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328 results on '"Pavan, William J."'

4. The RhoJ-BAD signaling network: An Achilles' heel for BRAF mutant melanomas.

Author

Ruiz, Rolando, Jahid, Sohail, Harris, Melissa, Marzese, Diego M, Espitia, Francisco, Vasudeva, Priya, Chen, Chi-Fen, de Feraudy, Sebastien, Wu, Jie, Gillen, Daniel L, Krasieva, Tatiana B, Tromberg, Bruce J, Pavan, William J, Hoon, Dave S, and Ganesan, Anand K

Subjects
Cell Line, Tumor, Melanocytes, Humans, Melanoma, Nevus, Cell Transformation, Neoplastic, Neoplasm Metastasis, rho GTP-Binding Proteins, Proto-Oncogene Proteins B-raf, Enzyme Inhibitors, Signal Transduction, Apoptosis, Gene Expression Regulation, Neoplastic, Mutation, bcl-Associated Death Protein, p21-Activated Kinases, Genetics, Cancer, Clinical Research, 2.1 Biological and endogenous factors, 5.1 Pharmaceuticals, Developmental Biology
Abstract

Genes and pathways that allow cells to cope with oncogene-induced stress represent selective cancer therapeutic targets that remain largely undiscovered. In this study, we identify a RhoJ signaling pathway that is a selective therapeutic target for BRAF mutant cells. RhoJ deletion in BRAF mutant melanocytes modulates the expression of the pro-apoptotic protein BAD as well as genes involved in cellular metabolism, impairing nevus formation, cellular transformation, and metastasis. Short-term treatment of nascent melanoma tumors with PAK inhibitors that block RhoJ signaling halts the growth of BRAF mutant melanoma tumors in vivo and induces apoptosis in melanoma cells in vitro via a BAD-dependent mechanism. As up to 50% of BRAF mutant human melanomas express high levels of RhoJ, these studies nominate the RhoJ-BAD signaling network as a therapeutic vulnerability for fledgling BRAF mutant human tumors.

Published
2017

5. Melanoma to Vitiligo: The Melanocyte in Biology & Medicine–Joint Montagna Symposium on the Biology of Skin/PanAmerican Society for Pigment Cell Research Annual Meeting

Author

Leachman, Sancy A., Hornyak, Thomas J., Barsh, Greg, Bastian, Boris C., Brash, Douglas E., Cleaver, James E., Cooper, Cynthia D., D’Orazio, John A., Fujita, Mayumi, Holmen, Sheri L., Indra, Arup K., Kraemer, Kenneth H., Le Poole, I. Caroline, Lo, Roger S., Lund, Amanda W., Manga, Prashiela, Pavan, William J., Setaluri, Vijayasaradhi, Stemwedel, Clara E., and Kulesz-Martin, Molly F.

Published
2020
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6. Strategic vision for improving human health at The Forefront of Genomics

Author

Green, Eric D., Gunter, Chris, Biesecker, Leslie G., Di Francesco, Valentina, Easter, Carla L., Feingold, Elise A., Felsenfeld, Adam L., Kaufman, David J., Ostrander, Elaine A., Pavan, William J., Phillippy, Adam M., Wise, Anastasia L., Dayal, Jyoti Gupta, Kish, Britny J., Mandich, Allison, Wellington, Christopher R., Wetterstrand, Kris A., Bates, Sarah A., Leja, Darryl, Vasquez, Susan, Gahl, William A., Graham, Bettie J., Kastner, Daniel L., Liu, Paul, Rodriguez, Laura Lyman, Solomon, Benjamin D., Bonham, Vence L., Brody, Lawrence C., Hutter, Carolyn M., and Manolio, Teri A.

Published
2020
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7. The MFSD12 p.Tyr182His common variant is sufficient to alter mouse agouti coat color.

Author

Watkins‐Chow, Dawn E., Incao, Arturo A., Rivas, Cecelia, Elliott, Gene, Garrett, Lisa J., and Pavan, William J.

Subjects
ANIMAL coloration, EAST Asians, CHINESE people, HUMAN skin color, MICE, PHENOTYPIC plasticity
Abstract

MFSD12 functions as a transmembrane protein required for import of cysteine into melanosomes and lysosomes. The MFSD12 locus has been associated with phenotypic variation in skin color across African, Latin American, and East Asian populations. The frequency of a particular MFSD12 coding variant, rs2240751 (MAF = 0.08), has been reported to correlate with solar radiation and occur at highest frequency in Peruvian (PEL MAF = 0.48) and Han Chinese (CHB MAF = 0.40) populations, suggesting it could be causative for associated phenotypic variation in skin color. We have generated a mouse knock‐in allele, Mfsd12Y182H, to model the human missense p.Tyr182His human variant. We demonstrate that the variant transcript is stably expressed and that agouti mice homozygote for the variant allele are viable with an altered coat color. This in vivo data confirms that the MFSD12 p.Tyr182His variant functions as a hypomorphic allele sufficient to alter mammalian pigmentation. [ABSTRACT FROM AUTHOR]

Published
2024
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8. Single‐cell profiling of MC1R‐inhibited melanocytes.

Author

Berns, H. Matthew, Watkins‐Chow, Dawn E., Lu, Sizhu, Louphrasitthiphol, Pakavarin, Zhang, Tongwu, Brown, Kevin M., Moura‐Alves, Pedro, Goding, Colin R., and Pavan, William J.

Subjects
HUMAN hair color, MELANOCORTIN receptors, MELANOCYTES, HUMAN skin color, RNA sequencing
Abstract

The human red hair color (RHC) trait is caused by increased pheomelanin (red‐yellow) and reduced eumelanin (black‐brown) pigment in skin and hair due to diminished melanocortin 1 receptor (MC1R) function. In addition, individuals harboring the RHC trait are predisposed to melanoma development. While MC1R variants have been established as causative of RHC and are a well‐defined risk factor for melanoma, it remains unclear mechanistically why decreased MC1R signaling alters pigmentation and increases melanoma susceptibility. Here, we use single‐cell RNA sequencing (scRNA‐seq) of melanocytes isolated from RHC mouse models to define a MC1R‐inhibited Gene Signature (MiGS) comprising a large set of previously unidentified genes which may be implicated in melanogenesis and oncogenic transformation. We show that one of the candidate MiGS genes, TBX3, a well‐known anti‐senescence transcription factor implicated in melanoma progression, binds both E‐box and T‐box elements to regulate genes associated with melanogenesis and senescence bypass. Our results provide key insights into further mechanisms by which melanocytes with reduced MC1R signaling may regulate pigmentation and offer new candidates of study toward understanding how individuals with the RHC phenotype are predisposed to melanoma. [ABSTRACT FROM AUTHOR]

Published
2024
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9. Loci associated with skin pigmentation identified in African populations

Author

Crawford, Nicholas G., Kelly, Derek E., Hansen, Matthew E. B., Beltrame, Marcia H., Fan, Shaohua, Bowman, Shanna L., Jewett, Ethan, Ranciaro, Alessia, Thompson, Simon, Lo, Yancy, Pfeifer, Susanne P., Jensen, Jeffrey D., Campbell, Michael C., Beggs, William, Hormozdiari, Farhad, Mpoloka, Sununguko Wata, Mokone, Gaonyadiwe George, Nyambo, Thomas, Meskel, Dawit Wolde, Belay, Gurja, Haut, Jake, Rothschild, Harriet, Zon, Leonard, Zhou, Yi, Kovacs, Michael A., Xu, Mai, Zhang, Tongwu, Bishop, Kevin, Sinclair, Jason, Rivas, Cecilia, Elliot, Eugene, Choi, Jiyeon, Li, Shengchao A., Hicks, Belynda, Burgess, Shawn, Abnet, Christian, Watkins-Chow, Dawn E., Oceana, Elena, Song, Yun S., Eskin, Eleazar, Brown, Kevin M., Marks, Michael S., Loftus, Stacie K., Pavan, William J., Yeager, Meredith, Chanock, Stephen, and Tishkoff, Sarah A.

Published
2017

10. SOX10 Ablation Arrests Cell Cycle, Induces Senescence, and Suppresses Melanomagenesis

Author

Cronin, Julia C, Watkins-Chow, Dawn E, Incao, Art, Hasskamp, Joanne H, Schönewolf, Nicola, Aoude, Lauren G, Hayward, Nicholas K, Bastian, Boris C, Dummer, Reinhard, Loftus, Stacie K, and Pavan, William J

Subjects
Cancer, Genetics, 2.1 Biological and endogenous factors, Aetiology, Animals, Apoptosis, Blotting, Western, Cell Cycle, Cell Proliferation, Cellular Senescence, Disease Models, Animal, Humans, Immunoenzyme Techniques, Melanoma, Mice, Mice, Transgenic, Phenotype, RNA, Messenger, Real-Time Polymerase Chain Reaction, Receptors, Metabotropic Glutamate, Reverse Transcriptase Polymerase Chain Reaction, SOXE Transcription Factors, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

The transcription factor SOX10 is essential for survival and proper differentiation of neural crest cell lineages, where it plays an important role in the generation and maintenance of melanocytes. SOX10 is also highly expressed in melanoma tumors, but a role in disease progression has not been established. Here, we report that melanoma tumor cell lines require wild-type SOX10 expression for proliferation and SOX10 haploinsufficiency reduces melanoma initiation in the metabotropic glutamate receptor 1 (Grm1(Tg)) transgenic mouse model. Stable SOX10 knockdown in human melanoma cells arrested cell growth, altered cellular morphology, and induced senescence. Melanoma cells with stable loss of SOX10 were arrested in the G1 phase of the cell cycle, with reduced expression of the melanocyte determining factor microphthalmia-associated transcription factor, elevated expression of p21WAF1 and p27KIP2, hypophosphorylated RB, and reduced levels of its binding partner E2F1. As cell-cycle dysregulation is a core event in neoplastic transformation, the role for SOX10 in maintaining cell-cycle control in melanocytes suggests a rational new direction for targeted treatment or prevention of melanoma.

Published
2013

11. Intrathecal 2-hydroxypropyl-β-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1–2 trial

Author

Ory, Daniel S, Ottinger, Elizabeth A, Farhat, Nicole Yanjanin, King, Kelly A, Jiang, Xuntian, Weissfeld, Lisa, Berry-Kravis, Elizabeth, Davidson, Cristin D, Bianconi, Simona, Keener, Lee Ann, Rao, Ravichandran, Soldatos, Ariane, Sidhu, Rohini, Walters, Kimberly A, Xu, Xin, Thurm, Audrey, Solomon, Beth, Pavan, William J, Machielse, Bernardus N, Kao, Mark, Silber, Steven A, McKew, John C, Brewer, Carmen C, Vite, Charles H, Walkley, Steven U, Austin, Christopher P, and Porter, Forbes D

Published
2017
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14. Niemann-Pick C1 Disease Gene: Homology to Mediators of Cholesterol Homeostasis

Author

Carstea, Eugene D., Morris, Jill A., Coleman, Katherine G., Loftus, Stacie K., Zhang, Dana, Cummings, Christiano, Gu, Jessie, Rosenfeld, Melissa A., Pavan, William J., Krizman, David B., Nagle, James, Polymeropoulos, Mihail H., Sturley, Stephen L., Ioannou, Yiannis A., Higgins, Maureen E., Comly, Marcella, Cooney, Adele, Brown, Anthony, Kaneski, Christine R., Blanchette-Mackie, E. Joan, Dwyer, Nancy K., Neufeld, Edward B., Chang, Ta-Yuan, Liscum, Laura, Strauss, Jerome F., Ohno, Kousaku, Zeigler, Marsha, Carmi, Rivka, Sokol, Jacob, Markie, David, O'Neill, Raymond R., van Diggelen, O. P., Elleder, Milan, Patterson, Marc C., Brady, Roscoe O., Vanier, Marie T., Pentchev, Peter G., and Tagle, Danilo A.

Published
1997

18. Meta-analysis of GWA studies provides new insights on the genetic architecture of skin pigmentation in recently admixed populations

Author

Lona-Durazo, Frida, Hernandez-Pacheco, Natalia, Fan, Shaohua, Zhang, Tongwu, Choi, Jiyeon, Kovacs, Michael A., Loftus, Stacie K., Le, Phuong, Edwards, Melissa, Fortes-Lima, Cesar A., Eng, Celeste, Huntsman, Scott, Hu, Donglei, Gómez-Cabezas, Enrique Javier, Marín-Padrón, Lilia Caridad, Grauholm, Jonas, Mors, Ole, Burchard, Esteban G., Norton, Heather L., Pavan, William J., Brown, Kevin M., Tishkoff, Sarah, Pino-Yanes, Maria, Beleza, Sandra, Marcheco-Teruel, Beatriz, and Parra, Esteban J.

Published
2019
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20. Glial-cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence

Author

Ibiza, Sales, Garcia-Cassani, Bethania, Ribeiro, Helder, Carvalho, Tania, Almeida, Luis, Marques, Rute, Misic, Ana M., Bartow-McKenney, Casey, Larson, Denise M., Pavan, William J., Eberl, Gerard, Grice, Elizabeth A., and Veiga-Fernandes, Henrique

Subjects
Neurotransmitters, Neuroglia -- Physiological aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Group 3 innate lymphoid cells (ILC3) are major regulators of inflammation and infection at mucosal barriers (1). ILC3 development is thought to be programmed (1), but how ILC3 perceive, integrate [...]

Published
2016

21. Modeling Smith-Lemli-Opitz syndrome with induced pluripotent stem cells reveals a causal role for Wnt/β-catenin defects in neuronal cholesterol synthesis phenotypes

Author

Francis, Kevin R., Ton, Amy N., Xin, Yao, O'Halloran, Peter E., Wassif, Christopher A., Malik, Nasir, Williams, Ian M., Cluzeau, Celine V., Trivedi, Niraj S., Pavan, William J., Cho, Wonhwa, Westphal, Heiner, and Porter, Forbes D.

Subjects
Cholesterol -- Properties, Stem cells -- Usage, Cellular signal transduction -- Models, Smith-Lemli-Opitz syndrome -- Models, Biological sciences, Health
Abstract

Smith-Lemli-Opitz syndrome (SLOS) is a malformation disorder caused by mutations in DHCR7, which impair the reduction of 7-dehydrocholesterol (7DHC) to cholesterol. SLOS results in cognitive impairment, behavioral abnormalities and nervous system defects, though neither affected cell types nor impaired signaling pathways are fully understood. Whether 7DHC accumulation or cholesterol loss is primarily responsible for disease pathogenesis is also unclear. Using induced pluripotent stem cells (iPSCs) from subjects with SLOS, we identified cellular defects that lead to precocious neuronal specification within SLOS derived neural progenitors. We also demonstrated that 7DHC accumulation, not cholesterol deficiency, is critical for SLOS-associated defects. We further identified downregulation of Wnt/β-catenin signaling as a key initiator of aberrant SLOS iPSC differentiation through the direct inhibitory effects of 7DHC on the formation of an active Wnt receptor complex. Activation of canonical Wnt signaling prevented the neural phenotypes observed in SLOS iPSCs, suggesting that Wnt signaling may be a promising therapeutic target for SLOS., Impaired cholesterol synthesis underlies a group of human disorders characterized by cognitive impairment, congenital malformations, and distinct behavioral phenotypes, including autism (1). The most common cholesterol synthesis disorder, Smith-Lemli-Opitz syndrome [...]

Published
2016
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31. Mutations in TRIOBP, which encodes a putative cytoskeletal-organizing protein, are associated with nonsyndromic recessive deafness

Author

Riazuddin, Saima, Khan, Shaheen N., Ahmed, Zubair M., Gosh, Manju, Caution, Kyle, Nazli, Sabiha, Kabra, Madhulika, Zafar, Ahmad U., Chen, Kevin, Naz, Sadaf, Antonellis, Anthony, Pavan, William J., Green, Eric D., Wilcox, Edward R., Friedman, Penelope L., Morell, Robert J., Riazuddin, Sheikh, and Friedman, Thomas B.

Subjects
United States. National Institutes of Health, Allelomorphism -- Research, Genetic markers -- Research, Gene mutations -- Research, Biological sciences
Published
2006

45. Frequent mutations in the MITF pathway in melanoma

Author

Cronin, Julia C., Wunderlich, John, Loftus, Stacie K., Prickett, Todd D., Wei, Xiaomu, Ridd, Katie, Vemula, Swapna, Burrell, Allison S., Agrawal, Neena S., Lin, Jimmy C., Banister, Carolyn E., Buckhaults, Phillip, Rosenberg, Steven A., Bastian, Boris C., Pavan, William J., and Samuels, Yardena

Published
2009
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46. Gpnmb is a melanoblast-expressed, MITF-dependent gene

Author

Loftus, Stacie K., Antonellis, Anthony, Matera, Ivana, Renaud, Gabriel, Baxter, Laura L., Reid, Duncan, Wolfsberg, Tyra G., Chen, Yidong, Wang, Chen Wei, Prasad, Megana K., Bessling, Seneca L., McCallion, Andrew S., Green, Eric D., Bennett, Dorothy C., and Pavan, William J.

Published
2009

48. A custom capture sequence approach for oculocutaneous albinism identifies structural variant alleles at the OCA2 locus.

Author

Loftus, Stacie K., Lundh, Linnea, Watkins‐Chow, Dawn E., Baxter, Laura L., Pairo‐Castineira, Erola, NISC Comparative Sequencing Program, Jackson, Ian J., Oetting, William S., Pavan, William J., and Adams, David R.

Abstract

Oculocutaneous albinism (OCA) is a heritable disorder of pigment production that manifests as hypopigmentation and altered eye development. Exon sequencing of known OCA genes is unsuccessful in producing a complete molecular diagnosis for a significant number of affected individuals. We sequenced the DNA of individuals with OCA using short‐read custom capture sequencing that targeted coding, intronic, and noncoding regulatory regions of known OCA genes, and genome‐wide association study‐associated pigmentation loci. We identified an OCA2 complex structural variant (CxSV), defined by a 143 kb inverted segment reintroduced in intron 1, upstream of the native location. The corresponding CxSV junctions were observed in 11/390 probands screened. The 143 kb CxSV presents in one family as a copy number variant duplication for the 143 kb region. In the remaining 10/11 families, the 143 kb CxSV acquired an additional 184 kb deletion across the same region, restoring exons 3–19 of OCA2 to a copy‐number neutral state. Allele‐associated haplotype analysis found rare SNVs rs374519281 and rs139696407 are linked with the 143 kb CxSV in both OCA2 alleles. For individuals in which customary molecular evaluation does not reveal a biallelic OCA diagnosis, we recommend preliminary screening for these haplotype‐associated rare variants, followed by junction‐specific validation for the OCA2 143 kb CxSV. [ABSTRACT FROM AUTHOR]

Published
2021
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