%0 Journal Article %J Pharm Res %D 2013 %T Bioactivity and bioavailability of ginsenosides are dependent on the glycosidase activities of the A/J mouse intestinal microbiome defined by pyrosequencing. %A Niu, Tao %A Smith, Diane L %A Yang, Zhen %A Gao, Song %A Yin, Taijun %A Jiang, Zhi-Hong %A You, Ming %A Gibbs, Richard A %A Petrosino, Joseph F %A Hu, Ming %K Animals %K Antineoplastic Agents, Phytogenic %K Bacteria %K Biological Availability %K Biotransformation %K Caco-2 Cells %K Cell Line, Tumor %K Cell Proliferation %K Drugs, Chinese Herbal %K Ginsenosides %K Glycoside Hydrolases %K Humans %K Hydrolysis %K Intestinal Mucosa %K Intestines %K Male %K Metagenome %K Mice %K Neoplasms %K Panax %K RNA, Bacterial %X

PURPOSE: To investigate the ability of bacteria in the intestinal microbiome to convert naturally occurring primary ginsenosides in red ginseng extract to active secondary ginsenosides.

METHODS: Anti-proliferative ginsenoside activity was tested using mouse lung cancer LM1 cells. Permeabilities were evaluated in Caco-2 cell monolayers. Systemic exposure of secondary ginsenosides was determined in A/J mice. 16S rRNA gene pyrosequencing was used to determine membership and abundance of bacteria in intestinal microbiome.

RESULTS: Secondary ginsenoside C-K exhibited higher anti-proliferative activity and permeability than primary ginsenosides. Significant amounts of secondary ginsenosides (F2 and C-K) were found in blood of A/J mice following oral administration of primary ginsenoside Rb1. Because mammalian cells did not hydrolyze ginsenoside, we determined the ability of bacteria to hydrolyze ginsenosides and found that Rb1 underwent stepwise hydrolysis to Rd, F2, and then C-K. Formation of F2 from Rd was the rate-limiting step in the biotransformation of Rb1 to C-K.

CONCLUSION: Conversion to F2 is the rate-limiting step in bioactivation of primary ginsenosides by A/J mouse intestinal microbiome, whose characterization reveals the presence of certain bacterial families capable of enabling the formation of F2 and C-K in vivo.

%B Pharm Res %V 30 %P 836-46 %8 2013 Mar %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/23254888?dopt=Abstract %R 10.1007/s11095-012-0925-z %0 Journal Article %J Clin Cancer Res %D 2009 %T Fine mapping of chromosome 6q23-25 region in familial lung cancer families reveals RGS17 as a likely candidate gene. %A You, Ming %A Wang, Daolong %A Liu, Pengyuan %A Vikis, Haris %A James, Michael %A Lu, Yan %A Wang, Yian %A Wang, Min %A Chen, Qiong %A Jia, Dongmei %A Liu, Yan %A Wen, Weidong %A Yang, Ping %A Sun, Zhifu %A Pinney, Susan M %A Zheng, Wei %A Shu, Xiao-Ou %A Long, Jirong %A Gao, Yu-Tang %A Xiang, Yong-Bing %A Chow, Wong-Ho %A Rothman, Nat %A Petersen, Gloria M %A de Andrade, Mariza %A Wu, Yanhong %A Cunningham, Julie M %A Wiest, Jonathan S %A Fain, Pamela R %A Schwartz, Ann G %A Girard, Luc %A Gazdar, Adi %A Gaba, Colette %A Rothschild, Henry %A Mandal, Diptasri %A Coons, Teresa %A Lee, Juwon %A Kupert, Elena %A Seminara, Daniela %A Minna, John %A Bailey-Wilson, Joan E %A Amos, Christopher I %A Anderson, Marshall W %K Aged %K Animals %K Cell Line, Tumor %K Chromosome Mapping %K Chromosomes, Human, Pair 6 %K Female %K Gene Knockdown Techniques %K Genetic Predisposition to Disease %K Genotype %K Haplotypes %K Humans %K Lung %K Lung Neoplasms %K Male %K Mice %K Mice, Nude %K Microsatellite Repeats %K Middle Aged %K Oligonucleotide Array Sequence Analysis %K Polymorphism, Single Nucleotide %K RGS Proteins %K RNA, Small Interfering %K Transplantation, Heterologous %X

PURPOSE: We have previously mapped a major susceptibility locus influencing familial lung cancer risk to chromosome 6q23-25. However, the causal gene at this locus remains undetermined. In this study, we further refined this locus to identify a single candidate gene, by fine mapping using microsatellite markers and association studies using high-density single nucleotide polymorphisms (SNP).

EXPERIMENTAL DESIGN: Six multigenerational families with five or more affected members were chosen for fine-mapping the 6q linkage region using microsatellite markers. For association mapping, we genotyped 24 6q-linked cases and 72 unrelated noncancer controls from the Genetic Epidemiology of Lung Cancer Consortium resources using the Affymetrix 500K chipset. Significant associations were validated in two independent familial lung cancer populations: 226 familial lung cases and 313 controls from the Genetic Epidemiology of Lung Cancer Consortium, and 154 familial cases and 325 controls from Mayo Clinic. Each familial case was chosen from one high-risk lung cancer family that has three or more affected members.

RESULTS: A region-wide scan across 6q23-25 found significant association between lung cancer susceptibility and three single nucleotide polymorphisms in the first intron of the RGS17 gene. This association was further confirmed in two independent familial lung cancer populations. By quantitative real-time PCR analysis of matched tumor and normal human tissues, we found that RGS17 transcript accumulation is highly and consistently increased in sporadic lung cancers. Human lung tumor cell proliferation and tumorigenesis in nude mice are inhibited upon knockdown of RGS17 levels.

CONCLUSION: RGS17 is a major candidate for the familial lung cancer susceptibility locus on chromosome 6q23-25.

%B Clin Cancer Res %V 15 %P 2666-74 %8 2009 Apr 15 %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/19351763?dopt=Abstract %R 10.1158/1078-0432.CCR-08-2335 %0 Journal Article %J Clin Cancer Res %D 2008 %T Quantitative monitoring of adenocarcinoma development in rodents by magnetic resonance imaging. %A Garbow, Joel R %A Wang, Min %A Wang, Yian %A Lubet, Ronald A %A You, Ming %K Adenocarcinoma %K Animals %K Carcinogens %K Disease Models, Animal %K Image Interpretation, Computer-Assisted %K Image Processing, Computer-Assisted %K Lung Neoplasms %K Magnetic Resonance Imaging %K Male %K Mice %K Mice, Inbred A %K Urethane %X

PURPOSE: Accurately following the time course of tumor progression and response to therapy in animal models of cancer is key to the development of better chemopreventive and chemotherapeutic agents. The goal of this work was to monitor quantitatively the development and progression of adenocarcinoma in a time course study of mice treated with the carcinogen urethane using in vivo small-animal magnetic resonance imaging (MRI).

EXPERIMENTAL DESIGN: Mice treated with a single dose of urethane were imaged at four time points beginning 8 months after treatment. High-resolution images of mouse lung were obtained in vivo using respiratory-gated MRI methods. Individual tumors were manually segmented and their volumes calculated. At the end of the study, mice were euthanized and MRI tumor quantification was validated by histology and histopathology.

RESULTS: Tumors as small as 0.4 mm in diameter can be detected and quantitatively measured in mice by in vivo MRI. Total tumor burden increased consistently in all mice studied, whereas the growth rate of individual tumors varied widely. The positions and diameters of individual tumors as measured by MRI correlated well with histology results. Histologic study of large, rapidly growing tumors showed that these were adenocarcinomas, whereas small, slowly growing lesions were predominantly adenomas.

CONCLUSIONS: Longitudinal in vivo MRI is a powerful modality that can be of great aid in elucidating the factors that control the onset of lung tumors and can serve as a platform for the development and preclinical testing of novel therapies having a high likelihood of efficacy in human clinical trials.

%B Clin Cancer Res %V 14 %P 1363-7 %8 2008 Mar 01 %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/18316556?dopt=Abstract %R 10.1158/1078-0432.CCR-07-1757 %0 Journal Article %J Cancer Res %D 2007 %T Fine mapping and candidate gene analyses of pulmonary adenoma resistance 1, a major genetic determinant of mouse lung adenoma resistance. %A Wang, Min %A Zhang, Zhongqiu %A Zhang, Zhuo %A Vikis, Haris %A Yan, Ying %A Wang, Yian %A You, Ming %K Adenoma %K Animals %K Carrier Proteins %K Chromosome Mapping %K Female %K Genes, Tumor Suppressor %K Intracellular Signaling Peptides and Proteins %K Lung Neoplasms %K Male %K Mice %K Mice, Inbred A %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %X

Pulmonary adenoma resistance 1 (Par1) is a major genetic determinant of mouse lung adenoma resistance. Although Par1 was previously mapped to mouse chromosome 11 by conventional linkage analyses, its candidate region was broad and undefined. In our present study, we generated Par1 congenic mice using two mouse strains A/J (Par1/-) and Mus spretus (Par1/+). Analyzing these congenic mice enabled us to fine map the Par1 quantitative trait loci (QTL) into a 2.0-cM (2.2 Mb) chromosomal region between genetic marker D11Mit70 and the gene Hoxb9. We then conducted systematic candidate gene screening through nucleotide polymorphism and expression analyses. Genes showing differential lung tissue expression or carrying nonsynonymous single nucleotide polymorphisms were identified and discussed. In particular, we evaluated tumor suppressor gene Tob1 for its Par1 candidacy. Our findings have narrowed the Par1 QTL region and will greatly facilitate the identification of the major genetic determinant of mouse lung adenoma resistance.

%B Cancer Res %V 67 %P 2508-16 %8 2007 Mar 15 %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/17363568?dopt=Abstract %R 10.1158/0008-5472.CAN-06-3157 %0 Journal Article %J Cancer Res %D 2007 %T Identification of a novel tumor suppressor gene p34 on human chromosome 6q25.1. %A Wang, Min %A Vikis, Haris G %A Wang, Yian %A Jia, Dongmei %A Wang, Daolong %A Bierut, Laura J %A Bailey-Wilson, Joan E %A Amos, Christopher I %A Pinney, Susan M %A Petersen, Gloria M %A de Andrade, Mariza %A Yang, Ping %A Wiest, Jonathan S %A Fain, Pamela R %A Schwartz, Ann G %A Gazdar, Adi %A Minna, John %A Gaba, Colette %A Rothschild, Henry %A Mandal, Diptasri %A Kupert, Elena %A Seminara, Daniela %A Liu, Yan %A Viswanathan, Avinash %A Govindan, Ramaswamy %A Anderson, Marshall W %A You, Ming %K Alleles %K Animals %K Base Sequence %K Chromosomes, Human, Pair 6 %K Codon %K Female %K Genes, Tumor Suppressor %K Genetic Predisposition to Disease %K Humans %K Loss of Heterozygosity %K Lung Neoplasms %K Mice %K Mice, Nude %K Molecular Sequence Data %K Polymorphism, Single Nucleotide %X

In this study, we observed loss of heterozygosity (LOH) in human chromosomal fragment 6q25.1 in sporadic lung cancer patients. LOH was observed in 65% of the 26 lung tumors examined and was narrowed down to a 2.2-Mb region. Single-nucleotide polymorphism (SNP) analysis of genes located within this region identified a candidate gene, termed p34. This gene, also designated as ZC3H12D, C6orf95, FLJ46041, or dJ281H8.1, carries an A/G nonsynonymous SNP at codon 106, which alters the amino acid from lysine to arginine. Nearly 73% of heterozygous lung cancer tissues with LOH and the A/G SNP also exhibited loss of the A allele. In vitro clonogenic and in vivo nude mouse studies showed that overexpression of the A allele exerts tumor suppressor function compared with the G allele. p34 is located within a recently mapped human lung cancer susceptibility locus, and association of the p34 A/G SNP was tested among these families. No significant association between the less frequent G allele and lung cancer susceptibility was found. Our results suggest that p34 may be a novel tumor suppressor gene involved in sporadic lung cancer but it seems not to be the candidate familial lung cancer susceptibility gene linked to chromosomal region 6q23-25.

%B Cancer Res %V 67 %P 93-9 %8 2007 Jan 01 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/17210687?dopt=Abstract %R 10.1158/0008-5472.CAN-06-2723 %0 Journal Article %J Exp Lung Res %D 2005 %T Analysis of the Par2 modifier of pulmonary adenoma formation in mice. %A Wang, Min %A Wang, Yian %A You, Ming %A Devereux, Theodora R %K Adenoma %K Amino Acid Sequence %K Animals %K Chromosome Mapping %K Gene Expression %K Genetic Predisposition to Disease %K Lung Neoplasms %K Mice %K Molecular Sequence Data %K Polymorphism, Genetic %K Quantitative Trait Loci %X

Inbred strains of mouse show various susceptibilities to spontaneous and chemical-induced lung tumorigenesis. Genetic analyses have revealed that lung tumor susceptibilities of inbred mouse strains are governed by quantitative trait loci (QLTs) located on multiple chromosomes. A major lung tumor resistance QLT, designated pulmonary adenoma resistance 2 (Par2), was mapped to the mouse chromosome 18 independently by several groups and accounted for up to 60% phenotype variance between susceptible A/J and more resistant BALB/c strains. The authors recently conducted studies to positionally clone the Par2 gene. This review summarizes the effort and progress towards the identification of Par2 candidates.

%B Exp Lung Res %V 31 %P 193-204 %8 2005 Mar %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/15828125?dopt=Abstract %R 10.1080/01902140490495598 %0 Journal Article %J Exp Lung Res %D 2005 %T Identification of genetic polymorphisms through comparative DNA sequence analysis on the K-ras gene: implications for lung tumor susceptibility. %A Wang, Min %A Wang, Yian %A You, Ming %K Animals %K Base Sequence %K Binding Sites %K Conserved Sequence %K DNA, Neoplasm %K Gene Deletion %K Genes, ras %K Genetic Predisposition to Disease %K Humans %K Lung Neoplasms %K Mice %K Mice, Inbred Strains %K Molecular Sequence Data %K Polymorphism, Genetic %K Promoter Regions, Genetic %K Rats %K Sequence Homology, Nucleic Acid %K Transcription Factors %X

In the present study, the authors performed a comparative sequence analysis of the K-ras gene. By comparing sequences from different mouse inbred strains, the authors have identified new nucleotide polymorphisms in the noncoding regions of mouse K-ras gene. They have also identified noncoding DNA segments evolutionarily conserved among the human, mouse, and rat. Computational analysis for transcription factor binding sites suggests that these polymorphic and conserved DNA sequences harbor potential cis-regulatory elements, which may contribute to the transcriptional regulation of the K-ras gene. Further studies on these potential regulatory sites may help to elucidate the fundamental mechanism underlying allele-specific activation and expression of K-ras gene in hybrid mouse lung tumors, which determines lung tumor susceptibility in mice.

%B Exp Lung Res %V 31 %P 165-77 %8 2005 Mar %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/15824019?dopt=Abstract %R 10.1080/01902140490495543 %0 Journal Article %J Oncogene %D 2005 %T Pas1c1 is a candidate for the mouse pulmonary adenoma susceptibility 1 locus. %A Wang, Min %A Futamura, Manabu %A Wang, Yian %A You, Ming %K Adenoma %K Amino Acid Sequence %K Animals %K Base Sequence %K DNA Primers %K Exons %K Genetic Predisposition to Disease %K Lung Neoplasms %K Mice %K Molecular Sequence Data %K Sequence Alignment %K Sequence Homology, Amino Acid %K Tumor Suppressor Proteins %X

Pas1 candidate 1 (Pas1c1) gene (also named Lmna-rs1) was found to encode two alternatively spliced mRNA transcripts (i.e. Pas1c1-Va and Pas1c1-Vb). In this study, we identified three additional mRNA transcripts encoded by the Pas1c1 gene, which were designated as Pas1c1-Vc, Pas1c1-Vd, and Pas1c1-Ve, respectively. Similar to Pas1c1-Vb, the newly identified transcripts were only expressed in mouse lung tissues from strains carrying the Pas1-susceptible (Pas1/s) allele. Pas1c1 transcripts were also detected in heart, testis, or brain but not in liver, spleen, or kidney. An 11-nucleotide polymorphism was found within the 3'-acceptor splice site of exon 8, which cosegregates with mouse strain Pas1 alleles and may underlie the strain-specific exon 8 skipping. We also found that ectopic expression of the Pas1c1-Va and Pas1c1-Vb in COS7 and NIH3T3 cells exhibited distinct intracellular distributions. These results support that Pas1c1 as a candidate for the Pas1 locus and the strain-specific isoforms may have differential effects on cell proliferation.

%B Oncogene %V 24 %P 1958-63 %8 2005 Mar 10 %G eng %N 11 %1 https://www.ncbi.nlm.nih.gov/pubmed/15688036?dopt=Abstract %R 10.1038/sj.onc.1208295 %0 Journal Article %J Cancer Res %D 2004 %T Pol iota is a candidate for the mouse pulmonary adenoma resistance 2 locus, a major modifier of chemically induced lung neoplasia. %A Wang, Min %A Devereux, Theodora R %A Vikis, Haris G %A McCulloch, Scott D %A Holliday, Wanda %A Anna, Colleen %A Wang, Yian %A Bebenek, Katarzyna %A Kunkel, Thomas A %A Guan, Kunliang %A You, Ming %K Adenoma %K Alternative Splicing %K Amino Acid Sequence %K Animals %K DNA Polymerase iota %K DNA-Directed DNA Polymerase %K Gene Expression Regulation, Neoplastic %K Humans %K Immunity, Innate %K Lung %K Lung Neoplasms %K Mice %K Mice, Inbred A %K Mice, Inbred BALB C %K Molecular Sequence Data %K Polymorphism, Single Nucleotide %K Proto-Oncogene Proteins %K Proto-Oncogene Proteins p21(ras) %K ras Proteins %K RNA, Messenger %K Sequence Homology, Amino Acid %K Tumor Cells, Cultured %X

In this study, we performed systematic candidate gene analyses of the Pulmonary adenoma resistance 2 locus. Differential gene expression in lung tissues and nucleotide polymorphisms in coding regions between A/J and BALB/cJ mice were examined using reverse transcription-PCR and direct sequencing. Although not all genes in the interval were analyzed at this moment due to the recent database updating, we have found that the Pol iota gene, encoding the DNA polymerase iota, contains 25 nucleotide polymorphisms in its coding region between A/J and BALB/cJ mice, resulting in a total of ten amino acid changes. Primer extension assays with purified BALB/cJ and A/J proteins in vitro demonstrate that both forms of Pol iota are active but that they may differ in substrate discrimination, which may affect the formation of Kras2 mutations in mouse lung tumors. Altered expression of POL iota protein and an amino acid-changing nucleotide polymorphism were observed in human lung cancer cells, suggesting a possible role in the development of lung cancer. Thus, our data support the Pol iota gene as a modifier of lung tumorigenesis by altering DNA polymerase activity.

%B Cancer Res %V 64 %P 1924-31 %8 2004 Mar 15 %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/15026325?dopt=Abstract %R 10.1158/0008-5472.can-03-3080 %0 Journal Article %J Dev Dyn %D 2003 %T Differentially expressed nucleolar TGF-beta1 target (DENTT) in mouse development. %A Ozbun, Laurent L %A Martínez, Alfredo %A Angdisen, Jerry %A Umphress, Sarah %A Kang, Yang %A Wang, Min %A You, Ming %A Jakowlew, Sonia B %K 3T3 Cells %K Animals %K Base Sequence %K Blotting, Northern %K Blotting, Western %K Bone and Bones %K Cardiovascular System %K Cell Cycle Proteins %K Cell Differentiation %K Cell Nucleolus %K Chorion %K Digestive System %K DNA-Binding Proteins %K Female %K Gene Expression Regulation, Developmental %K Genes, Reporter %K Heart %K Humans %K Immunohistochemistry %K Male %K Mice %K Mice, Inbred C57BL %K Molecular Sequence Data %K Nervous System %K Nuclear Proteins %K Placenta %K Reverse Transcriptase Polymerase Chain Reaction %K RNA, Messenger %K Sequence Homology, Amino Acid %K Transcriptional Activation %K Transforming Growth Factor beta %K Transforming Growth Factor beta1 %X

Differentially expressed nucleolar TGF-beta1 target (DENTT) is a recently identified gene whose mRNA is differentially affected by TGF-beta1 in TGF-beta1-responsive human lung cancer cells and who is a new member of the TSPY/TSPY-like/SET/NAP-1 (TTSN) protein superfamily. Here, we report that mouse DENTT mRNA contains a 2031-bp open reading frame that encodes a predicted polypeptide of 677-amino acids with a relative molecular mass of 77,671 Da. The mouse and human DENTT sequences show 77% and 78% homology at the nucleotide and amino acid level, respectively. Mouse DENTT is predicted to be a nuclear protein with two nuclear localization signals (NLS), two coiled-coil regions, and a domain that shows significant identity to a region that defines the TTSN superfamily. Green fluorescent protein (GFP)-tagged full-length mouse DENTT transfected into COS-7 cells showed localization predominantly in the nucleolus. Reverse transcription-polymerase chain reaction amplification, Northern hybridization, and Western blot analyses showed expression of mouse DENTT mRNA and protein throughout mouse embryogenesis. Immunohistochemical staining analysis showed that DENTT is expressed in multiple tissues in a defined spatiotemporal pattern during mouse embryogenesis. The heart and primitive brain were the first organs of the embryo that showed immunoreactivity for the DENTT antibody by day 8 of development (E8). In the developing mouse brain, the choroid plexus was intensely stained for DENTT in all stages of development. The spinal cord and dorsal root ganglia were also positive for DENTT staining beginning in the 11-day-old embryo (E11), where homogeneous immunostaining was observed throughout the developing neurons. By day 16 of development (E16), only a small subset of the neuronal population in the spinal cord and dorsal root ganglia was positively stained for DENTT. DENTT immunoreactivity increased steadily with maturation as the differentiation of cartilage and osteoblasts proceeded and reached a maximum in the growth plate during endochondral ossification. DENTT expression was also detected in multiple rodent cell types in vitro, including mouse F9 embryonal carcinoma (EC) cells. Addition of retinoic acid or sodium butyrate to F9 EC cells showed a rapid decrease in expression of DENTT protein occurring by 1 hr that continued to decrease to almost undetectable levels after 24 hr. Cotransfection of full-length mouse DENTT expression plasmid with 3TPLux or COL7A1Luc Luciferase reporter plasmids into F9 EC cells significantly increased the level of 3TPLux reporter transcription while decreasing the level of COL7A1Luc reporter transcription, suggesting that DENTT may play multiple roles in modulating transcriptional responses. These findings suggest new roles for the TTSN superfamily during embryogenesis and differentiation.

%B Dev Dyn %V 226 %P 491-511 %8 2003 Mar %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/12619135?dopt=Abstract %R 10.1002/dvdy.10257 %0 Journal Article %J Cancer Res %D 2003 %T Fine mapping and identification of candidate pulmonary adenoma susceptibility 1 genes using advanced intercross lines. %A Wang, Min %A Lemon, William J %A Liu, Gongjie %A Wang, Yian %A Iraqi, Fuad A %A Malkinson, Alvin M %A You, Ming %K Adenoma %K Animals %K Chromosome Mapping %K Crosses, Genetic %K Gene Expression Profiling %K Genes, ras %K Genetic Predisposition to Disease %K Immunity, Innate %K Lod Score %K Lung Neoplasms %K Mice %K Mice, Inbred A %K Mice, Inbred C57BL %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Regression Analysis %K Reverse Transcriptase Polymerase Chain Reaction %K Software %K Urethane %X

In the present study, we used newly developed F(11) generation mouse advanced intercross lines (AIL) to fine map Pas1-3 quantitative trait loci (QTL). The (A/J x C57BL/6) F(11) AIL mouse population was created by crossing lung tumor-resistant C57BL/6 mice with lung tumor-susceptible A/J mice. By selectively genotyping 30% of the population, we have confirmed the Pas1 QTL and narrowed it to an interval of approximately 1.0 cM or 1.3 Mb in the vicinity of the Kras2 gene. The Pas2 QTL was detected by both ANOVA and regression analysis but not by MapMaker EXP/QTL software. In addition, an interaction between the Pas1 and Pas2 QTLs was revealed. However, the Pas3 QTL was not confirmed in this study. It was either lost during the development of the AIL or too weak to be detected using AIL. The Pas1 locus is now sufficiently fine-mapped that candidate gene(s) for the Pas1 locus can be characterized by positional cloning. In this study, all 27 of the known or predicted genes located in the Pas1 candidate region were characterized as possible candidate Pas genes. Six genes were selected for additional analyses because of their relevant function in tumorigenesis or allelic changes between A/J and C57BL/6 mice. The Lrmp gene bears amino acid polymorphisms among various mouse strains that are highly correlated with the Pas1 allele status. The Pas1c1 gene (RIKEN Ak016641), encoding an intermediate filament tail domain-containing protein, produces alternatively spliced transcripts across inbred strains of mice, and its splicing pattern cosegregates with the Pas1 allele. The genetic and expression data support these two genes as strong candidates for the Pas1 locus. Of the other four genes (Eca39, RIKEN Ak015530, mHoj-1, and Krag), no functional polymorphisms or differential gene expression were found in Eca39, mHoj-1, and Krag between lung tumor-susceptible and -resistant strains. The Ak015530 carries an amino acid polymorphism, but this polymorphism does not cosegregate with mouse lung tumor susceptibility. Thus, these 4 genes are less likely candidates for the Pas1 locus.

%B Cancer Res %V 63 %P 3317-24 %8 2003 Jun 15 %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/12810665?dopt=Abstract %0 Journal Article %J Proc Natl Acad Sci U S A %D 2003 %T Positional cloning of the major quantitative trait locus underlying lung tumor susceptibility in mice. %A Zhang, Zhongqiu %A Futamura, Manabu %A Vikis, Haris G %A Wang, Min %A Li, Jie %A Wang, Yian %A Guan, Kun-Liang %A You, Ming %K Adenoma %K Amino Acid Sequence %K Animals %K Base Sequence %K Blotting, Northern %K Chromosome Mapping %K Ciona intestinalis %K Cloning, Molecular %K DNA Primers %K Genetic Markers %K Genetic Predisposition to Disease %K Humans %K Lung Neoplasms %K Male %K Mice %K Mice, Inbred A %K Mice, Inbred C57BL %K Mice, Nude %K Microsatellite Repeats %K Molecular Sequence Data %K Proto-Oncogene Proteins %K Proto-Oncogene Proteins p21(ras) %K Quantitative Trait Loci %K ras Proteins %K Reverse Transcriptase Polymerase Chain Reaction %K Sequence Alignment %K Sequence Homology, Amino Acid %X

Pulmonary adenoma susceptibility 1 (Pas1), located on chromosome 6, is the major locus affecting inherited predisposition to lung tumor development in mice. We have fine mapped the Pas1 locus to a region of approximately 0.5 megabases by using congenic strains of mice, constructed by placing the Pas1 region of chromosome 6 from A/J mice onto the genetic background of C57BL/6J mice. Systematic characterization of Pas1 candidates establishes the Las1 (lung adenoma susceptibility 1) and Kras2 (Kirsten rat sarcoma oncogene 2) genes as primary candidates for the Pas1 locus. Clearly, Kras2 affects lung tumor progression only, and Las1 is likely to affect lung tumor multiplicity.

%B Proc Natl Acad Sci U S A %V 100 %P 12642-7 %8 2003 Oct 28 %G eng %N 22 %1 https://www.ncbi.nlm.nih.gov/pubmed/14583591?dopt=Abstract %R 10.1073/pnas.2133947100