Neil Box
University of Colorado Denver, Department of Dermatology, Faculty Member
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Mdm2, an E3 ubiquitin ligase, negatively regulates the tumour suppressor p53. Loss of Mdm2 in mice results in p53-dependent apoptosis and embryonic lethality. This phenotype was rescued by the p53(515C) allele, which encodes an... more
Mdm2, an E3 ubiquitin ligase, negatively regulates the tumour suppressor p53. Loss of Mdm2 in mice results in p53-dependent apoptosis and embryonic lethality. This phenotype was rescued by the p53(515C) allele, which encodes an apoptosis-deficient p53R172P protein. However, these mice died within 2 weeks of birth, due to a severe impairment of progenitor cell expansion during postnatal haematopoiesis and cerebellar development, leading to p53-dependent cell cycle arrest. Loss of Mdm2 led to phosphorylation of the p53R172P protein, p53R172P stability and activation of the cell cycle inhibitor p21 in proliferating cells, but not in differentiated cells, in multiple tissue compartments. Proliferating cells of epithelial origin were not affected. The haematopoietic and neural defects were alleviated in mice lacking Mdm2 and containing one p53(515C) and one p53-null allele, but spermatogenesis was arrested. These findings establish a crucial role for the p53-Mdm2 network in regulating proliferation and progenitor expansion in many cell lineages and have important implications for the use of drugs that aim to disrupt the p53-Mdm2 interaction.
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MC1R gene variants have previously been associated with red hair and fair skin color, moreover skin ultraviolet sensitivity and a strong association with melanoma has been demonstrated for three variant alleles that are active in... more
MC1R gene variants have previously been associated with red hair and fair skin color, moreover skin ultraviolet sensitivity and a strong association with melanoma has been demonstrated for three variant alleles that are active in influencing pigmentation: Arg151Cys, Arg160Trp, and Asp294His. This study has confirmed these pigmentary associations with MC1R genotype in a collection of 220 individuals drawn from the Nambour community in Queensland, Australia, 111 of whom were at high risk and 109 at low risk of basal cell carcinoma and squamous cell carcinoma. Comparative allele frequencies for nine MC1R variants that have been reported in the Caucasian population were determined for these two groups, and an association between prevalence of basal cell carcinoma, squamous cell carcinoma, solar keratosis and the same three active MC1R variant alleles was demonstrated [odds ratio = 3.15 95% CI (1.7, 5.82)]. Three other commonly occurring variant alleles: Val60Leu, Val92Met, and Arg163Gln were identified as having a minimal impact on pigmentation phenotype as well as basal cell carcinoma and squamous cell carcinoma risk. A significant heterozygote effect was demonstrated where individuals carrying a single MC1R variant allele were more likely to have fair and sun sensitive skin as well as carriage of a solar lesion when compared with those individuals with a consensus MC1R genotype. After adjusting for the effects of pigmentation on the association between MC1R variant alleles and basal cell carcinoma and squamous cell carcinoma risk, the association persisted, confirming that presence of at least one variant allele remains informative in terms of predicting risk for developing a solar-induced skin lesion beyond that information wained through observation of pigmentation phenotype.
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Genetic Epidemiology, Polymorphism, Humans, Queensland, Ultraviolet, and 15 moreSquamous Cell Carcinoma, Risk factors, Phenotype, Clinical Sciences, Oral Squamous Cell Carcinoma (OSCC), Skin Pigmentation, Genotype, Basal cell carcinoma, Genetic variation, Risk Factors, Skin Color, INVESTIGATIVE, Low Risk, Allele Frequency, and Skin Neoplasms
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Melanocytic nevi (moles) and freckles are well known biomarkers of melanoma risk, and they are influenced by similar UV light exposures and genetic susceptibilities to those that increase melanoma risk. Nevertheless, the selective... more
Melanocytic nevi (moles) and freckles are well known biomarkers of melanoma risk, and they are influenced by similar UV light exposures and genetic susceptibilities to those that increase melanoma risk. Nevertheless, the selective interactions between UV exposures and nevus and freckling genes remain largely undescribed. We conducted a longitudinal study from ages 6 through 10 years in 477 Colorado children who had annual information collected for sun exposure, sun protection behaviors, and full body skin exams. MC1R and HERC2/OCA2 rs12913832 were genotyped and linear mixed models were used to identify main and interaction effects. All measures of sun exposure (chronic, sunburns, and waterside vacations) contributed to total nevus counts, and cumulative chronic exposure acted as the major driver of nevus development. Waterside vacations strongly increased total nevus counts in children with rs12913832 blue eye color alleles and facial freckling scores in those with MC1R red hair col...
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ABSTRACT Human skin color ranges in hue from dark brown to light pink, decreasing in pigmentation with distance from the equator, perhaps to balance generating vitamin D3 and providing UV protection. With increased UV exposure,... more
ABSTRACT Human skin color ranges in hue from dark brown to light pink, decreasing in pigmentation with distance from the equator, perhaps to balance generating vitamin D3 and providing UV protection. With increased UV exposure, melanocytes produce more of the pigment melanin in melanosomes, which is transferred to nearby keratinocytes, where it forms caps around the nuclei to protect DNA from UV damage. The genetics behind pigmentation is extremely complex, involving multiple gene networks and hundreds of genetic loci, many of which remain to be functionally characterized. This article is protected by copyright. All rights reserved.
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Clinical observations, as well as data obtained from the analysis of genetically engineered mouse models, firmly established the gain-of-function (GOF) properties of certain p53 mutations. However, little is known about the underlying... more
Clinical observations, as well as data obtained from the analysis of genetically engineered mouse models, firmly established the gain-of-function (GOF) properties of certain p53 mutations. However, little is known about the underlying mechanisms. We have used two independent microarray platforms to perform a comprehensive and global analysis of tumors arising in a model of metastatic skin cancer progression, which compares the consequences of a GOF p53(R172H) mutant vs p53 deficiency. DNA profiling revealed a higher level of genomic instability in GOF vs loss-of-function (LOF) p53 squamous cell carcinomas (SCCs). Moreover, GOF p53 SCCs showed preferential amplification of Myc with a corresponding increase in its expression and deregulation of Aurora Kinase A. Fluorescent in situ hybridization confirmed amplification of Myc in primary GOF p53 SCCs and its retention in metastatic tumors. We also identified by RNA profiling distinct gene expression profiles in GOF p53 tumors, which included enriched integrin and Rho signaling, independent of tumor stage. Thus, the progression of GOF p53 papillomas to carcinoma was marked by the acquisition of epithelial-to-mesenchymal transition and metastatic signatures. In contrast, LOF p53 tumors showed enrichment of genes associated with cancer proliferation and chromosomal instability. Collectively, these observations suggest that genomic instability has a prominent role in the early stages of GOF p53 tumor progression (that is, papillomas), whereas it is implicated at a later stage in LOF p53 tumors (that is, SCCs). This model will allow us to identify specific targets in mutant p53 SCCs, which may lead to the development of new therapeutic agents for the treatment of metastatic SCCs.
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Now that the mouse and human genome sequences are complete, biologists need systematic approaches to determine the function of each gene. A powerful way to discover gene function is to determine the consequence of mutations in living... more
Now that the mouse and human genome sequences are complete, biologists need systematic approaches to determine the function of each gene. A powerful way to discover gene function is to determine the consequence of mutations in living organisms. Large-scale production of mouse mutations with the point mutagen N-ethyl-N-nitrosourea (ENU) is a key strategy for analysing the human genome because mouse mutants will reveal functions unique to mammals, and many may model human diseases. To examine genes conserved between human and mouse, we performed a recessive ENU mutagenesis screen that uses a balancer chromosome, inversion chromosome 11 (refs 4, 5). Initially identified in the fruitfly, balancer chromosomes are valuable genetic tools that allow the easy isolation of mutations on selected chromosomes. Here we show the isolation of 230 new recessive mouse mutations, 88 of which are on chromosome 11. This genetic strategy efficiently generates and maps mutations on a single chromosome, even as mutations throughout the genome are discovered. The mutations reveal new defects in haematopoiesis, craniofacial and cardiovascular development, and fertility.
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The complete 24,667 nucleotide sequence spanning the human TYRP1 gene has been determined from the inserts of two overlapping lambda clones. A LINE-1 repeat element is immediately adjacent to and may demarcate the immediate... more
The complete 24,667 nucleotide sequence spanning the human TYRP1 gene has been determined from the inserts of two overlapping lambda clones. A LINE-1 repeat element is immediately adjacent to and may demarcate the immediate 5' promoter region of the gene. A search for polymorphism within the seven TYRP1 coding exons has been performed by an RNase mismatch detection procedure. Analysis of the TYRP1 gene in 100 Caucasian individuals of varying hair color has found no amino acid sequence variation nor revealed any hemizygous mutant allele in the hypopigmented phenotype of two 9p- syndrome patients.
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MC1R gene variants have previously been associated with red hair and fair skin color, moreover skin ultraviolet sensitivity and a strong association with melanoma has been demonstrated for three variant alleles that are active in... more
MC1R gene variants have previously been associated with red hair and fair skin color, moreover skin ultraviolet sensitivity and a strong association with melanoma has been demonstrated for three variant alleles that are active in influencing pigmentation: Arg151Cys, Arg160Trp, and Asp294His. This study has confirmed these pigmentary associations with MC1R genotype in a collection of 220 individuals drawn from the Nambour community in Queensland, Australia, 111 of whom were at high risk and 109 at low risk of basal cell carcinoma and squamous cell carcinoma. Comparative allele frequencies for nine MC1R variants that have been reported in the Caucasian population were determined for these two groups, and an association between prevalence of basal cell carcinoma, squamous cell carcinoma, solar keratosis and the same three active MC1R variant alleles was demonstrated [odds ratio = 3.15 95% CI (1.7, 5.82)]. Three other commonly occurring variant alleles: Val60Leu, Val92Met, and Arg163Gln were identified as having a minimal impact on pigmentation phenotype as well as basal cell carcinoma and squamous cell carcinoma risk. A significant heterozygote effect was demonstrated where individuals carrying a single MC1R variant allele were more likely to have fair and sun sensitive skin as well as carriage of a solar lesion when compared with those individuals with a consensus MC1R genotype. After adjusting for the effects of pigmentation on the association between MC1R variant alleles and basal cell carcinoma and squamous cell carcinoma risk, the association persisted, confirming that presence of at least one variant allele remains informative in terms of predicting risk for developing a solar-induced skin lesion beyond that information wained through observation of pigmentation phenotype.
Research Interests:
Genetic Epidemiology, Polymorphism, Humans, Queensland, Ultraviolet, and 15 moreSquamous Cell Carcinoma, Risk factors, Phenotype, Clinical Sciences, Oral Squamous Cell Carcinoma (OSCC), Skin Pigmentation, Genotype, Basal cell carcinoma, Genetic variation, Risk Factors, Skin Color, INVESTIGATIVE, Low Risk, Allele Frequency, and Skin Neoplasms
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The association between MSHR coding region variation and hair colour in humans has been examined by genotyping 25 red haired and 62 non-red Caucasians, all of whom were 12 years of age and members of a twin pair study. Twelve amino acid... more
The association between MSHR coding region variation and hair colour in humans has been examined by genotyping 25 red haired and 62 non-red Caucasians, all of whom were 12 years of age and members of a twin pair study. Twelve amino acid substitutions were seen at 11 different sites, nine of these being newly described MSHR variants. The previously reported Val92Met allele shows no association with hair colour, but the three alleles Arg151Cys, Arg160Trp and Asp294His were associated with red hair and one Val60Leu variant was most frequent in fair/blonde and light brown hair colours. Variant MSHR genotypes are associated with lighter skin types and red hair (P < 0.001). However, comparison of the MSHR genotypes in dizygotic twin pairs discordant for red hair colour indicates that the MSHR gene cannot be solely responsible for the red hair phenotype, since five of 13 pairs tested had both haplotypes identical by state (with three of the five having both identical by descent). Rather, it is likely that additional modifier genes exist, making variance in the MSHR gene necessary but not always sufficient, for red hair production.
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BACKGROUND: Ultraviolet (UV) photography has been used to motivate sun safety in behavioral interventions. The relationship between sun damage shown in UV photographs and melanoma risk has not been systematically investigated. OBJECTIVE:... more
BACKGROUND: Ultraviolet (UV) photography has been used to motivate sun safety in behavioral interventions. The relationship between sun damage shown in UV photographs and melanoma risk has not been systematically investigated. OBJECTIVE: To examine the relationship between severity of sun damage in UV photographs and phenotypic melanoma risk factors in children. METHODS: UV, standard visible and cross-polarized photographs were recorded for 585 children. Computer software quantified sun damage. Full-body nevus counts, skin color by colorimetry, facial freckling, hair and eye color were collected in skin examinations. Demographic data were collected in telephone interviews of parents. RESULTS: Among 12-year-old children, sun damage shown in UV photographs correlated with phenotypic melanoma risk factors. Sun damage was greatest for children who were non-Hispanic white and those who had red hair, blue eyes, increased facial freckling, light skin and greater number of nevi (all P value...
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Information Systems, Genetics, Genomics, Cell line, Humans, and 19 moreLiver, Melanoma, Animals, Oxidoreductases, Polymerase Chain Reaction, DNA hybridization, Genetic Map, Proteins, Introns, Molecular cloning, Genomic DNA, Hominidae, Amino Acid Sequence, Base Sequence, Structure activity Relationship, Gene Family, Isomerases, Protein Biosynthesis, and DNA sequence
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Genetics, Polymorphism, Molecular Evolution, Gene expression, DNA, and 17 moreHumans, Mice, Haplotypes, Animals, Male, Polymerase Chain Reaction, Gene, Transcription Factor, Single Nucleotide Polymorphism, HeLa cells, Linkage Disequilibrium, Adrenocorticotropic Hormone, Melanocytes, Amino Acid Sequence, Base Sequence, Poly A, and Mutation Rate
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Biological Sciences, Humans, Mice, Animals, Cell, and 3 moreMale, Cell Proliferation, and Response Elements
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Genetics, Pigmentation, Comparative Genomics, Membrane Proteins, Biological Sciences, and 18 moreHumans, Keratinocytes, Mice, Female, Animals, Male, Oxidoreductases, Albinism, Proteins, Membrane transport proteins, Enzyme, Skin Pigmentation, Hair Color, Genetic variation, Melanocytes, Genetic Association, Amino Acid Sequence, and Cell Surface Markers
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Archives, Prospective studies, Humans, Child, Follow-up studies, and 14 moreRisk factors, Clinical Sciences, Colorado, Prevalence, Skin Pigmentation, Time Factors, Randomized Controlled Trial, Age Factors, Hair Color, Disease Progression, Risk Factors, Skin Color, Managed Care Organization, and Skin Neoplasms
We have examined MC1R variant allele frequencies in the general population of South East Queensland and in a collection of adolescent dizygotic and monozygotic twins and family members to define statistical associations with hair and skin... more
We have examined MC1R variant allele frequencies in the general population of South East Queensland and in a collection of adolescent dizygotic and monozygotic twins and family members to define statistical associations with hair and skin color, freckling, and mole count. Results of these studies are consistent with a linear recessive allelic model with multiplicative penetrance in the inheritance of red hair. Four alleles, D84E, R151C, R160W, and D294H, are strongly associated with red hair and fair skin with multinomial regression analysis showing odds ratios of 63, 118, 50, and 94, respectively. An additional three low-penetrance alleles V60L, V92M, and R163Q have odds ratios 6, 5, and 2 relative to the wild-type allele. To address the cellular effects of MC1R variant alleles in signal transduction, we expressed these receptors in permanently transfected HEK293 cells. Measurement of receptor activity via induction of a cAMP-responsive luciferase reporter gene found that the R151C and R160W receptors were active in the presence of NDP-MSH ligand, but at much reduced levels compared with that seen with the wild-type receptor. The ability to stimulate phosphorylation of the cAMP response element binding protein (CREB) transcription factor was also apparent in all stimulated MC1R variant allele-expressing HEK293 cell extracts as assessed by immunoblotting. In contrast, human melanoma cell lines showed wide variation in the their ability to undergo cAMP-mediated CREB phosphorylation. Culture of human melanocytes of known MC1R genotype may provide the best experimental approach to examine the functional consequences for each MC1R variant allele. With this objective, we have established more than 300 melanocyte cell strains of defined MC1R genotype.
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Pigmentation, Risk, Biological Sciences, Population, Humans, and 20 moreMutation, Female, Melanoma, Male, Frequency, Gene, Pedigree, Association, Melanocortin receptor, Risk Factor, Gen, Genotype, Chromosome segregation, Genetic variation, Allele, Radiation Tolerance, Exon, Proportional Hazards Models, Variant, and The American
Risk of cutaneous malignant melanoma (CMM) is increased in sun-exposed whites, particularly those with a pale complexion. This study was designed to investigate the relationship of the melanocortin-1 receptor (MC1R) genotype to CMM risk,... more
Risk of cutaneous malignant melanoma (CMM) is increased in sun-exposed whites, particularly those with a pale complexion. This study was designed to investigate the relationship of the melanocortin-1 receptor (MC1R) genotype to CMM risk, controlled for pigmentation phenotype. We report the occurrence of five common MC1R variants in an Australian population-based sample of 460 individuals with familial and sporadic CMM and 399 control individuals-and their relationship to such other risk factors as skin, hair, and eye color; freckling; and nevus count. There was a strong relationship between MC1R variants and hair color and skin type. Moreover, MC1R variants were found in 72% of the individuals with CMM, whereas only 56% of the control individuals carried at least one variant (P<.001), a finding independent of strength of family history of melanoma. Three active alleles (Arg151Cys, Arg160Trp, and Asp294His), previously associated with red hair, doubled CMM risk for each additional allele carried (odds ratio 2.0; 95% confidence interval 1. 6-2.6). No such independent association could be demonstrated with the Val60Leu and Asp84Glu variants. Among pale-skinned individuals alone, this association between CMM and MC1R variants was absent, but it persisted among those reporting a medium or olive/dark complexion. We conclude that the effect that MC1R variant alleles have on CMM is partly mediated via determination of pigmentation phenotype and that these alleles may also negate the protection normally afforded by darker skin coloring in some members of this white population.