Kent W. Hunter
National Institutes of Health
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Featured researches published by Kent W. Hunter.
Nature Reviews Genetics | 2003
Oduola Abiola; Joe M. Angel; Philip Avner; Alexander A. Bachmanov; John K. Belknap; Beth Bennett; Elizabeth P. Blankenhorn; David A. Blizard; Valerie J. Bolivar; Gudrun A. Brockmann; Kari J. Buck; Jean François Bureau; William L. Casley; Elissa J. Chesler; James M. Cheverud; Gary A. Churchill; Melloni N. Cook; John C. Crabbe; Wim E. Crusio; Ariel Darvasi; Gerald de Haan; Peter Demant; R. W. Doerge; Rosemary W. Elliott; Charles R. Farber; Lorraine Flaherty; Jonathan Flint; Howard K. Gershenfeld; J. P. Gibson; Jing Gu
This white paper by eighty members of the Complex Trait Consortium presents a communitys view on the approaches and statistical analyses that are needed for the identification of genetic loci that determine quantitative traits. Quantitative trait loci (QTLs) can be identified in several ways, but is there a definitive test of whether a candidate locus actually corresponds to a specific QTL?
Immunity | 1994
David H. Lynch; Mark L. Watson; Mark R. Alderson; Peter R. Baum; Robert E. Miller; Teresa W. Tough; Marylou Gibson; Terri Davis-Smith; Craig A. Smiths; Kent W. Hunter; Deepti Bhat; Wenie S. Din; Raymond G. Goodwin; Michael F. Seldin
The gene for the mouse Fas ligand was cloned and its chromosomal position determined. Fasl was tightly linked to gld (no crossovers in 567 meiotic events) on mouse chromosome 1 and closely linked with a novel member of the same TNF family of ligands, the Ox40 ligand (Ox40l, 1 crossover in 567 meiotic events). Southern blot analysis did not reveal any difference between the Fasl gene from gld and wild-type mice and levels of Fasl mRNA transcripts were similar in PMA and ionomycin induced wild-type and coisogenic gld T cells. Sequence analysis of the gld gene indicated a single amino acid change (Phe Leu) in the COOH terminal portion of this type II transmembrane protein, and COS cells transfected with Fasl cDNA from gld mice failed to induce apoptosis of Fas-expressing target cells. Thus, the data demonstrate that the gld phenotype is the result of a point mutation in the Fasl gene and that Fasl is part of a complex of ligands structurally related to TNF mapping within a small region of mouse chromosome 1.
International Journal of Cancer | 1998
Traci Lifsted; Thomas Le Voyer; Max Williams; William J. Muller; Andres J. Klein-Szanto; Kenneth H. Buetow; Kent W. Hunter
Metastasis is one of the most important and complex processes in human neoplastic disease. A large number of both positive and negative events must occur to permit a tumor cell to colonize a distant site successfully. To identify mouse strains that harbor dominant genetic modifiers of this process, a strain survey was initiated utilizing a transgenic mouse mammary tumor model that exhibits a high incidence of pulmonary metastases. The transgenic animal was bred to 27 different inbred strains of mice and scored for the metastatic organ tropism and metastatic density. Thirteen strains were identified that had a statistically significant reduction in the numbers of pulmonary metastases. In addition, 10 strains were identified that altered the kinetics of induction of the primary mammary tumor. These strains will likely provide useful model systems for the analysis of genetic interactions in the initiation and progression of mammary adenocarcinomas. Int. J. Cancer 77:640–644, 1998.
Proceedings of the National Academy of Sciences of the United States of America | 2002
Kartiki Vasant Desai; Nianqing Xiao; Weili Wang; Lisa Gangi; John M. Greene; John Powell; Robert C. Dickson; Priscilla A. Furth; Kent W. Hunter; Raju Kucherlapati; Richard Simon; Edison T. Liu; Jeffrey Green
Molecular expression profiling of tumors initiated by transgenic overexpression of c-myc, c-neu, c-ha-ras, polyoma middle T antigen (PyMT) or simian virus 40 T/t antigen (T-ag) targeted to the mouse mammary gland have identified both common and oncogene-specific events associated with tumor formation and progression. The tumors shared great similarities in their gene-expression profiles as compared with the normal mammary gland with an induction of cell-cycle regulators, metabolic regulators, zinc finger proteins, and protein tyrosine phosphatases, along with the suppression of some protein tyrosine kinases. Selection and hierarchical clustering of the most variant genes, however, resulted in separating the mouse models into three groups with distinct oncogene-specific patterns of gene expression. Such an identification of targets specified by particular oncogenes may facilitate development of lesion-specific therapeutics and preclinical testing. Moreover, similarities in gene expression between human breast cancers and the mouse models have been identified, thus providing an important component for the validation of transgenic mammary cancer models.
Mammalian Genome | 2002
David W. Threadgill; Kent W. Hunter; Robert W. Williams
Department of Genetics, CB#7264, Lineberger Comprehensive Cancer Center, Rm 11-109, University of North Carolina, Chapel Hill, North Carolina 27599, USA Laboratory of Population Genetics, DCEG/NCI/NIH, Bldg 41, Rm 702, 41 Library Drive, Bethesda, Maryland 20892, USA Center for Genomics and Bioinformatics, University of Tennessee Health Science Center, 858 Madison Avenue, Rm 101A, Memphis, Tennessee 38163, USA
Breast Cancer Research | 2008
Kent W. Hunter; Nigel P.S. Crawford; Jude Alsarraj
Metastasis is an enormously complex process that remains to be a major problem in the management of cancer. The fact that cancer patients might develop metastasis after years or even decades from diagnosis of the primary tumor makes the metastatic process even more complex. Over the years many hypotheses were developed to try to explain the inefficiency of the metastatic process, but none of these theories completely explains the current biological and clinical observations. In this review we summarize some of the proposed models that were developed in attempt to understand the mechanisms of tumor dissemination and colonization as well as metastatic progression.
Nature Genetics | 2005
Yeong-Gwan Park; Xiaohong Zhao; Fabienne Lesueur; Douglas R. Lowy; Mindy Lancaster; Paul Pharoah; Xiaolan Qian; Kent W. Hunter
We previously identified loci in the mouse genome that substantially influence the metastatic efficiency of mammary tumors. Here, we present data supporting the idea that the signal transduction molecule, Sipa1, is a candidate for underlying the metastasis efficiency modifier locus Mtes1. Analysis of candidate genes identified a nonsynonymous amino acid polymorphism in Sipa1 that affects the Sipa1 Rap-GAP function. Spontaneous metastasis assays using cells ectopically expressing Sipa1 or cells with knocked-down Sipa1 expression showed that metastatic capacity was correlated with cellular Sipa1 levels. We examined human expression data and found that they were consistent with the idea that Sipa1 concentration has a role in metastasis. Taken together, these data suggest that the Sipa1 polymorphism is one of the genetic polymorphisms underlying the Mtes1 locus. This report is also the first demonstration, to our knowledge, of a constitutional genetic polymorphism affecting tumor metastasis.
Proceedings of the National Academy of Sciences of the United States of America | 2008
Nigel P.S. Crawford; Jude Alsarraj; Luanne Lukes; Renard C. Walker; Jennifer S. Officewala; Howard H. Yang; Maxwell P. Lee; Keiko Ozato; Kent W. Hunter
Previous work identified the Rap1 GTPase-activating protein Sipa1 as a germ-line-encoded metastasis modifier. The bromodomain protein Brd4 physically interacts with and modulates the enzymatic activity of Sipa1. In vitro analysis of a highly metastatic mouse mammary tumor cell line ectopically expressing Brd4 demonstrates significant reduction of invasiveness without altering intrinsic growth rate. However, a dramatic reduction of tumor growth and pulmonary metastasis was observed after s.c. implantation into mice, implying that activation of Brd4 may somehow be manipulating response to tumor microenvironment in the in vivo setting. Further in vitro analysis shows that Brd4 modulates extracellular matrix gene expression, a class of genes frequently present in metastasis-predictive gene signatures. Microarray analysis of the mammary tumor cell lines identified a Brd4 activation signature that robustly predicted progression and/or survival in multiple human breast cancer datasets analyzed on different microarray platforms. Intriguingly, the Brd4 signature also almost perfectly matches a molecular classifier of low-grade tumors. Taken together, these data suggest that dysregulation of Brd4-associated pathways may play an important role in breast cancer progression and underlies multiple common prognostic signatures.
Gastroenterology | 2012
Stephanie Roessler; Ezhou Lori Long; Anuradha Budhu; Yidong Chen; Xuelian Zhao; Junfang Ji; Robert L. Walker; Hu–Liang Jia; Ye Qh; Lun Xiu Qin; Zhao-You Tang; Ping He; Kent W. Hunter; Snorri S. Thorgeirsson; Paul S. Meltzer; Xin Wei Wang
BACKGROUND & AIMS Hepatocellular carcinoma (HCC) is an aggressive malignancy; its mechanisms of development and progression are poorly understood. We used an integrative approach to identify HCC driver genes, defined as genes whose copy numbers associate with gene expression and cancer progression. METHODS We combined data from high-resolution, array-based comparative genomic hybridization and transcriptome analysis of HCC samples from 76 patients with hepatitis B virus infection with data on patient survival times. Candidate genes were functionally validated using in vitro and in vivo models. RESULTS Unsupervised analyses of array comparative genomic hybridization data associated loss of chromosome 8p with poor outcome (reduced survival time); somatic copy number alterations correlated with expression of 27.3% of genes analyzed. We associated expression levels of 10 of these genes with patient survival times in 2 independent cohorts (comprising 319 cases of HCC with mixed etiology) and 3 breast cancer cohorts (637 cases). Among the 10-gene signature, a cluster of 6 genes on 8p, (DLC1, CCDC25, ELP3, PROSC, SH2D4A, and SORBS3) were deleted in HCCs from patients with poor outcomes. In vitro and in vivo analyses indicated that the products of PROSC, SH2D4A, and SORBS3 have tumor-suppressive activities, along with the known tumor suppressor gene DLC1. CONCLUSIONS We used an unbiased approach to identify 10 genes associated with HCC progression. These might be used in assisting diagnosis and to stage tumors based on gene expression patterns.
Nature Genetics | 1999
Yun-Liang Yang; Lei Guo; Shuang Xu; Christine A. Holland; Toshio Kitamura; Kent W. Hunter; James M. Cunningham
The onset of leukaemia caused by type C retroviruses (MLV) in mice is accelerated by the emergence of recombinant polytropic or mink cell focus–forming (MCF) viruses. Susceptibility to infection by polytropic/MCF and also by closely related xenotropic MLV has been mapped to Rmc1 on mouse chromosome 1 (refs 5, 6 and 7). To identify this gene, we introduced an expression cDNA library prepared from mouse NIH3T3 fibroblasts into nonpermissive hamster cells and screened these cells for acquired susceptibility to MCF viruses encoding β–galactosidase and G418 resistance. From hamster cell clones identified in the screen, we recovered a mouse cDNA that maps to Rmc1 and confers MCF MLV infection when expressed in nonpermissive cell lines. It encodes a membrane protein related to Syg1p (suppressor of yeast Gα deletion; ref. 8). The receptor–binding domain of the MCF MLV envelope protein binds specifically to Xenopus laevis oocytes that express mouse Syg1, suggesting it functions as a receptor that mediates virus entry. We also obtained the cDNA encoding human SYG1. When expressed in hamster cells, it establishes infectivity by MCF MLV as well as xenotropic MLV, which do not infect laboratory mice.