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PubMed2000

[Tuberculosis control of urban areas in Japan].

The rates of tuberculosis remain high in urban areas. The declining speed of tuberculosis incidence rate in urban areas has been slower than other areas. Efforts and resources to tuberculosis control must be concentrated on urban locations to eradicate tuberculosis in Japan. 1. Tuberculosis control in a public health center of urban area: Teru OGURA and Chiyo INOGUCHI (Toshima City, Ikebukuro Public Health Center, Tokyo Metropolitan) A wide range of TB control measures is implemented by public health centers, such as a patient registration, home-visit guidance, contact examination in urban areas. Directors of every health center have the direct responsibility for tuberculosis control measures in their jurisdiction. Ikebukuro is urban areas where there are many offices, shopping and amusement facilities. Urban people is often on the move looking for job, so public health centers are often not easy to carry out contact examinations as planned. In recent years, homelessness has been recognized as a growing urban social problem. Their incidence of tuberculosis is high. Special TB control program must be carried out in urban areas. 2. Tuberculosis Control in Tokyo Metropolitan: Kazumasa MATSUKI (Department of Infectious Diseases and Tuberculosis, Bureau of Public Health, Tokyo Metropolitan) There has been a steady decline in the TB wards. The beds for TB patients are running short and even smear positive TB cases cannot be put in a hospital without waiting several days. Staffs of an urban emergency department must protect tuberculosis infection by environmental controls of emergency room. Tokyo Metropolitan government supports the engineering improvements of emergency room to hospitals. Directly observed therapy for tuberculosis patients at a district has been implemented to complete their therapy. On DOT, a trained health worker observes the patient take anti-TB medication. 3. Usefulness of Molecular Epidemiologic approach on Tuberculosis Control: Atsushi HASE (Osaka City Institute Laboratory of Health and Environment) DNA fingerprinting establishes the genetic relatedness of Mycobacterium tuberculosis isolates and has become a powerful tool in tuberculosis epidemiology. To use DNA fingerprinting to assess the efficacy of current tuberculosis infection-control practices. Combining conventional epidemiologic techniques with DNA fingerprinting of M. tuberculosis can improve the understanding of how tuberculosis is transmitted. Patients were assigned to clusters based on mycobacterial isolates with identical DNA fingerprints. Clusters were assumed to have arisen from recent transmission. We analyzed M. tuberculosis isolates from patients reported to the tuberculosis registry by RFLP techniques. These results were interpreted along with demographic data. Patients infected with the same strains were identified according to their RFLP patterns, and patients with identical patterns were grouped in clusters. RFLP patterns of high incidence districts have more variations than other areas. This suggests that the source of tuberculosis infection are quite diverse and complicated. Tuberculosis patients may accumulate to high incidence districts from other places after infection. 4. Structure of High Incidence of Tuberculosis and Control Plan in Osaka City: Yoichi TATSUMI (Bureau of Infection Control, Osaka City Office) The case notification rate in Osaka City is the highest in Japan. That of all TB cases and smear positive TB cases was 1573 and 216 per 100,000 population in 1997 at Airin District in Osaka City. The main reason for this highest incidence rate is that there are many homeless people and it is a mobile population. Most of residents are daily laborers. They come from all over Japan and stay there, mainly in rented rooms, to look for jobs. Thousands of homeless people also live in tents on streets or in parks. We are making to new strategic plan to intensify tuberculosis control measures throughout the city. Osaka city government h

Ill-Housed Persons↗
PubMed2004

Transgenic-Bt potato plant resistance to the colorado potato beetle affect the aphid parasitoid Aphidius nigripes.

Using the biotechnological plant resistance for herbivore control with less reliance on chemicals in integrated pest management (IPM) programs critically depends on predictable interactions with no-target organisms of various trophic levels. Plant resistance to insect pests based on recombinant Bacillus thuringiensis could interfere with natural enemies of non target pests. Performance of the potato aphid parasitoid Aphidius nigripes was studied on the 'Superior-BT line transgenic for the CryllIA toxin of B. thuringiensis, resistance to the Colorado potato beetle; and none transformed 'Superior' line which served as control. Parasitoid survival was significantly lower on the 'Superior-BT' line compared to control. Adult females were largest on 'Superior' and smallest on BT potatoes. This difference was reflected on parasitoid fecundity, which was lowest on 'Superior-BT', and highest on Superior. The results indicate that factor of potato resistance to the Colorado potato beetle affected the fitness of a parasitold of the aphid Macrosiphum euphorbiae, a secondary pest of potato. The effects on the parasitoid were complex but were generally interpretable in terms of host aphid quality variation among potato lines used as food by the aphids during parasitoid development.

Animals↗
PubMed2006

Developmental and hormonal regulation of direct shoot organogenesis and somatic embryogenesis in sugarcane (Saccharum spp. interspecific hybrids) leaf culture.

Rapid and efficient in vitro regeneration methods that minimise somaclonal variation are critical for the genetic transformation and mass propagation of commercial varieties. Using a transverse thin cell layer culture system, we have identified some of the developmental and physiological constraints that limit high-frequency regeneration in sugarcane leaf tissue. Tissue polarity and consequently the orientation of the explant in culture, size and developmental phase of explant, and auxin concentration play a significant role in determining the organogenic potential of leaf tissue in culture. Both adventitious shoot production and somatic embryogenesis occurred on the proximal cut surface of the explant, and a regeneration gradient, decreasing gradually from the basal to the distal end, exists in the leaf roll. Importantly, auxin, when added to the culture medium, reduced this spatial developmental constraint, as well as the effect of genotype on plant regeneration. Transverse sections (1-2 mm thick) obtained from young leaf spindle rolls and orienting explants with its distal end facing the medium (directly in contact with medium) are critical for maximum regeneration. Shoot regeneration was observed as early as 3 weeks on MS medium supplemented with alpha-naphthalenencetic acid (NAA) and 6-benzyladenine, while somatic embryogenesis or both adventitious shoot organogenesis and somatic embryogenesis occurred on medium with NAA and chlorophenoxyacetic acid. Twenty shoots or more could be generated from a single transverse section explant. These shoots regenerated roots and successfully established after transplanted to pots. Large numbers of plantlets can be regenerated directly and rapidly using this system. SmartSett, the registered name for this process and the plants produced, will have significant practical applications for the mass propagation of new cultivars and in genetic modification programs. The SmartSett system has already been used commercially to produce substantial numbers of plants of orange rust-resistant and new cultivars in Australia.

Cell Polarity↗
PubMed2004

Genetic diversity in and conservation strategy considerations for Navajo Churro sheep.

The objectives of this study were to 1) evaluate the genetic diversity of Navajo-Churro sheep using pedigree information; 2) examine the distribution of the Navajo-Churro population; and 3) evaluate the effect of breeder dynamics on genetic conservation of the breed. Pedigree data and breeder information (city and state) were obtained from the Navajo-Churro Sheep Breed Association. Inbreeding coefficients were calculated for each individual animal using pedigree information. A geographic information system program was used to divide the United States into four regions and overlay breeder locations, flock size, and flock inbreeding level. The small correlation between level of inbreeding and flock size (r = -0.07, P = 0.07) indicated that inbreeding levels are not different across flock sizes. The mean flock inbreeding levels ranged from 0 to 11% across regions. The level of inbreeding did not differ among regions (P = 0.15), except for Region 4 (Kansas and Missouri; P = 0.001). The number of breeders registering sheep averaged 34 per year. Most of the breeders were transient, with only eight breeders maintaining ownership for more than 7 yr. Average inbreeding level for 2000 was found to be 1.2%, with a linear increase in inbreeding of 0.1%/yr over the period studied, suggesting a minimal loss of genetic diversity for the Navajo-Churro. However, given the relatively small effective population size (92) and the transient nature of the breeders, development of an ex situ cryo-preserved germplasm bank may be the best long-term strategy for maintaining this breed's genetic diversity.

Animals↗
PubMed1998

Pedigree analysis package (PAP) vs. MORGAN: model selection and hypothesis testing on a large pedigree.

The MORGAN package of programs is compared to a commonly used package, PAP, with respect to model selection in segregation analysis of a quantitative trait. MORGAN uses Monte Carlo Markov chain (MCMC) methods to estimate the likelihood, whereas both versions of PAP used employ an approximation to the likelihood for the mixed model. Comparisons are done by using results obtained from simulated data. All simulations were done on the same 232-member pedigree using data generated under each of several variations of models, which included different combinations of environmental, polygenic, and major gene components. PAP, version 4.0, and MORGAN gave similar results with respect to model selection for the majority of situations, suggesting that MCMC methods provide a computationally tractable approach for analysis of more complex models that cannot be analyzed by more direct computational methods. PAP, version 3.0, gave somewhat more disparate results compared with either PAP version 4.0 or MORGAN. Both MORGAN and the two versions of PAP confirmed that the major gene component is much easier to detect in the presence of some dominance. All three packages frequently falsely accepted the polygenic model when there was high residual heritability.

Computer Simulation↗
PubMed1987

Programmed gene rearrangements altering gene expression.

Programmed gene rearrangements are used in nature to to alter gene copy number (gene amplification and deletion), to create diversity by reassorting gene segments (as in the formation of mammalian immunoglobulin genes), or to control the expression of a set of genes that code for the same function (such as surface antigens). Two major mechanisms for expression control are DNA inversion and DNA transposition. In DNA inversion a DNA segment flips around and is rejoined by site-specific recombination, disconnecting or connecting a gene to sequences required for its expression. In DNA transposition a gene moves into an expression site where it displaces its predecessor by gene conversion. Gene rearrangements altering gene expression have mainly been found in some unicellular organisms. They allow a fraction of the organisms to preadapt to sudden changes in environment, that is, to alter properties such as surface antigens in the absence of an inducing stimulus. The antigenic variation that helps the causative agents of African trypanosomiasis, gonorrhea, and relapsing fever to elude host defense is controlled in this way.

Animals↗
PubMed2000

NOS3 Glu298Asp genotype and blood pressure response to endurance training: the HERITAGE family study.

Endothelium-dependent vasodilation is a mechanism that may affect blood pressure response to endurance training. Because NO plays a central role in this process, the endothelial NO synthase gene is a good candidate for the regulation of exercise blood pressure. We investigated the associations between an endothelial NO synthase gene polymorphism (Glu298Asp) and endurance training-induced changes in resting and submaximal exercise blood pressure in 471 white subjects of the HERITAGE Family Study. Two submaximal exercise tests at 50 W were conducted both before and after a 20-week endurance training program. Steady-state exercise blood pressure was measured twice in each test with an automated unit. The Glu298Asp polymorphism was typed with a PCR-based method and digestion with BAN:II. Both systolic and diastolic blood pressure at 50 W decreased in response to the training program, whereas resting blood pressure remained unchanged. The decrease in diastolic blood pressure at 50 W was greater (P=0.0005, adjusted for age, gender, baseline body mass index, and baseline diastolic blood pressure at 50 W) in the Glu/Glu homozygotes (4.4 [SEM 0.4] mm Hg, n=187) than in the heterozygotes (3.1 [0.4] mm Hg, n=213) and the Asp/Asp homozygotes (1.3 [0.7] mm Hg, n=71). The genotype accounted for 2.3% of the variance in diastolic blood pressure at 50 W training response. Both the Glu298 homozygotes and the heterozygotes had a greater (P=0.013) training-induced reduction in rate-pressure product at 50 W than the Asp298 homozygotes. These data suggest that DNA sequence variation in the endothelial NO synthase gene locus is associated with the endurance training-induced decreases in submaximal exercise diastolic blood pressure and rate-pressure product in sedentary normotensive white subjects.

Adult↗
PubMed2002

Metapopulation dynamics and spatial heterogeneity in cancer.

With the advent of drugs targeting specific molecular defects in cancerous cells [Gorre, M. E., et al. (2001) Science 293, 876-880], it is important to understand the degree of genetic heterogeneity present in tumor cell populations and the rules that govern microdiversity in human cancer. Here, we first show that populations with different genotypes in genes influencing cell growth and programmed cell death coexist in advanced malignant tumors of the colon, exhibiting microsatellite instability. Detailed, physical mapping of the diverse populations shows them to be arranged in small, intermingling areas, resulting in a variegated pattern of diversity. Using computational modeling of the experimental data, we find that the coexistence between similar competitors is enhanced, instead of deterred, by spatial dynamics [Hanski, I. (1999) Metapopulation Dynamics (Oxford Univ. Press, New York)]. The model suggests a simple and plausible scenario for the generation of spatial heterogeneity during tumor progression. The emergence and persistence of the patterns of diversity encountered in the tumors can be generated without a need to invoke differences in mutation rates, neutrality of interactions, or separated time scales. We posit that the rules that apply to spatial ecology and explain the maintenance of diversity are also at work in tumors and may underlie tumor microheterogeneity.

Adenocarcinoma↗
PubMed2001

Satellite-tagged transcribing sequences in Bubalus bubalis genome undergo programmed modulation in meiocytes: possible implications for transcriptional inactivation.

We cloned and sequenced a 1378 bp BamHI satellite DNA fraction from the water buffalo Bubalus bubalis and have studied its expression in different tissues. The GC-rich sequences of the resultant contig pDS5 crosshybridize only with bovid DNA and are not conserved evolutionarily. Typing of buffalo genomic DNA using pDS5 with several restriction enzymes revealed multilocus monomorphic bands. Similar typing of cattle, buffalo, goat, sheep, and gaur genomic DNA revealed variations in copy number and allele length giving rise to species-specific band patterns. Expression study of pDS5 in bubaline samples by RNA slot-blot, Northern blot, and RT-PCR showed various levels of signal in all the somatic tissues and germline cells except heart. A GenBank database search revealed homology of pDS5 sequences in the 5' region from nt 1-1261 with collagen gene. An AluI typing analysis of DNA from bubaline semen samples showed consistent loss of two bands. The presence of corresponding bands in somatic tissues suggests a sequence modulation within the pDS5 array in meiocytes during spermatogenesis, which is restored in the somatic cells after fertilization. Modulation of the satellite-tagged transcribing sequence in the meiocytes may be a mechanism of its inactivation.

Animals↗
PubMed1996

Bluetongue disease and the molecular epidemiology of viruses from the western United States.

Prototype and field isolates of United States bluetongue viruses were evaluated for genetic heterogeneity by sequence analyses. Prototype viruses BTV 2, 10, 11, 13 and 17 from the United States, BTV 10 vaccine virus, and field isolates of BTV 10 and 17 from California were analyzed. Gene segment 2 from BTV 10 and 17 isolated in 1980-81 and 1990 was sequenced along with gene segment 9 from BTV 10 isolates. The Wisconsin Package was used to analyze nucleotide sequences and to predict amino acid composition of the putative proteins. Phylogenetic analyses were done using DNADIST and FITCH programs of the PHYLIP Package, v. 3.4. Gene segment 2 segregated into two monophyletic groups of BTV 2 and 13 and BTV 10, 11 and 17. BTV prototype 10, isolated in 1953 and field isolates through 1980 were similar, whereas the 1990 isolates differed by 4.5%, indicating two BTV 10 monophyletic groups over 37 years. Gene segment 2 of BTV 17 prototype virus differed from the California isolates. Gene segment 9 of BTV 10 field isolates formed into two monophyletic groups. This gene segment reassorted with all serotypes. Gene segment 9 of the 1953 BTV 10 vaccine virus was essentially the same as gene segment 9 of the BTV 13 prototype virus, isolated in Idaho in 1967. This suggested that prototype BTV 13 is a reassortant virus with gene segment 9 derived from a vaccine virus parent.

Amino Acid Sequence↗
PubMed2006

Mapping antigenic diversity and strain specificity of mumps virus: a bioinformatics approach.

Mumps is an acute infectious disease caused by mumps virus, a member of the family Paramyxoviridae. With the implementation of vaccination programs, mumps infection is under control. However, due to resurgence of mumps epidemics, there is a renewed interest in understanding the antigenic diversity of mumps virus. Hemagglutinin-neuraminidase (HN) is the major surface antigen and is known to elicit neutralizing antibodies. Mutational analysis of HN of wild-type and vaccine strains revealed that the hypervariable positions are distributed over the entire length with no detectable pattern. In the absence of experimentally derived 3D structure data, the structure of HN protein of mumps virus was predicted using homology modeling. Mutations mapped on the predicted structures were found to cluster on one of the surfaces. A predicted conformational epitope encompasses experimentally characterized epitopes suggesting that it is a major site for neutralization. These analyses provide rationale for strain specificity, antigenic diversity and varying efficacy of mumps vaccines.

Antigenic Variation↗
PubMedDate not supplied

Interspousal transmission of hepatitis C virus: application of comparing the variability of HVR1 nucleotide region.

BACKGROUND/AIMS: The interspousal transmission of hepatitis C virus (HCV) has been a controversial issue in previous studies. We thus aim to investigate the possibility of HCV transmission between spouses by comparing the variability of HCV hypervariable region 1 (HVR1) between spouses and non-spouses. METHODOLOGY: Four spouses both positive for anti-HCV antibody and HCV RNA were enrolled in our study. Reverse transcriptional polymerase chain reaction (PCR) of HVR1 region was done from each patient for blood samples. The amplified PCR products were molecularly cloned, and eight to ten clones from each patient were analyzed. In addition to the phylogenetic analysis, comparing the variability of nucleotide and deduced amino acid sequences of HVR1 and outside HVR1 from these clones by a computer software program PHYLIP version 3.57 was performed in each patient, between spouse and among non-family patients. RESULTS: All eight patients were infected with genotype Ib HCV. The sequences of eight to ten clones of HCV HVR1 in each patient showed quasispecies nature of HCV. Moreover, the variabilities of nucleotide sequence and deduced amino acid sequence of HVR1 were much higher than those outside of HVR1. Between spouses, the variabilities of HVR1 were significantly lower (p<0.001) than those of non-family members in 3 of 4 families. Clones of the same patient displayed the closest relationship in the phylogenetic tree. In addition, spouses of three families showed a closer relationship than other non-family patients. CONCLUSIONS: This study strongly suggests that sexual transmission does exist, which can be confirmed by comparing the variability of HVR1 nucleotide region of HCV.

Female↗
PubMed2005

Genetic relatedness of oral yeasts within and between patients with marginal periodontitis and subjects with oral health.

BACKGROUND: Yeasts are found in periodontal pockets at a frequency of 15-21%. However, the genetic relatedness of oral yeasts within and between patients with marginal periodontitis is not clear. OBJECTIVES: Assay genetic relatedness of oral yeasts from marginal periodontitis patients and oral health subjects, as well as genetic relatedness of yeasts from different oral sites in these two groups of participants. MATERIAL AND METHODS: Yeast isolates were collected from 23 marginal periodontitis patients and 19 oral health subjects. Random amplified polymorphic DNA (RAPD) fingerprinting and the Dendron computer-assisted program for gel analyses were applied for estimation of genetic relatedness of yeasts. RESULTS: The similarity coefficient (S(AB)) of the marginal periodontitis group ranged from 0.49 to 1.00 with an average of 0.64 +/- 0.11, whereas the S(AB) of the oral health group ranged from 0.62 to 1.00 with an average of 0.72 +/- 0.07. Three genetic clusters and 73 genotypes were obtained from the marginal periodontitis group, whereas three genetic clusters and 55 genotypes were found in the oral health group. In the pooled dendrogram, 57% of the yeast isolates and the type strain of Candida albicans fell in a major cluster V. There were no significant differences between the frequencies of clusters from the different oral sites within the two participant groups. CONCLUSIONS: Genetically heterogeneous yeasts were found in the oral cavities of marginal periodontitis patients and oral health subjects. Similar genetic clustering patterns were obtained from the yeasts of the two groups, with cluster V being most predominant. Yeasts of the marginal periodontitis group were more genetically diverse than yeasts of the oral health group, and some yeasts of the marginal periodontitis group exhibited unique genetic patterns. There was no clear association between yeast genetic clusters and oral sites in the two participant groups.

Adolescent↗
PubMed2006

Through the viewfinder: Positive Exposure a year later.

Positive Exposure, a non-profit organization founded and directed by former fashion photographer Rick Guidotti and co-directed by psychiatrist Dr. Diane McLean, uses photography and video interviews to explore the lived experiences of people affected with genetic conditions. Positive Exposure challenges pervasive social biases and stereotypes about genetic variation and strives to broaden and enrich societal perceptions of human beauty and spirit. Presented here are the open-ended personal reflections completed by four individuals with craniofacial differences recruited from a support group, Inner Faces. These four case studies aim to relay the professional photo-shoot experiences of people who may be challenged by the stigma associated with craniofacial differences. Questions addressed issues of perceived self-esteem, stigma, hopefulness, and photography experiences. These personal reflections were gathered 1 year following participation in a Positive Exposure photo-shoot. Participants described the ways in which the photo-shoot has been a lasting and life-promoting experience. In addition, these individuals emphasize the integral and enduring role the photographer, Rick Guidotti, played in their personal awakening. Positive Exposure provided these individuals with renewed identification of both inner and outer sources of beauty. These four case studies suggest that Positive Exposure may serve as a sustainable intervention to bolster self-esteem and self-image. Published 2006 Wiley-Liss, Inc.

Adaptation, Psychological↗
PubMed1976

Genetic determination of the beta-galactosidase developmental program in mouse liver.

The developmental program for beta-galactosidase in C57BL/6J and related strains of mice differs from that seen in most other mouse strains. Mice of the C57BL/6 group show a rise in liver enzyme activity during development that is not seen in mice of other strains. The developmental pattern of beta-galactosidase activity in heart and brain of C57BL/6 mice is similar to that in other strains. Physical, kinetic, and immunological tests indicate that the developmental increase in C57BL/6 enzyme activity is an increase in the number of molecules of the same species of enzyme protein that is present in other strains. In genetic crosses, the presence of the developmental rise in liver enzyme activity segregates as if determined by a single genetic factor showing additive expression in heterozygotes. This factor is closely linked to the beta-galactosidase structural gene on chromosome 9. The existence of a genetic variant with these properties is evidence that programmatic information capable of regulating the temporal expression of a structural gene can be encoded in DNA.

Animals↗
PubMed2003

Variety of interpretation systems for human immunodeficiency virus type 1 genotyping: confirmatory information or additional confusion?

The emergence of drug resistance remains a major problem during antiretroviral treatment of patients infected with human immunodeficiency virus type 1 (HIV-1). As phenotypic drug resistance is laborious and expensive to determine, and because numerous specific mutations are known to be correlated with different resistance patterns, genotyping of the reverse transcriptase and protease genes of HIV is fast becoming an integral part of HIV management in industrialized countries. A number of software-based interpretation systems have been developed for the interpretation of the resulting complex nucleotide sequences. These programs either employ rule-based algorithms or are based on a genotype-phenotype database. This paper reviews recent publications that compare different such systems, trying to identify the degree of discordance between different systems and the reasons underlying such discrepant interpretations. The highest discordance rate was observed for nucleoside reverse transcriptase inhibitors (NRTIs) followed by protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). For the NRTIs, it is the role of nucleoside analogue associated mutations, for the PIs and for the NNRTIs, that of secondary mutations that causes most discrepancies. As the complexity of the mutation pattern is likely to increase further with new drugs becoming available, rule-based genotype interpretation algorithms need to be updated frequently. Whilst not recommending one particular system, the authors believe that the correlation of genotypic with clinical data is probably the best way to develop an optimal algorithm.

Algorithms↗
PubMed2006

Regulated degradation is a mechanism for suppressing stochastic fluctuations in gene regulatory networks.

Cellular events that execute life programs are ordered and reproducible, despite the noise and randomness underlying their biochemical reactions. The identification of the processes that ensure this robust operation is essential not only to uncover the salient design principles in organisms, but also to forward-engineer reliable genetic networks for biotechnological and therapeutic purposes. The use of feedback for noise reduction has been suggested as a recurring motif in genetic networks. In this work, we show that regulated degradation of proteins implements a negative feedback loop that enhances robustness against stochastic fluctuations and cellular noise. The analysis is carried out in the context of the bacterial heat shock response where the tight control of the amount of heat shock proteins is achieved through an intricate architecture of feedback loops involving the sigma(32)-factor. The sigma(32) regulates the transcription of heat shock proteins under normal and stress conditions. An essential feature of the heat shock response is a feedback loop regulating the degradation of sigma(32). We investigate the noise-rejection properties of this loop, therefore illustrating our point in a biologically plausible example.

Computer Simulation↗
PubMed2006

Expression profiling of UVB response in melanocytes identifies a set of p53-target genes.

Epidermal melanocytes execute specific physiological programs in response to UV radiation (UVR) at the cutaneous interface. Many melanocytic responses, including increased dendrite formation, enhanced melanogenesis/melanization, and cell cycle arrest impact the ability of melanocytes to survive and to attenuate the UVR insult. Although some of the molecules that underlie these UVR programs are known, a coherent view of UVR-induced transcriptional changes is lacking. Using primary melanocyte cultures, we assessed for UVR-mediated alterations in over 47,000 transcripts using Affymetrix Human Genome U133 Plus 2.0 microarrays. From the 100 most statistically robust changes in transcript level, there were 84 genes that were suppressed >2.0-fold by UVR; among these transcripts, the identities of 48 of these genes were known. Similarly, there were 99 genes that were induced >2.0-fold by UVR; the identity of 57 of these genes were known. We then subjected these top 100 changes to the Ingenuity Pathway analysis program and identified a group of p53 targets including the cell cycle regulator CDKN1A (p21CIP), the WNT pathway regulator DKK1 (dickkopf homolog 1), the receptor tyrosine kinase EPHA2, growth factor GDF15, ferrodoxin reductase (FDXR), p53-inducible protein TP53I3, transcription factor ATF3, DNA repair enzyme DDB2, and the beta-adrenergic receptor ADBR2. These genes were also found to be consistently elevated by UVR in six independent melanocyte lines, although there were interindividual variations in magnitude. WWOX, whose protein product interacts and regulates p53 and p73, was found to be consistently suppressed by UVR. There was also a subgroup of neurite/axonal developmental genes that were altered in response to UVR, suggesting that melanocytic and neuronal arborization may share similar mechanisms. When compared to melanomas, the basal levels of many of these p53-responsive genes were greatly dysregulated. Three genes--CDKN1A, DDB2 and ADRB2--exhibited a trend towards loss of expression in melanomas thereby raising the possibility of a linked role in tumorigenesis. These expression data provide a global view of UVR-induced changes in melanocytes and, more importantly, generate novel hypotheses regarding melanocyte physiology.

Cell Line, Tumor↗