1 transcript. We further demonstrated that the genes encoding miR-17 and miR-432 are frequently amplified in melanoma and that aberrant hypomethylation of the imprinted DLK1-DIO3 region in chromosome 14 can also drive miR-432 overexpression.
  The Journal of clinical investigation 05/2013; · 15.39 Impact Factor
• Article: Senescence evasion in melanoma progression: uncoupling of DNA-damage signaling from p53 activation and p21 expression.

  Alastair D Mackenzie Ross, Martin G Cook, Heung Chong, Mehnaz Hossain, Hardev S Pandha, Dorothy C Bennett
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  ABSTRACT: The best-established function of the melanoma-suppressor p16 is mediation of cell senescence, a permanent arrest following cell proliferation or certain stresses. The importance of p16 in melanoma suggests indolence of the other major senescence pathway through p53. Little or no p53 is expressed in senescent normal human melanocytes, but p16-deficient melanocytes can undergo p53-mediated senescence. Since p16 expression occurs in nevi but falls with progression towards melanoma, we here investigated whether p53-dependent senescence occurs at some stage, and if not, what defects were detectable in this pathway, using immunohistochemistry. Phosphorylated checkpoint kinase 2 (CHEK2) can mediate DNA-damage signaling, and under some conditions senescence, by phosphorylating and activating p53. Remarkably we detected no prevalent p53-mediated senescence in any of six classes of lesions. Two separate defects in p53 signaling appeared common: in nevi, lack of p53 phosphorylation by activated CHEK2, and in melanomas defective p21 upregulation by p53 even when phosphorylated. © 2012 John Wiley & Sons A/S.
  Pigment Cell & Melanoma Research 12/2012; · 5.06 Impact Factor
• Source

  Available from: Juan S. Bonifacino

  Article: Differential recognition of a dileucine-based sorting signal by AP-1 and AP-3 reveals a requirement for both BLOC-1 and AP-3 in delivery of OCA2 to melanosomes.

  Anand Sitaram, Megan K Dennis, Rittik Chaudhuri, Wilfredo De Jesus-Rojas, Danièle Tenza, Subba Rao Gangi Setty, Christopher S Wood, Elena V Sviderskaya, Dorothy C Bennett, Graça Raposo, Juan S Bonifacino, Michael S Marks
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  ABSTRACT: Cell types that generate unique lysosome-related organelles (LROs), such as melanosomes in melanocytes, populate nascent LROs with cargoes that are diverted from endosomes. Cargo sorting toward melanosomes correlates with binding via cytoplasmically exposed sorting signals to either heterotetrameric adaptor AP-1 or AP-3. Some cargoes bind both adaptors, but the relative contribution of each adaptor to cargo recognition and their functional interactions with other effectors during transport to melanosomes are not clear. Here we exploit targeted mutagenesis of the acidic dileucine-based sorting signal in the pigment cell-specific protein OCA2 to dissect the relative roles of AP-1 and AP-3 in transport to melanosomes. We show that binding to AP-1 or AP-3 depends on the primary sequence of the signal and not its position within the cytoplasmic domain. Mutants that preferentially bound either AP-1 or AP-3 each trafficked toward melanosomes and functionally complemented OCA2 deficiency, but AP-3 binding was necessary for steady-state melanosome localization. Unlike tyrosinase, which also engages AP-3 for optimal melanosomal delivery, both AP-1- and AP-3-favoring OCA2 variants required BLOC-1 for melanosomal transport. These data provide evidence for distinct roles of AP-1 and AP-3 in OCA2 transport to melanosomes and indicate that BLOC-1 can cooperate with either adaptor during cargo sorting to LROs.
  Molecular biology of the cell 06/2012; 23(16):3178-92. · 5.98 Impact Factor
• Source

  Available from: Tracey Ferrara

  Article: Genome-wide association analyses identify 13 new susceptibility loci for generalized vitiligo.

  Ying Jin, Stanca A Birlea, Pamela R Fain, Tracey M Ferrara, Songtao Ben, Sheri L Riccardi, Joanne B Cole, Katherine Gowan, Paulene J Holland, Dorothy C Bennett, [......], Alain Taïeb, Thomas Jouary, Khaled Ezzedine, Margaret R Wallace, Wayne T McCormack, Mauro Picardo, Giovanni Leone, Andreas Overbeck, Nanette B Silverberg, Richard A Spritz
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  ABSTRACT: We previously reported a genome-wide association study (GWAS) identifying 14 susceptibility loci for generalized vitiligo. We report here a second GWAS (450 individuals with vitiligo (cases) and 3,182 controls), an independent replication study (1,440 cases and 1,316 controls) and a meta-analysis (3,187 cases and 6,723 controls) identifying 13 additional vitiligo-associated loci. These include OCA2-HERC2 (combined P = 3.80 × 10(-8)), MC1R (P = 1.82 × 10(-13)), a region near TYR (P = 1.57 × 10(-13)), IFIH1 (P = 4.91 × 10(-15)), CD80 (P = 3.78 × 10(-10)), CLNK (P = 1.56 × 10(-8)), BACH2 (P = 2.53 × 10(-8)), SLA (P = 1.58 × 10(-8)), CASP7 (P = 3.56 × 10(-8)), CD44 (P = 1.78 × 10(-9)), IKZF4 (P = 2.75 × 10(-14)), SH2B3 (P = 3.54 × 10(-18)) and TOB2 (P = 6.81 × 10(-10)). Most vitiligo susceptibility loci encode immunoregulatory proteins or melanocyte components that likely mediate immune targeting and the relationships among vitiligo, melanoma, and eye, skin and hair coloration.
  Nature Genetics 05/2012; 44(6):676-80. · 35.53 Impact Factor
• Source

  Available from: W Nicol Keith

  Article: Cancer cell senescence: a new frontier in drug development.

  Claire J Cairney, Alan E Bilsland, T R Jeffry Evans, Jon Roffey, Dorothy C Bennett, Masashi Narita, Christopher J Torrance, W Nicol Keith
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  ABSTRACT: Senescence forms a universal block to tumorigenesis which impacts on all hallmarks of cancer, making it an attractive target for drug discovery. Therefore a strategy must be devised to focus this broad potential into a manageable drug discovery programme. Several issues remain to be addressed including the lack of robust senescence-inducing compounds and causally related biomarkers to measure cellular response. Here, we review the latest progress in translating senescence as a target for cancer therapy and some promising approaches to drug and biomarker discovery. Finally, we discuss the potential application of a senescence-induction therapy in a clinical setting.
  Drug discovery today 03/2012; 17(5-6):269-76. · 6.63 Impact Factor
• Source

  Available from: W Nicol Keith

  Article: Cancer cell senescence: a new frontier in drug development

  Claire J. Cairney, Alan E. Bilsland, T.R. Jeffry Evans, Jon Roffey, Dorothy C. Bennett, Masashi Narita, Christopher J. Torrance, W. Nicol Keith
  Drug Discovery Today 01/2012; · 6.83 Impact Factor
• Source

  Available from: pnas.org

  Article: Targeting protein-trafficking pathways alters melanoma treatment sensitivity.

  Zhi-ming Huang, Milka Chinen, Philip J Chang, Tong Xie, Lily Zhong, Stephanie Demetriou, Mira P Patel, Rebecca Scherzer, Elena V Sviderskaya, Dorothy C Bennett, Glenn L Millhauser, Dennis H Oh, James E Cleaver, Maria L Wei
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  ABSTRACT: Protein-trafficking pathways are targeted here in human melanoma cells using methods independent of oncogene mutational status, and the ability to up-regulate and down-regulate tumor treatment sensitivity is demonstrated. Sensitivity of melanoma cells to cis-diaminedichloroplatinum II (cDDP, cis-platin), carboplatin, dacarbazine, or temozolomide together with velaparib, an inhibitor of poly (ADP ribose) polymerase 1, is increased by up to 10-fold by targeting genes that regulate both protein trafficking and the formation of melanosomes, intracellular organelles unique to melanocytes and melanoma cells. Melanoma cells depleted of either of the protein-trafficking regulators vacuolar protein sorting 33A protein (VPS33A) or cappuccino protein (CNO) have increased nuclear localization of cDDP, increased nuclear DNA damage by platination, and increased apoptosis, resulting in increased treatment sensitivity. Depleted cells also exhibit a decreased proportion of intracellular, mature melanosomes compared with undepleted cells. Modulation of protein trafficking via cell-surface signaling by binding the melanocortin 1 receptor with the antagonist agouti-signaling protein decreased the proportion of mature melanosomes formed and increased cDDP sensitivity, whereas receptor binding with the agonist melanocyte-stimulating hormone resulted in an increased proportion of mature melanosomes formed and in decreased sensitivity (i.e., increased resistance) to cDDP. Mutation of the protein-trafficking gene Hps6, known to impair the formation of mature melanosomes, also increased cDDP sensitivity. Together, these results indicate that targeting protein-trafficking molecules markedly increases melanoma treatment sensitivity and influences the degree of melanosomes available for sequestration of therapeutic agents.
  Proceedings of the National Academy of Sciences 12/2011; 109(2):553-8. · 9.68 Impact Factor
• Article: (V600E)Braf::Tyr-CreERT2::K14-Kitl mice do not develop superficial spreading-like melanoma: keratinocyte Kit ligand is insufficient to "translocate" (V600E)Braf-driven melanoma to the epidermis.

  Joel Rae, Amaya Viros, Robert Hayward, Dorothy C Bennett, Nathalie Dhomen, B Jack Longley, Jorge S Reis-Filho, Richard Marais
  Journal of Investigative Dermatology 11/2011; 132(2):488-91. · 6.31 Impact Factor
• Article: Receptor tyrosine kinases and their activation in melanoma

  David J. Easty, Steven G. Gray, Kenneth J. O’Byrne, Dearbhaile O’Donnell, Dorothy C. Bennett
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  ABSTRACT: Receptor tyrosine kinases (RTKs) and their downstream signalling pathways have long been hypothesized to play key roles in melanoma development. A decade ago, evidence was derived largely from animal models, RTK expression studies and detection of activated RAS isoforms in a small fraction of melanomas. Predictions that overexpression of specific RTKs implied increased kinase activity and that some RTKs would show activating mutations in melanoma were largely untested. However, technological advances including rapid gene sequencing, siRNA methods and phospho-RTK arrays now give a more complete picture. Mutated forms of RTK genes including KIT, ERBB4, the EPH and FGFR families and others are known in melanoma. Additional over- or underexpressed RTKs and also protein tyrosine phosphatases (PTPs) have been reported, and activities measured. Complex interactions between RTKs and PTPs are implicated in the abnormal signalling driving aberrant growth and survival in malignant melanocytes, and indeed in normal melanocytic signalling including the response to ultraviolet radiation. Kinases are considered druggable targets, so characterization of global RTK activity in melanoma should assist the rational development of tyrosine kinase inhibitors for clinical use.
  Pigment Cell & Melanoma Research 05/2011; 24(3):446 - 461. · 5.06 Impact Factor
• Article: Koebner’s phenomenon in vitiligo: European position paper

  Nanja van Geel, Reinhart Speeckaert, Alain Taieb, Mauro Picardo, Markus Böhm, David J. Gawkrodger, Karin Schallreuter, Dorothy C. Bennett, Wietze van der Veen, Maxine Whitton, Silvia Moretti, Wiete Westerhof, Khaled Ezzedine, Yvon Gauthier, on behalf of the other VETF members
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  ABSTRACT: Koebner’s phenomenon (KP) has been observed in a number of skin diseases, including vitiligo. Its clinical significance in vitiligo with respect to disease activity and course is still debatable, while its relevance for surgical techniques has been demonstrated in some reports. We present a literature review on the currently known facts about KP in vitiligo, including details of clinical, experimental, and histopathological changes. The consensus view is that there are still no methods to define and assess KP in vitiligo. A new classification is proposed to allow an evaluation of KP in daily practice or in experimental studies. However, many unanswered questions still remain after redefining KP in patients with vitiligo. Active research focusing on KP in vitiligo may not only provide unexpected clues in the pathogenesis of vitiligo but also help to tailor novel therapies against this chronic and often psychologically devastating skin disease.
  Pigment Cell & Melanoma Research 03/2011; 24(3):564 - 573. · 5.06 Impact Factor
• Source

  Available from: W Nicol Keith

  Article: Malignancy without immortality? Cellular immortalization as a possible late event in melanoma progression.

  Julia K Soo, Alastair D Mackenzie Ross, David M Kallenberg, Carla Milagre, W Heung Chong, Jade Chow, Lucy Hill, Stacey Hoare, Rebecca S Collinson, Mehnaz Hossain, W Nicol Keith, Richard Marais, Dorothy C Bennett
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  ABSTRACT: Cell senescence is a permanent growth arrest following extended proliferation. Cultured cancer cells including metastatic melanoma cells often appear immortal (proliferate indefinitely), while uncultured benign nevi (moles) show senescence markers. Here, with new explantation methods, we investigated which classes of primary pigmented lesions are typically immortal. Nevi yielded a few proliferating cells, consistent with most nevus cells being senescent. No nevus culture (0/28) appeared immortal. Some thin and thick melanoma cultures proved immortal under these conditions, but surprisingly few (4/37). All arrested cultures displayed three senescence markers in some cells: β-galactosidase, nuclear p16, and heterochromatic foci/aggregates. However, melanoma cultures also showed features of telomeric crisis (arrest because of ultrashort telomeres). Moreover, crisis markers including anaphase bridges were frequent in uncultured vertical growth-phase (VGP) melanomas. Conversely, all immortal melanoma cultures expressed telomerase reverse transcriptase and telomerase, showing aneuploidy. The findings suggest that primary melanomas are typically precrisis, with immortalization/telomere maintenance as a late event.
  Pigment Cell & Melanoma Research 03/2011; 24(3):490-503. · 5.06 Impact Factor
• Source

  Available from: Steven G Gray

  Article: Receptor tyrosine kinases and their activation in melanoma.

  David J Easty, Steven G Gray, Kenneth J O'Byrne, Dearbhaile O'Donnell, Dorothy C Bennett
  [show abstract] [hide abstract]
  ABSTRACT: Receptor tyrosine kinases (RTKs) and their downstream signalling pathways have long been hypothesized to play key roles in melanoma development. A decade ago, evidence was derived largely from animal models, RTK expression studies and detection of activated RAS isoforms in a small fraction of melanomas. Predictions that overexpression of specific RTKs implied increased kinase activity and that some RTKs would show activating mutations in melanoma were largely untested. However, technological advances including rapid gene sequencing, siRNA methods and phospho-RTK arrays now give a more complete picture. Mutated forms of RTK genes including KIT, ERBB4, the EPH and FGFR families and others are known in melanoma. Additional over- or underexpressed RTKs and also protein tyrosine phosphatases (PTPs) have been reported, and activities measured. Complex interactions between RTKs and PTPs are implicated in the abnormal signalling driving aberrant growth and survival in malignant melanocytes, and indeed in normal melanocytic signalling including the response to ultraviolet radiation. Kinases are considered druggable targets, so characterization of global RTK activity in melanoma should assist the rational development of tyrosine kinase inhibitors for clinical use.
  Pigment Cell & Melanoma Research 02/2011; 24(3):446-61. · 5.06 Impact Factor
• Article: Genome-wide analysis identifies a quantitative trait locus in the MHC class II region associated with generalized vitiligo age of onset.

  Ying Jin, Stanca A Birlea, Pamela R Fain, Katherine Gowan, Sheri L Riccardi, Paulene J Holland, Dorothy C Bennett, Deborah M Herbstman, Margaret R Wallace, Wayne T McCormack, [......], Anthony P Weetman, Mauro Picardo, Giovanni Leone, Alain Taïeb, Thomas Jouary, Khaled Ezzedine, Nanny van Geel, Jo Lambert, Andreas Overbeck, Richard A Spritz
  [show abstract] [hide abstract]
  ABSTRACT: Generalized vitiligo is a common autoimmune disease in which acquired patchy depigmentation of skin, hair, and mucous membranes results from loss of melanocytes from involved areas. Previous genetic analyses have focused on vitiligo susceptibility, and have identified a number of genes involved in disease risk. Age of onset of generalized vitiligo also involves a substantial genetic component, but has not previously been studied systematically. In this study, we report a genome-wide association study of vitiligo age of onset in 1,339 generalized vitiligo patients, with replication in an independent cohort of 677 cases. We identified a quantitative trait locus for vitiligo age of onset in the major histocompatibility complex (MHC) class II region, located near c6orf10-BTNL2 (rs7758128; P=8.14 × 10(-11)), a region that is also associated with generalized vitiligo susceptibility. In contrast, there was no association of vitiligo age of onset with any other MHC or non-MHC loci that are associated with vitiligo susceptibility. These findings highlight the differing roles played by genes involved in vitiligo susceptibility versus vitiligo age of onset, and illustrate that genome-wide analyses can be used to identify genes involved in quantitative aspects of disease natural history, as well as disease susceptibility per se.
  Journal of Investigative Dermatology 02/2011; 131(6):1308-12. · 6.31 Impact Factor
• Article: Isolation and culture of melanoma and naevus cells and cell lines.

  Julia K Soo, Alastair D Mackenzie Ross, Dorothy C Bennett
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  ABSTRACT: Recently developed methods are described for the culture of cells from primary human melanomas and benign or dysplastic naevi (moles). These allow the culture of viable cells from the great majority of such lesions, and the maintenance of what appears to be the predominant population of pigmented cells. These methods should facilitate the study of typical lesional cells, which appear somewhat different from the cell lines that have been established previously under more restrictive conditions: intermediate between these and normal melanocytes. The conditions involve the use of growth-inactivated keratinocytes initially, and a combination of mitogens similar to those routinely used for normal human melanocytes: stem cell factor, endothelin 1, TPA, and cholera toxin.
  Methods in molecular biology (Clifton, N.J.) 01/2011; 731:141-50.
• Article: Comprehensive association analysis of candidate genes for generalized vitiligo supports XBP1, FOXP3, and TSLP.

  Stanca A Birlea, Ying Jin, Dorothy C Bennett, Deborah M Herbstman, Margaret R Wallace, Wayne T McCormack, E Helen Kemp, David J Gawkrodger, Anthony P Weetman, Mauro Picardo, Giovanni Leone, Alain Taïeb, Thomas Jouary, Khaled Ezzedine, Nanja van Geel, Jo Lambert, Andreas Overbeck, Pamela R Fain, Richard A Spritz
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  ABSTRACT: We previously carried out a genome-wide association study of generalized vitiligo (GV) in non-Hispanic whites, identifying 13 confirmed susceptibility loci. In this study, we re-analyzed the genome-wide data set (comprising 1,392 cases and 2,629 controls) to specifically test association of all 33 GV candidate genes that have previously been suggested for GV, followed by meta-analysis incorporating both current and previously published data. We detected association of three of the candidate genes tested: TSLP (rs764916, P=3.0E-04, odds ratio (OR)=1.60; meta-P for rs3806933=3.1E-03), XBP1 (rs6005863, P=3.6E-04, OR=1.17; meta-P for rs2269577=9.5E-09), and FOXP3 (rs11798415, P=5.8E-04, OR=1.19). Association of GV with CTLA4 (rs12992492, P=5.9E-05, OR=1.20; meta-P for rs231775=1.0E-04) seems to be secondary to epidemiological association with other concomitant autoimmune diseases. Within the major histocompatibility complex (MHC), at 6p21.33, association with TAP1-PSMB8 (rs3819721, P=5.2E-06) seems to derive from linkage disequilibrium with major primary signals in the MHC class I and class II regions.
  Journal of Investigative Dermatology 11/2010; 131(2):371-81. · 6.31 Impact Factor
• Article: Common variants in FOXP1 are associated with generalized vitiligo.

  Ying Jin, Stanca A Birlea, Pamela R Fain, Christina M Mailloux, Sheri L Riccardi, Katherine Gowan, Paulene J Holland, Dorothy C Bennett, Margaret R Wallace, Wayne T McCormack, [......], Anthony P Weetman, Mauro Picardo, Giovanni Leone, Alain Taïeb, Thomas Jouary, Khaled Ezzedine, Nanny van Geel, Jo Lambert, Andreas Overbeck, Richard A Spritz
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  ABSTRACT: In a recent genome-wide association study of generalized vitiligo, we identified ten confirmed susceptibility loci. By testing additional loci that showed suggestive association in the genome-wide study, using two replication cohorts of European descent, we observed replicated association of generalized vitiligo with variants at 3p13 encompassing FOXP1 (rs17008723, combined P=1.04x10(-8)) and with variants at 6q27 encompassing CCR6 (rs6902119, combined P=3.94x10(-7)).
  Nature Genetics 07/2010; 42(7):576-8. · 35.53 Impact Factor
• Source

  Available from: Elizabeth Helen Kemp

  Article: Variant of TYR and autoimmunity susceptibility loci in generalized vitiligo.

  Ying Jin, Stanca A Birlea, Pamela R Fain, Katherine Gowan, Sheri L Riccardi, Paulene J Holland, Christina M Mailloux, Alexandra J D Sufit, Saunie M Hutton, Anita Amadi-Myers, [......], Anthony P Weetman, Mauro Picardo, Giovanni Leone, Alain Taïeb, Thomas Jouary, Khaled Ezzedine, Nanny van Geel, Jo Lambert, Andreas Overbeck, Richard A Spritz
  [show abstract] [hide abstract]
  ABSTRACT: Generalized vitiligo is an autoimmune disease characterized by melanocyte loss, which results in patchy depigmentation of skin and hair, and is associated with an elevated risk of other autoimmune diseases. To identify generalized vitiligo susceptibility loci, we conducted a genomewide association study. We genotyped 579,146 single-nucleotide polymorphisms (SNPs) in 1514 patients with generalized vitiligo who were of European-derived white (CEU) ancestry and compared the genotypes with publicly available control genotypes from 2813 CEU persons. We then tested 50 SNPs in two replication sets, one comprising 677 independent CEU patients and 1106 CEU controls and the other comprising 183 CEU simplex trios with generalized vitiligo and 332 CEU multiplex families. We detected significant associations between generalized vitiligo and SNPs at several loci previously associated with other autoimmune diseases. These included genes encoding major-histocompatibility-complex class I molecules (P=9.05x10(-23)) and class II molecules (P=4.50x10(-34)), PTPN22 (P=1.31x10(-7)), LPP (P=1.01x10(-11)), IL2RA (P=2.78x10(-9)), UBASH3A (P=1.26x10(-9)), and C1QTNF6 (P=2.21x10(-16)). We also detected associations between generalized vitiligo and SNPs in two additional immune-related loci, RERE (P=7.07x10(-15)) and GZMB (P=3.44x10(-8)), and in a locus containing TYR (P=1.60x10(-18)), encoding tyrosinase. We observed associations between generalized vitiligo and markers implicating multiple genes, some associated with other autoimmune diseases and one (TYR) that may mediate target-cell specificity and indicate a mutually exclusive relationship between susceptibility to vitiligo and susceptibility to melanoma.
  New England Journal of Medicine 05/2010; 362(18):1686-97. · 53.30 Impact Factor
• Chapter: Index

  M. Lynn Lamoreux, Véronique Delmas, Lionel Larue, Dorothy C. Bennett
  05/2010: pages 286 - 297; , ISBN: 9781444319651
• Source

  Available from: Alexey M Eroshkin

  Article: A role for ATF2 in regulating MITF and melanoma development.

  Meera Shah, Anindita Bhoumik, Vikas Goel, Antimone Dewing, Wolfgang Breitwieser, Harriet Kluger, Stan Krajewski, Maryla Krajewska, Jason Dehart, Eric Lau, David M Kallenberg, Hyeongnam Jeong, Alexey Eroshkin, Dorothy C Bennett, Lynda Chin, Marcus Bosenberg, Nic Jones, Ze'ev A Ronai
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  ABSTRACT: The transcription factor ATF2 has been shown to attenuate melanoma susceptibility to apoptosis and to promote its ability to form tumors in xenograft models. To directly assess ATF2's role in melanoma development, we crossed a mouse melanoma model (Nras(Q61K)::Ink4a⁻/⁻) with mice expressing a transcriptionally inactive form of ATF2 in melanocytes. In contrast to 7/21 of the Nras(Q61K)::Ink4a⁻/⁻ mice, only 1/21 mice expressing mutant ATF2 in melanocytes developed melanoma. Gene expression profiling identified higher MITF expression in primary melanocytes expressing transcriptionally inactive ATF2. MITF downregulation by ATF2 was confirmed in the skin of Atf2⁻/⁻ mice, in primary human melanocytes, and in 50% of human melanoma cell lines. Inhibition of MITF transcription by MITF was shown to be mediated by ATF2-JunB-dependent suppression of SOX10 transcription. Remarkably, oncogenic BRAF (V600E)-dependent focus formation of melanocytes on soft agar was inhibited by ATF2 knockdown and partially rescued upon shMITF co-expression. On melanoma tissue microarrays, a high nuclear ATF2 to MITF ratio in primary specimens was associated with metastatic disease and poor prognosis. Our findings establish the importance of transcriptionally active ATF2 in melanoma development through fine-tuning of MITF expression.
  PLoS Genetics 01/2010; 6(12):e1001258. · 8.69 Impact Factor
• Article: Functional neurons and melanocytes induced from immortal lines of postnatal neural crest-like stem cells.

  Elena V Sviderskaya, David J Easty, Mark A Lawrence, Daniel P Sánchez, Yuri A Negulyaev, Ricken H Patel, Praveen Anand, Yuri E Korchev, Dorothy C Bennett
  [show abstract] [hide abstract]
  ABSTRACT: Stem cells, that is, cells that can both reproduce themselves and differentiate into functional cell types, attract much interest as potential aids to healing and disease therapy. Embryonic neural crest is pluripotent and generates the peripheral nervous system, melanocytes, and some connective tissues. Neural-crest-related stem cells have been reported previously in postnatal skin: committed melanocytic stem cells in the hair follicle, and pluripotent cell types from the hair follicle and papilla that can produce various sets of lineages. Here we describe novel pluripotent neural crest-like stem cells from neonatal mouse epidermis, with different potencies, isolated as 3 independent immortal lines. Using alternative regulatory factors, they could be converted to large numbers of either Schwann precursor cells, pigmented melanocytes, chondrocytes, or functional sensory neurons showing voltage-gated sodium channels. Some of the neurons displayed abundant active TRPV1 and TRPA1 receptors. Such functional neurons have previously been obtained in culture only with difficulty, by explantation. The system was also used to generate comparative gene expression data for the stem cells, melanocytes, and melanoblasts that sufficiently explain the lack of pigment in melanoblasts and provide a rationale for some genes expressed apparently ectopically in melanomas, such as ephrin receptors.
  The FASEB Journal 06/2009; 23(9):3179-92. · 5.71 Impact Factor