Mark A Nelson

Interests

Teaching

Cancer BiologyPathology

Research

• Neurologic Disease of Unknown Origin• Inflammation • Cancer Biology• Pharmacology

Courses

Scholarly Contributions

Journals/Publications

• Nelson, M. A. (2022). Liquid biopsy, using a novel DNA methylation signature, distinguishes pancreatic adenocarcinoma from benign pancreatic disease. Clinical Epigenetics.
• Dhanalakshmi, C., Janakiraman, U., Moutal, A., Fukunaga, K., Khanna, R., & Nelson, M. A. (2020). Evaluation of the effects of the T-type calcium channel enhancer SAK3 in a rat model of TAF1 deficiency. Neurobiology of disease, 149, 105224.
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  The TATA-box binding protein associated factor 1 (TAF1) is part of the TFIID complex that plays a key role during the initiation of transcription. Variants of TAF1 are associated with neurodevelopmental disorders. Previously, we found that CRISPR/Cas9 based editing of the TAF1 gene disrupts the morphology of the cerebral cortex and blunts the expression as well as the function of the CaV3.1 (T-type) voltage gated calcium channel. Here, we tested the efficacy of SAK3 (ethyl 8'-methyl-2', 4-dioxo-2-(piperidin-1-yl)-2'H-spiro [cyclopentane-1, 3'-imidazo [1, 2-a] pyridine]-2-ene-3-carboxylate), a T-type calcium channel enhancer, in an animal model of TAF1 intellectual disability (ID) syndrome. At post-natal day 3, rat pups were subjected to intracerebroventricular (ICV) injection of either gRNA-control or gRNA-TAF1 CRISPR/Cas9 viruses. At post-natal day 21, the rat pups were given SAK3 (0.25 mg/kg, p.o.) or vehicle for 14 days (i.e. till post-natal day 35) and then subjected to behavioral, morphological, and molecular studies. Oral administration of SAK3 (0.25 mg/kg, p.o.) significantly rescued locomotion abnormalities associated with TAF1 gene editing. SAK3 treatment prevented the loss of cortical neurons and GFAP-positive astrocytes observed after TAF1 gene editing. In addition, SAK3 protected cells from apoptosis. SAK3 also restored the Brain-derived neurotrophic factor/protein kinase B/Glycogen Synthase Kinase 3 Beta (BDNF/AKT/GSK3β) signaling axis in TAF1 edited animals. Finally, SAK3 normalized the levels of three GSK3β substrates - CaV3.1, FOXP2, and CRMP2. We conclude that the T-type calcium channel enhancer SAK3 is beneficial against the deleterious effects of TAF1 gene-editing, in part, by stimulating the BDNF/AKT/GSK3β signaling pathway.
• Janakiraman, U., Dhanalakshmi, C., Yu, J., Moutal, A., Boinon, L., Fukunaga, K., Khanna, R., & Nelson, M. A. (2020). The investigation of the T-type calcium channel enhancer SAK3 in an animal model of TAF1 intellectual disability syndrome. Neurobiology of disease, 143, 105006.
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  T-type calcium channels, in the central nervous system, are involved in the pathogenesis of many neurodegenerative diseases, including TAF1 intellectual disability syndrome (TAF1 ID syndrome). Here, we evaluated the efficacy of a novel T-type Ca channel enhancer, SAK3 (ethyl 8'-methyl-2', 4-dioxo-2-(piperidin-1-yl)-2'H-spiro [cyclopentane-1, 3'-imidazo [1, 2-a] pyridine]-2-ene-3-carboxylate) in an animal model of TAF1 ID syndrome. At post-natal day 3, rat pups were subjected to intracerebroventricular (ICV) injection of either gRNA-control or gRNA-TAF1 CRISPR/Cas9 viruses. At post-natal day 21 animals were given SAK3 (0.25 mg/kg, p.o.) or vehicle up to post-natal day 35 (i.e. 14 days). Rats were subjected to behavioral, morphological, electrophysiological, and molecular studies. Oral administration of SAK3 (0.25 mg/kg, p.o.) significantly rescued the behavior abnormalities in beam walking test and open field test caused by TAF1 gene editing. We observed an increase in calbindin-positive Purkinje cells and GFAP-positive astrocytes as well as a decrease in IBA1-positive microglia cells in SAK3-treated animals. In addition, SAK3 protected the Purkinje and granule cells from apoptosis induced by TAF-1 gene editing. SAK3 also restored the excitatory post synaptic current (sEPSCs) in TAF1 edited Purkinje cells. Finally, SAK3 normalized the BDNF/AKT signaling axis in TAF1 edited animals. Altogether, these observations suggest that SAK3 could be a novel therapeutic agent for TAF1 ID syndrome.
• Nelson, M. A. (2018). TAF1-gene editing impairs Purkinje cell morphology and function. Neurobiology of Disease.
• Vrba, L., Oshiro, M. M., Kim, S. S., Garland, L. L., Placencia, C., Mahadevan, D., Nelson, M. A., & Futscher, B. W. (2019). DNA methylation biomarkers discovered detect cancer in liquid biopsies from non-small cell lung cancer patients. Epigenetics, 1-12.
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  Identification of cancer-specific methylation of DNA released by tumours can be used for non-invasive diagnostics and monitoring. We previously reported identification of DNA methylation loci specifically hypermethylated in common human cancers that could be used as epigenetic biomarkers. Using DNA methylation specific qPCR we now clinically tested a group of these cancer-specific loci on cell-free DNA (cfDNA) extracted from the plasma fraction of blood samples from healthy controls and non-small cell lung cancer (NSCLC) patients. These DNA methylation biomarkers distinguish lung cancer cases from controls with high sensitivity and specificity (AUC = 0.956), and furthermore, the signal from the markers correlates with tumour size and decreases after surgical resection of lung tumours. Presented observations suggest the clinical value of these DNA methylation biomarkers for NSCLC diagnostics and monitoring. Since we successfully validated the biomarkers using independent DNA methylation data from multiple additional common carcinoma cohorts (bladder, breast, colorectal, oesophageal, head and neck, pancreatic or prostate cancer) we predict that these DNA methylation biomarkers will detect additional carcinoma types from plasma samples as well.
• Khanna, R., Parker, S. S., Khanna, M., Hammer, M., Rice, S. A., Nelson, M. A., Nelson, M. A., Rice, S. A., Hammer, M., Khanna, M., Parker, S. S., & Khanna, R. (2018). A Novel Variant of the TAF1 Gene Associated with Cerebellar Atrophy Discovered Using Genomic and Transcriptomic Sequencing. Neuronal Signaling, 2(3).
• Nelson, M. A. (2018). A Novel Mutation in TAF1 Affects Gene Expression and is Associated with X-linked TAF1 Intellectual Disability Syndrome. Neuronal Signaling.
• Briehl, M. M., Nelson, M. A., Krupinski, E. A., Erps, K. A., Holcomb, M. J., Weinstein, R. S., & Weinstein, J. B. (2016). Flexer 2.0–Longitudinal study of student participation in a campus-wide general pathology course for graduate students. Academic Pathology, 3, 1-13. doi:10.1177/2374289516680217
• Hanlon, K. E., Lozano-Ondoua, A. N., Umaretiya, P. J., Symons-Liguori, A. M., Chandramouli, A., Moy, J. K., Kwass, W. K., Mantyh, P. W., Nelson, M. A., & Vanderah, T. W. (2016). Modulation of breast cancer cell viability by a cannabinoid receptor 2 agonist, JWH-015, is calcium dependent. Breast cancer (Dove Medical Press), 8, 59-71.
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  Cannabinoid compounds, both nonspecific as well as agonists selective for either cannabinoid receptor 1 (CB1) or cannabinoid receptor 2 (CB2), have been shown to modulate the tumor microenvironment by inducing apoptosis in tumor cells in several model systems. The mechanism of this modulation remains only partially delineated, and activity induced via the CB1 and CB2 receptors may be distinct despite significant sequence homology and structural similarity of ligands.
• Nelson, M. A., Briehl, M. M., Krupinski, E. A., Erps, K. A., Holcomb, M. J., Weinstein, J. B., & Weinstein, R. S. (2016). Flexner 2.0- Longitudinal study of student participation in a campus -wide general pathology course for graduate students at the University of Arizona. Academic Pathology, 3, 1-13.
• Babiker, H. M., Green, M. R., Nelson, M. A., & Elquza, E. (2015). Oxaliplatin-induced neuropathy: a tale of two electrolytes. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 23(6), 1483-5.
• Bucur, O., Almasan, A., Zubarev, R., Friedman, M., Nicolson, G. L., Sumazin, P., Leabu, M., Nikolajczyk, B. S., Avram, D., Kunej, T., Calin, G. A., Godwin, A. K., Adami, H., Zaphiropoulos, P. G., Richardson, D. R., Schmitt-Ulms, G., Westerblad, H., Keniry, M., Grau, G. E., , Carbonetto, S., et al. (2015). An updated h-index measures both the primary and total scientific output of a researcher. Discoveries, 3(3).
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  The growing interest in scientometry stems from ethical concerns related to the proper evaluation of scientific contributions of an author working in a hard science. In the absence of a consensus, institutions may use arbitrary methods for evaluating scientists for employment and promotion. There are several indices in use that attempt to establish the most appropriate and suggestive position of any scientist in the field he/she works in. A scientist's Hirsch-index (h-index) quantifies their total effective published output, but h-index summarizes the total value of their published work without regard to their contribution to each publication. Consequently, articles where the author was a primary contributor carry the same weight as articles where the author played a minor role. Thus, we propose an updated h-index named Hirsch(p,t)-index that informs about both total scientific output and output where the author played a primary role. Our measure, h(p,t) = h(p),h(t), is composed of the h-index h(t) and the h-index calculated for articles where the author was a key contributor; i.e. first/shared first or senior or corresponding author. Thus, a h(p,t) = 5,10 would mean that the author has 5 articles as first, shared first, senior or corresponding author with at least 5 citations each, and 10 total articles with at least 10 citations each. This index can be applied in biomedical disciplines and in all areas where the first and last position on an article are the most important. Although other indexes, such as r- and w-indexes, were proposed for measuring the authors output based on the position of researchers within the published articles, our simpler strategy uses the already established algorithms for h-index calculation and may be more practical to implement.
• Mercado-Pimentel, M. E., Onyeagucha, B. C., Li, Q., Pimentel, A. C., Jandova, J., & Nelson, M. A. (2015). Research Article: The S100P/RAGE-Receptor Signaling Regulates Expression of microRNA-21 in colon cancer cells. FEBS Letters, 589(18), 2388-2393. doi:10.1016/j.febslet.2015.07.010
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  S100P signaling through the receptor for advanced glycation end-products (RAGE) contributes to colon cancer invasion and metastasis, but the mechanistic features of this process are obscure. Here, we investigate whether activation of S100P/RAGE signaling regulates oncogenic microRNA-21 (miR-21). We show that exogenous S100P up-regulates miR-21 levels in human colon cancer cells, whereas knockdown of S100P results in a decrease of miR-21. Furthermore, blockage of RAGE with anti-RAGE antibody suppresses S100P induction of miR-21. In addition, we found that S100P induction of miR-21 expression involves ERK and is suppressed by the MEK inhibitor U0126. Also, S100P treatment stimulates the enrichment of c-Fos, and AP-1 family members, at the miR-21 gene promoter.
• Mercado-Pimentel, M. E., Onyeagucha, B. C., Li, Q., Pimentel, A. C., Jandova, J., & Nelson, M. A. (2015). The S100P/RAGE signaling pathway regulates expression of microRNA-21 in colon cancer cells. FEBS letters, 589(18), 2388-93.
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  S100P signaling through the receptor for advanced glycation end-products (RAGE) contributes to colon cancer invasion and metastasis, but the mechanistic features of this process are obscure. Here, we investigate whether activation of S100P/RAGE signaling regulates oncogenic microRNA-21 (miR-21). We show that exogenous S100P up-regulates miR-21 levels in human colon cancer cells, whereas knockdown of S100P results in a decrease of miR-21. Furthermore, blockage of RAGE with anti-RAGE antibody suppresses S100P induction of miR-21. In addition, we found that S100P induction of miR-21 expression involves ERK and is suppressed by the MEK inhibitor U0126. Also, S100P treatment stimulates the enrichment of c-Fos, and AP-1 family members, at the miR-21 gene promoter.
• Nelson, M., Baines, A., Taylor-Parker, M., Goulet, A., Renaud, C., Gerner, E. W., & Nelson, M. A. (0). Selenomethionine inhibits growth and suppresses cyclooxygenase-2 (COX-2) protein expression in human colon cancer cell lines. Cancer biology & therapy, 1(4).
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  Currently, selenium (in the form of high selenium containing yeast or selenomethionine) is being evaluated for anticancer effects against both human colon polyp recurrence and human prostate cancer, respectively. Chemical speciation analysis of the high selenium containing yeast indicates that selenomethionine (SeMet) is a major constituent of selenized yeast. We tested the hypothesis that SeMet might affect colon cancer cell growth by mechanisms involving cyclooxygenases (COX). The growth of all four-colon cancer cell lines tested was inhibited by selenomethionine. Furthermore, selenomethionine decreased COX-2 protein and PGE2 levels in HCA-7 cells. Selenomethionine suppressed COX-2 RNA levels in HCA-7 cells which could account for decreased COX-2 protein levels. Finally, the addition of PGE2 protected cells from the antiproliferative effects of selenomethionine in a concentration dependent manner. Selenomethionine might regulate COX-2 at the transcriptional level. These data suggests that Se-Met-induced cell growth inhibition may be, in part, mediated by COX-2 dependent mechanisms. The results of this study support the use of selenium agents in colon cancer chemoprevention trials.
• Nelson, M., Goulet, A., Einsphar, J. G., Alberts, D. S., Beas, A., Burk, C., Bhattacharyya, A., Bangert, J., Harmon, J. M., Fujiwara, H., Koki, A., & Nelson, M. A. (0). Analysis of cyclooxygenase 2 (COX-2) expression during malignant melanoma progression. Cancer biology & therapy, 2(6).
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  Cyclooxygenase 2 (COX-2) is an inducible enzyme involved in the production of prostaglandins and thromboxanes during inflammation. There are now several lines of evidence indicating that increased expression of COX-2 plays a functional role in the development and progression of malignant epithelial cancers. However, there is only limited data regarding the role of COX-2 in melanoma pathogenesis. In the present work, we retrospectively examined lesions through out the development of melanoma and metastatic disease (dysplastic nevi n = 10, melanoma in situ n = 4, stage II melanoma n = 10, stage III n = 4, stage IV n = 3, stage V n = 2, melanoma metastasis lymph nodes n = 13 metastasis to other sites n = 3). COX-2 was consistently observed in keratinocytes, dermal fibroblasts, and inflammatory cells in regions adjacent to benign evi and primary cutaneous melanomas. However, no COX-2 staining was detected in the nevi nor in the primary skin melanoma cells. In addition, COX-2 was undetected in all vertical and radial growth phase cases Interestingly, 13 out of 13 of the lymph node metastasis expressed extremely high levels of COX-2 in overlying epithelium and inflammatory cells, and COX-2 was strongly detected in the metastatic cancer cells per se. For additional information on the expression of COX-2 in malignant melanoma, we determined the expression of COX-2 protein in several different melanoma cell lines. We found that 3We found that 5 out of 7 of the melanoma cells over expressed COX-2 compared to normal melanocytes. Collectively, these data suggest that COX-2 may play a functional role in metastases of melanoma, and treatment with COX-2 inhibitors may be efficacious for malignant melanoma.
• Nelson, M., Hutchison, J., Cohen, Z., Onyeagucha, B. C., Funk, J., & Nelson, M. A. (2013). How microRNAs influence both hereditary and inflammatory-mediated colon cancers. Cancer genetics.
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  MicroRNAs have emerged as important post-translational regulators of gene expression and are involved in several physiological and pathological states including the pathogenesis of human colon cancers. In regards to tumor development, microRNAs can act as oncogenes or tumor suppressors. Two hereditary predispositions (i.e., Lynch syndrome and familial adenomatous polyposis) contribute to the development of colon cancer. In addition, individuals who suffer from inflammatory bowel diseases such as Crohn's disease or ulcerative colitis have a higher risk of developing colon cancer. Here, we discuss the occurrence of the deregulated expression of microRNAs in colon cancer that arise as a result of hereditary predisposition and inflammatory bowel disease.
• Nelson, M., Onyeagucha, B. C., Mercado-Pimentel, M. E., Hutchison, J., Flemington, E. K., & Nelson, M. A. (2013). S100P/RAGE signaling regulates microRNA-155 expression via AP-1 activation in colon cancer. Experimental cell research, 319(13).
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  Accumulating evidence indicates that elevated S100P promotes the pathogenesis of cancers, including colon cancer. S100P exerts its effects by binding to and activating the Receptor for Advance Glycation End-products (RAGE). The effects of up-regulated S100P/RAGE signaling on cell functions are well documented. Despite these observations, little is known about the downstream targets of S100P/RAGE signaling. In the present study, we demonstrated for the first time that activation of RAGE by S100P regulates oncogenic microRNA-155 (miR-155) expression through Activator Protein-1 (AP-1) stimulation in colon cancer cells. Ectopic S100P up-regulated miR-155 levels in human colon cancer cells. Conversely, knockdown of S100P resulted in a decrease in miR-155 levels. Exogenous S100P induced miR-155 expression, but blockage of the RAGE with anti-RAGE antibody suppressed the induction of miR-155 by exogenous S100P. Attenuation of AP-1 activation through pharmacological inhibition of MEK activation or genetic inhibition of c-Jun activation using dominant negative c-Jun (TAM67) suppressed miR-155 induction by exogenous S100P. Also, S100P treatment stimulated the enrichment of c-Fos, an AP-1 family member, at the miR-155 host gene promoter site. Finally, a functional study demonstrated that miR-155 knockdown decreases colon cancer cell growth, motility, and invasion. Altogether, these data demonstrate that the expression of miR-155 is regulated by S100P and is dependent on RAGE activation and stimulation of AP-1.
• Nelson, M., Chandramouli, A., Onyeagucha, B. C., Mercado-Pimentel, M. E., Stankova, L., Shahin, N. A., LaFleur, B. J., Heimark, R. L., Bhattacharyya, A. K., & Nelson, M. A. (2012). MicroRNA-101 (miR-101) post-transcriptionally regulates the expression of EP4 receptor in colon cancers. Cancer biology & therapy, 13(3).
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  Expression of the PGE2 receptor, EP4, is up-regulated during colorectal carcinogenesis. However the mechanism leading to deregulation of the EP4 receptor is not known. The present study was conducted to investigate the regulation of EP4 receptor by miRNAs.
• Nelson, M., Shi, J., Hershey, J. W., & Nelson, M. A. (2009). Phosphorylation of the eukaryotic initiation factor 3f by cyclin-dependent kinase 11 during apoptosis. FEBS letters, 583(6).
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  eIF3f is a subunit of eukaryotic initiation factor 3 (eIF3). We previously showed that eIF3f is phosphorylated by cyclin dependent kinase 11 (CDK11(p46)) which is an important effector in apoptosis. Here, we identified a second eIF3f phosphorylation site (Thr119) by CDK11(p46) during apoptosis. We demonstrated that eIF3f is directly phosphorylated by CDK11(p46) in vivo. Phosphorylation of eIF3f plays an important role in regulating its function in translation and apoptosis. Phosphorylation of eIF3f enhances the association of eIF3f with the core eIF3 subunits during apoptosis. Our data suggested that eIF3f may inhibit translation by increasing the binding to the eIF3 complex during apoptosis.
• Nelson, M., Cherukuri, D. P., & Nelson, M. A. (2008). Role of reactive oxygen species (ROS) and JNKs in selenite-induced apoptosis in HepG2 cells. Cancer biology & therapy, 7(5).
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  Dietary selenium (Se) supplementation has been shown to be effective against reducing the risk of incidence of different human cancers. Selenium exists in both organic and inorganic forms. Different chemical forms of selenium metabolize differently in vivo, activate distinct molecular mechanisms and exhibit varying degree of anti-carcinogenicity in different cancer types. The effectiveness of a Se compound could also vary depending on the genetic background of the tumor cells. Therefore, understanding the molecular mechanism(s) by which different Se compounds exert their anti-tumorigenic effects is necessary for their use in cancer chemoprevention.
• Nelson, M., & Nelson, M. A. (2007). Inhibition of lipoxygenase activity: implications for the treatment and chemoprevention of prostate cancer. Cancer biology & therapy, 6(2).
• Nelson, M., Chandramouli, A., Shi, J., Feng, Y., Holubec, H., Shanas, R. M., Bhattacharyya, A. K., Zheng, W., & Nelson, M. A. (2007). Haploinsufficiency of the cdc2l gene contributes to skin cancer development in mice. Carcinogenesis, 28(9).
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  The Cdc2L gene encodes for the cyclin-dependent kinase 11 (CDK11) protein. Loss of one allele of Cdc2L and reduced CDK11 expression has been observed in several cancers, implicating its association with carcinogenesis. To directly investigate the role of CDK11 in carcinogenesis, we first generated cdc2l haploinsufficient mice by gene trap technology and then studied the susceptibility of these gene-trapped (cdc2l(GT)) mice to chemical-mediated skin carcinogenesis in the 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced two-stage skin carcinogenesis model. Wild-type and cdc2l(GT) mice were subjected to a single topical application of initiation by DMBA and promotion twice a week for 19 weeks with TPA. At 19 weeks, 70% of the cdc2l(GT) mice and 60% of the cdc2l+/+ mice developed benign papillomas. However, there was an overall 3-fold increase in the average number of tumors per mouse observed in cdc2l(GT) mice as compared with cdc2l+/+ mice. There was also an increased frequency of larger papillomas in cdc2l(GT) mice. By using the polymerase chain reaction-restriction fragment length polymorphism assay, we found A to T transversion mutations at the 61st codon of H-ras gene in the papilloma tissue of both cdc2l(GT) mice and cdc2l+/+ mice. Ki-67 staining revealed increased proliferation in the papillomas of cdc2l(GT) (77.75%) as compared with cdc2l+/+ (30.84%) tumors. These studies are the first to show that loss of one allele of cdc2l gene, encoding CDK11, facilitates DMBA/TPA-induced skin carcinogenesis in vivo.
• Nelson, M., Cherukuri, D. P., Chen, X. B., Goulet, A., Young, R. N., Han, Y., Heimark, R. L., Regan, J. W., Meuillet, E., & Nelson, M. A. (2007). The EP4 receptor antagonist, L-161,982, blocks prostaglandin E2-induced signal transduction and cell proliferation in HCA-7 colon cancer cells. Experimental cell research, 313(14).
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  Accumulating evidence indicates that elevated levels of prostaglandin E(2) (PGE(2)) can increase intestinal epithelial cell proliferation, and thus play a role in colorectal tumorigenesis. PGE(2) exerts its effects through four G-protein-coupled PGE receptor (EP) subtypes, named the EP1, EP2, EP3, and EP4. Increased phosphorylation of extracellular regulated kinases (ERK1/2) is required for PGE(2) to stimulate cell proliferation of human colon cancer cells. However, the EP receptor(s) that are involved in this process remain unknown. We provide evidence that L-161,982, a selective EP4 receptor antagonist, completely blocks PGE(2)-induced ERK phosphorylation and cell proliferation of HCA-7 cells. In order to identify downstream target genes of ERK1/2 signaling, we found that PGE(2) induces expression of early growth response gene-1 (EGR-1) downstream of ERK1/2 and regulates its expression at the level of transcription. PGE(2) treatment induces phosphorylation of cyclic AMP response element binding protein (CREB) at Ser133 residue and CRE-mediated luciferase activity in HCA-7 cells. Studies with dominant-negative CREB mutant (ACREB) provide clear evidence for the involvement of CREB in PGE(2) driven egr-1 transcription in HCA-7 cells. In conclusion, this study reveals that egr-1 is a target gene of PGE(2) in HCA-7 cells and is regulated via the newly identified EP4/ERK/CREB pathway. Finally our results support the notion that antagonizing EP4 receptors may provide a novel therapeutic approach to the treatment of colon cancer.
• Nelson, M., Goulet, A., Watts, G., Lord, J. L., & Nelson, M. A. (2007). Profiling of selenomethionine responsive genes in colon cancer by microarray analysis. Cancer biology & therapy, 6(4).
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  High-selenium containing yeast is being evaluated in clinical trials against colon polyp recurrence. However, the molecular targets for the anticancer effects of selenium remain unclear. Previous studies by our group demonstrated that selenomethionine-induced growth arrest appears to be mediated by activation of ERK and subsequent phosphorylation of RSK and histone H3. These results suggest that selenomethionine can alter gene expression. In the present study, we have used cDNA microarrays to determine whether gene expression differences exist in HCT116 colon cancer cells treated with selenomethionine. These experiments reveal statistically significant expression changes for 50 genes. Genes we found to increase with selenomethionine treatment include KLK6, ATOX1, SGK, GJB2, DAP-1, PLAU, VIM, DPYSL2, STC2 and PXN. Conversely, genes downregulated by selenomethionine include PRKACB, LIM, DEPP, MYC, CDH5, ELF3, VSNL1, SAT and EGLN3. Further analysis of those genes using chromatin immunoprecipitation experiments showed that phosphorylated histone H3 on serine 10 bound to the GJB2 promoter (connexin 26) or the serum glucocorticoid kinase promoter is increased with selenomethionine treatment. Cells overexpressing CX26 or DAP-1 displayed a reduced number of colonies which suggests that these two genes could play a functional role in the growth inhibitory effects of selenomethionine. These data support the notion that selenomethionine-induced growth inhibition is associated with global changes in gene expression. They also demonstrate that selenomethionine can modify chromatin state to alter gene transcription. Finally, our studies provide a practical foundation for the further development of biomarkers to monitor the efficacy of selenomethionine in clinical trials.
• Nelson, M., Shi, J., Kahle, A., Hershey, J. W., Honchak, B. M., Warneke, J. A., Leong, S. P., & Nelson, M. A. (2006). Decreased expression of eukaryotic initiation factor 3f deregulates translation and apoptosis in tumor cells. Oncogene, 25(35).
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  The eukaryotic initiation factor 3f (eIF3f) is the p47 subunit of the multi-subunit eIF3 complex. eIF3 plays an important role in translation initiation. In the present study, we investigate the biological function of eIF3f in translation and apoptosis in tumor cells. We demonstrated for the first time that eIF3f is downregulated in most human tumors using a cancer profiling array and confirmed by real-time reverse transcription PCR in melanoma and pancreatic cancer. Overexpression of eIF3f inhibits cell proliferation and induces apoptosis in melanoma and pancreatic cancer cells. Silencing of eIF3f protects melanoma cells from apoptosis. We further investigated the biological function of eIF3f. In vitro translation studies indicate that eIF3f is a negative regulator of translation and that the region between amino acids 170 and 248 of eIF3f is required for its translation regulatory function. Ectopic expression of eIF3f inhibits translation and overall cellular protein synthesis. Ribosome profile and ribosomal RNA (rRNA) fragmentation assays revealed that eIF3f reduces ribosomes, which may be associated with rRNA degradation. We propose that eIF3f may play a role in ribosome degradation during apoptosis. These data provide critical insights into the cellular function of eIF3f and in linking translation initiation and apoptosis.
• Nelson, M., Baruch, A. C., Shi, J., Feng, Y., & Nelson, M. A. (2005). New developments in the staging of melanoma. Cancer investigation, 23(6).
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  As the incidence of melanoma increases, so does the search for new staging techniques that may provide important prognostic information and aid in the detection of early metastatic disease. The application of molecular techniques may provide powerful new tools in this search. This review summarizes recent findings obtained by means of conventional RT-PCR, cDNA arrays, and proteomics in the investigation of human melanoma. The molecular tools discussed in this review demonstrate how global transcript and protein analysis might contribute not only to the staging of melanoma, but may hold great promise in improving the diagnosis and treatment of this disease.
• Nelson, M., Cherukuri, D. P., & Nelson, M. A. (2005). Could the combination of celecoxib and 4HPR be an effective lung cancer treatment?. Cancer biology & therapy, 4(8).
• Nelson, M., Cherukuri, D. P., Goulet, A., Inoue, H., & Nelson, M. A. (2005). Selenomethionine regulates cyclooxygenase-2 (COX-2) expression through nuclear factor-kappa B (NF-kappaB) in colon cancer cells. Cancer biology & therapy, 4(2).
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  Previously, we showed that selenomethionine (Se-Met) inhibits growth of colon cancer cells via suppressing COX-2 expression at both mRNA and protein level. However, the molecular mechanism by which Se-Met suppresses COX-2 expression remains to be elucidated. To this end, we transiently transfected HCA-7 cells with different COX-2 promoter constructs followed by Se-Met treatment (90 microM) for 12 h. The results suggested the role of nuclear factor-kappa B (NF-kappaB) in transcriptional regulation of COX-2. We also observed complete inhibition of DNA binding activity of NF-kappaB in Se-Met (90 microM) treated HCA-7 cells as shown by electrophoretic mobility shift assay (EMSA). Supershift assays with anti-p65 antibody identified p65 subunit in the protein complex. We further demonstrate dose-dependent inhibition of nuclear translocation of NF-kappaB/p65 in Se-Met treated HCA-7 cells, which could explain the observed reduction in DNA binding of NF-kappaB/p65. These results suggest that Se-Met regulates COX-2 at transcriptional level by modulating the activity of NF-kappaB transcription factor.
• Nelson, M., Feng, Y., Ariza, M. E., Goulet, A., Shi, J., & Nelson, M. A. (2005). Death-signal-induced relocalization of cyclin-dependent kinase 11 to mitochondria. The Biochemical journal, 392(Pt 1).
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  Fas receptor-Fas ligand interaction appears to be important in carcinogenesis, tumour outgrowth and metastasis. Emerging evidence suggests that CDK11 (cyclin-dependent kinase 11) plays a role in apoptosis and melanoma development. Here, we show that CDK11p110 protein kinase was cleaved after induction of apoptosis by Fas. The N-terminal portion of CDK11p110, CDK11p60, was translocated from the nucleus to the mitochondria. The targeting of CDK11p60 to mitochondria occurred as early as 12 h after treatment. Overexpression of EGFP (enhanced green fluorescent protein)-tagged CDK11p60 could partially break down the mitochondrial membrane potential, induce cytochrome c release and promote apoptosis. Reduction of endogenous CDK11p110 protein levels with siRNA (small interfering RNA) resulted in the suppression of both cytochrome c release and apoptosis. In addition, subcellular fractionation studies of Fas-mediated apoptosis demonstrated that CDK11p60 was associated with the mitochondrial import motor, mitochondrial heat shock protein 70. Taken together, our data suggest that CDK11p60 can contribute to apoptosis by direct signalling at the mitochondria, thereby amplifying Fas-induced apoptosis in melanoma cells.
• Nelson, M., Feng, Y., Qi, W., Martinez, J., & Nelson, M. A. (2005). The cyclin-dependent kinase 11 interacts with 14-3-3 proteins. Biochemical and biophysical research communications, 331(4).
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  Cyclin-dependent kinase 11 isoforms (CDK11) are members of the p34(cdc2) superfamily. They have been shown to play a role in RNA processing and apoptosis. In the present study, we investigate whether CDK11 interacts with 14-3-3 proteins. Our study shows that the putative 14-3-3 binding site (113-RHRSHS-118) within the N-terminal domain of CDK11(p110) is functional. Endogenous CDK11(p110) binds directly to 14-3-3 proteins and phosphorylation of the serine 118 within the RHRSHS motif seems to be required for the binding. Besides, CDK11(p110) is capable of interacting with several different isoforms of 14-3-3 proteins both in vitro and in vivo. The interaction of 14-3-3 gamma with CDK11(p110) occurs throughout the entire cell cycle and reaches maximum at the G2/M phase. Interestingly, 14-3-3 gamma shows strong interaction with N-terminal portion of caspase-cleaved CDK11(p110) (CDK11(p60)) product at 48 h after Fas treatment, which correlates with the maximal cleavage level of CDK11(p110) and the maximum activation level of CDK11 kinase activity during apoptosis. Collectively, these results suggest that CDK11 kinases could be regulated by interaction with 14-3-3 proteins during cell cycle and apoptosis.
• Nelson, M., Goulet, A., Chigbrow, M., Frisk, P., & Nelson, M. A. (2005). Selenomethionine induces sustained ERK phosphorylation leading to cell-cycle arrest in human colon cancer cells. Carcinogenesis, 26(1).
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  Selenomethionine (SeMet) is being tested alone and in combination with other agents in cancer chemoprevention trials. However, the molecular targets and the signaling mechanism underlying the anticancer effect of this compound are not completely clear. Here, we provide evidence that SeMet can induce cell-growth arrest and that the growth inhibition is associated with S-G2/M cell-cycle arrest. Coincidentally with the cell-cycle arrest, we observed a striking increase in cyclin B as well as phosphorylation of the cyclin-dependent kinase Cdc2. Since activation of the mitogen-activated protein kinase (MAPK) cascade has been associated with cell-cycle arrest and growth inhibition, we evaluated the activation of extracellular signal-regulated kinase (ERK). We found that SeMet induced phosphorylation of the MAPK ERK in a dose-dependent manner. We also demonstrate phosphorylation of ribosomal S6 kinase (p90RSK) by SeMet. Additionally, we show phosphorylation of histone H3 in a concentration-dependent manner. Furthermore, the phosphorylation of p90RSK and histone H3 were both antagonized by the MEK inhibitor U0126, implying that SeMet-induced phosphorylation of p90RSK and histone H3 are at least in part ERK pathway dependent. Based on these results, we propose that SeMet induced growth arrest and phosphorylation of histone H3 are mediated by persistent ERK and p90RSK activation. These new data provide valuable insights into the biological effects of SeMet at clinically relevant concentrations.
• Nelson, M., Shi, J., & Nelson, M. A. (2005). The cyclin-dependent kinase 11 interacts with NOT2. Biochemical and biophysical research communications, 334(4).
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  The caspase-processed cyclin-dependent kinase 11 (formerly known as PITSLRE) is implicated in apoptotic signaling. However, the mechanism of apoptotic signal transduction through CDK11(p46) is still unclear. We used a yeast two-hybrid screening strategy and identified NOT2 as an interacting partner of caspase-processed C-terminal kinase domain of CDK11 (CDK11(p46)). We demonstrate that CDK11(p46) directly interacts with NOT2 in vitro and in human cells. The NOT domain in the C-terminal part of NOT2 is responsible for the association between CDK11(p46) and NOT2. Both NOT2 and CDK11(p46) predominantly co-localized in the nucleus. Furthermore, we show that overexpression of NOT2 reduces luciferase mRNA and induces apoptosis. However, NOT2 is not phosphorylated by CDK11(p46). These findings suggest that CDK11 may contribute to apoptosis by regulating the activity of NOT2 independent of its kinase activity.
• Nelson, M., Cherukuri, D. P., & Nelson, M. A. (2004). Do elevated levels of eicosanoids play a role in head and neck cancer recurrence and metastasis? Implications for prevention and treatment. Cancer biology & therapy, 3(9).
• Nelson, M., Cherukuri, D. P., & Nelson, M. A. (2004). Glioma growth inhibition by selective COX-2 inhibitors via cyclooxygenase independent pathways: implications for therapy. Cancer biology & therapy, 3(1).
• Nelson, M., Feng, Y., Goulet, A., & Nelson, M. A. (2004). Identification and characterization of the human Cdc2l2 gene promoter. Gene, 330.
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  The CDK11 (cyclin-dependent kinase 11, formerly known as PITSLRE) protein kinases are part of the large family of p34(cdc2)-related kinases and have been shown to play a role in cell cycle progression, RNA processing and apoptosis. They are encoded by two genes-cell division control like 1 (Cdc2L1) and cell division control like 2 (Cdc2L2). To date, little is known about the transcription factors controlling their expression. To understand the mechanisms underlying the regulation of CDK11 gene expression, we cloned and identified the Cdc2L2 promoter and determined its transcriptional regulatory elements. By deletion analysis, a region between nucleotides -145 and +10 was identified to be critical for basal level transcription of the Cdc2L2 gene. Sequencing analysis revealed that the proximal promoter of the Cdc2L2 gene is GC rich and does not contain TATA and CAAT boxes. However, multiple consensus and near consensus transcription factor binding sites were found to be present in this region, such as two Ets-1, one cAMP-responsive element (CRE) and one TCF11/LCR-F1/Nrf1 binding sites. Site-directed mutagenesis and transfection studies revealed that all these binding sites were necessary to achieve sustained transcriptional activity. Electrophoretic mobility shift assay confirmed that transcription factors Ets-1 and CREB bind to the Cdc2L2 promoter elements, indicating their potential role in the transcriptional regulation of Cdc2L2 gene. More importantly, Ets-1, CREB and phosphorylated CREB were found binding to the endogenous Cdc2L2 promoter using chromatin immunoprecipitation (CHIP) assay. Our results provide the foundation for further studies into the regulation of Cdc2L2 gene expression in normal homeostasis and cancer.
• Nelson, M., Meuillet, E., Stratton, S., Prasad Cherukuri, D., Goulet, A., Kagey, J., Porterfield, B., & Nelson, M. A. (2004). Chemoprevention of prostate cancer with selenium: an update on current clinical trials and preclinical findings. Journal of cellular biochemistry, 91(3).
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  Prostate cancer is the most common cancer diagnosed and the second leading cause of cancer-related deaths in men in the United States. The etiological factors that give rise to prostate cancer are not known. Therefore, it is not possible to develop primary intervention strategies to remove the causative agents from the environment. However, secondary intervention strategies with selenium (Se) compounds and other agents represent a viable option to reduce the morbidity and mortality of prostate cancer. In this review, we discuss ongoing clinical trials. In addition, we discuss preclinical mechanistic studies that provide insights into the biochemical and molecular basis for the anti-carcinogenic activity of both inorganic and organic forms of Se.
• Nelson, M., Mikolajczyk, M., & Nelson, M. A. (2004). Regulation of stability of cyclin-dependent kinase CDK11p110 and a caspase-processed form, CDK11p46, by Hsp90. The Biochemical journal, 384(Pt 3).
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  CDK11p110 (cyclin-dependent kinase 11p110, formerly known as PITSLRE) is a member of the CDK superfamily. It associates with cyclin L and is involved in the regulation of transcription and in premRNA splicing. During staurosporine-, Fas- and tumour necrosis factor a-induced apoptosis, CDK11p110, is cleaved by caspases to generate smaller 46-50 kDa proteins containing the catalytic kinase domain. Ectopic expression of the caspase-processed form CDK11p46 induces apoptosis. The mechanisms that regulate activation and stability of CDK11 isoforms are still unclear. In the present study, we demonstrate that in human melanoma cells CDK11p110 and CDK11p46 interact with Hsp90 (heat-shock protein 90) and its co-chaperone cdc37. Furthermore, we show that the treatment of cells with the Hsp90-specific inhibitor geldanamycin leads to ubiquitination and enhanced degradation of both CDK11p110 and CDK11p46 through a proteasome-dependent pathway. We also determined that geldanamycin-triggered degradation of CDK11p46 slows down the progression of apoptosis. These results indicate that Hsp90 and cdc37 stabilize CDK11 kinase, and suggest that this stabilization is crucial for its pro-apoptotic function.
• Nelson, M., Mikolajczyk, M., Shi, J., Vaillancourt, R. R., Sachs, N. A., & Nelson, M. A. (2003). The cyclin-dependent kinase 11(p46) isoform interacts with RanBPM. Biochemical and biophysical research communications, 310(1).
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  We identified Ran-binding protein (RanBPM) as an interacting partner of the caspase-processed C-terminal domain of cyclin-dependent kinase 11 (CDK11(p46)) by using the yeast two-hybrid system. CDK11(p110) protein kinases are members of the cyclin-dependent kinase superfamily. During staurosporine-, Fas-, and tumor necrosis factor alpha-induced apoptosis caspase-processed activated CDK11(p46) is generated from larger CDK11(p110) isoforms. CDK11(p46) promotes apoptosis when it is ectopically expressed in human cells. However, the mechanism of signal transduction through CDK11(p46) is still unclear. In this study, we demonstrate that CDK11(p46) directly interacts with RanBPM in vitro and in human cells. RanBPM contains a conserved SPRY (repeats in splA and Ryr) domain and is localized both in the nucleus and cytoplasm. The SPRY domain of RanBPM is responsible for the association between CDK11(p46) and RanBPM. Furthermore, we show that CDK11(46) phosphorylates RanBPM.
• Nelson, M., Shi, J., Feng, Y., Goulet, A., Vaillancourt, R. R., Sachs, N. A., Hershey, J. W., & Nelson, M. A. (2003). The p34cdc2-related cyclin-dependent kinase 11 interacts with the p47 subunit of eukaryotic initiation factor 3 during apoptosis. The Journal of biological chemistry, 278(7).
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  Cyclin-dependent kinase 11 (CDK11; also named PITSLRE) is part of the large family of p34(cdc2)-related kinases whose functions appear to be linked with cell cycle progression, tumorigenesis, and apoptotic signaling. However, substrates of CDK11 during apoptosis have not been identified. We used a yeast two-hybrid screening strategy and identified eukaryotic initiation factor 3 p47 protein (eIF3 p47) as an interacting partner of caspase-processed C-terminal kinase domain of CDK11 (CDK11(p46)). We demonstrate that the eIF3 p47 can interact with CDK11 in vitro and in vivo, and the interaction can be strengthened by stimulation of apoptosis. EIF3 p47 contains a Mov34/JAB domain and appears to interact with CDK11(p46) through this motif. We show in vitro that the caspase-processed CDK11(p46) can phosphorylate eIF3 p47 at a specific serine residue (Ser(46)) and that eIF3 p47 is phosphorylated in vivo during apoptosis. Purified recombinant CDK11(p46) inhibited translation of a reporter gene in vitro in a dose-dependent manner. In contrast, a kinase-defective mutant CDK11(p46M) did not inhibit translation of the reporter gene. Stable expression of CDK11(p46) in vivo inhibited the synthesis of a transfected luciferase reporter protein and overall cellular protein synthesis. These data provide insight into the cellular function of CDK11 during apoptosis.
• Nelson, M., Baines, A. T., Holubec, H., Basye, J. L., Thorne, P., Bhattacharyya, A. K., Spallholz, J., Shriver, B., Cui, H., Roe, D., Clark, L. C., Earnest, D. L., & Nelson, M. A. (2000). The effects of dietary selenomethionine on polyamines and azoxymethane-induced aberrant crypts. Cancer letters, 160(2).
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  We evaluated the effects of dietary selenomethionine supplementation on colonic polyamine levels and the ability of L-selenomethionine supplementation to modulate the carcinogenic activity of azoxymethane (AOM) in the rat colon. Four-week-old male F344 rats were treated with 15 mg/kg body weight of AOM once a week for 2 weeks. Dietary selenomethionine at a concentration of either 1 or 2 ppm was administered in AIN-76A rodent diet to AOM-treated animals for 16 weeks. Aberrant crypt foci (ACF), precursor lesions of colon cancer, were investigated after the 16 week treatment course. Selenomethionine given in the diet at 2 ppm markedly reduced the number of aberrant crypt foci. The multiplicity of ACFs (i.e. the number of aberrant crypts/focus) and the percentage of microadenomas were also affected by selenomethionine in a dose dependent manner. However, evaluation of the colonic tissue polyamine levels between control and treated groups showed no significant difference. These results demonstrate that selenomethionine can modulate the development of AOM-induced premalignant lesions through a polyamine-independent mechanism.
• Nelson, M., Redman, C., Scott, J. A., Baines, A. T., Basye, J. L., Clark, L. C., Calley, C., Roe, D., Payne, C. M., & Nelson, M. A. (1998). Inhibitory effect of selenomethionine on the growth of three selected human tumor cell lines. Cancer letters, 125(1-2).
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  Selenium supplementation has been shown for many years to work as an anticarcinogenic agent both in epidemiology and in in vitro studies. Selenium supplementation has recently been shown to decrease total cancer incidence. However, the mechanism of action of selenium as an anticarcinogenic agent has yet to be elucidated. Selenomethionine was the predominant form of selenium in the dietary supplement in the study by Clark et al. (Clark, L.C., Combs, G.F., Turnbull, W.B., Slate, E.H., Chalker, D.K., Chow, J., Davis, L.S., Glover, R.A., Graham, G.F., Gross, E.G., Krongrad, A., Lesher, J.L., Park, H.K., Sanders, B.B., Smith, C.L., Taylor, J.R. and The Nutritional Prevention of Cancer Study Group (1996) Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin: a randomized controlled trial. J. Am. Med. Assoc., 276 (24), 1957-1963) and therefore we evaluated the growth inhibitory effects of selenomethionine against human tumor cells. Selenomethionine was tested against each of three human tumor cell lines (MCF-7/S breast carcinoma, DU-145 prostate cancer cells and UACC-375 melanoma) and against normal human diploid fibroblasts. All cell lines demonstrated a dose-dependent manner of growth inhibition by selenomethionine. Selenomethionine inhibited the growth of all of the human tumor cell lines in the micromolar (microM) range (ranging from 45 to 130 microM) while growth inhibition of normal diploid fibroblasts required 1 mM selenomethionine, approximately 1000-fold higher than for the cancer cell lines. In short, normal diploid fibroblasts were less sensitive than the cancer cell lines to the growth inhibitory effects of selenomethionine. Furthermore, we show that selenomethionine administration to these cancer cell lines results in apoptotic cell death and aberrant mitoses. These results demonstrate the differential sensitivity of tumor cells and normal cells to selenomethionine.
• Nelson, M., Barks, J. H., Thompson, F. H., Taetle, R., Yang, J. M., Stone, J. F., Wymer, J. A., Khavari, R., Guan, X. Y., Trent, J. M., Pinkel, D., & Nelson, M. A. (1997). Increased chromosome 20 copy number detected by fluorescence in situ hybridization (FISH) in malignant melanoma. Genes, chromosomes & cancer, 19(4).
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  DNA amplification is an important mechanism of tumor progression that allows cancer cells to up-regulate the expression of critical genes such as oncogenes and genes conferring drug resistance. Recent studies using comparative genomic hybridization (CGH) revealed increased DNA copies of 20q sequences in 7 melanoma cell lines and B archival metastatic melanoma lesions. To evaluate chromosome 20 abnormalities in more detail and to resolve discrepancies between karyotype and CGH findings, we performed FISH analysis of metaphase cells in 13 melanoma cell lines (including the 7 lines used for CGH) and 9 primary melanoma specimens by using a whole chromosome paint specific for chromosome 20. All 13 cell lines (100%) and 8/9 primary tumors (89%) showed extra copies of chromosome 20 relative to tumor ploidy. Additionally, 6/14 cell lines (43%) and 2/8 primary tumors (25%) showed translocated chromosome 20 material previously undetected by standard cytogenetics. Cytologic evidence for gene amplification was also found in one cell line, which contained an add(20)(p13), with additional DNA being derived from 20q sequences. These data suggest that overrepresentation of a gene or genes important for melanoma pathogenesis resides on the long arm of chromosome 20.
• Nelson, M., Redman, C., Xu, M. J., Peng, Y. M., Scott, J. A., Payne, C., Clark, L. C., & Nelson, M. A. (1997). Involvement of polyamines in selenomethionine induced apoptosis and mitotic alterations in human tumor cells. Carcinogenesis, 18(6).
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  The efficacy of dietary selenium supplementation is currently being evaluated in intervention trials. However, the biological mechanisms underlying the cancer chemopreventive effects of selenium supplementation have yet to be elucidated. Selenium metabolism and polyamine biosynthesis are linked in their common requirement for S-adenosylmethionine. Selenomethionine was the predominant form of selenium in the dietary supplement, therefore we evaluated the anti-tumorigenic effects of selenomethionine. We found that selenomethionine inhibited tumor growth (both in A549 lung and HT29 colon cancer cells) in a dose-dependent manner. At 24 and 72 h, polyamine content of A549 and HT29 cancer cell lines was decreased at doses that inhibited 50% of normal growth. Selenomethionine treatment induced apoptosis in both cancer cell lines. Exogenous spermine administration, which replenishes intracellular polyamine levels, prevented selenomethionine induced apoptosis. Selenomethionine administration to the cancer cell lines increased the number of cells in metaphase. This cell cycle effect appeared to be reversed with the co-administration of selenomethionine and spermine. These data suggested that at least part of the anti-carcinogenic effects of selenium supplementation might be due to a depletion in polyamine levels. This depletion of polyamines leads to an induction in apoptosis and perturbations in the cell cycle.
• Nelson, M., Thompson, F. H., Taetle, R., Trent, J. M., Liu, Y., Massey-Brown, K., Scott, K. M., Weinstein, R. S., Emerson, J. C., Alberts, D. S., & Nelson, M. A. (1997). Band 1p36 abnormalities and t(1;17) in ovarian carcinoma. Cancer genetics and cytogenetics, 96(2).
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  In a series of 128 karyotyped ovarian carcinomas, 42% of cases with chromosome 1 clonal structural abnormalities had breaks at band 1p36 (usually involving translocations of unknown material). Fluorescent in situ hybridization (FISH) studies using combinations of 1 centromere and 1p36.3-specific probes (16 cases) or 1 centromeric and 17 whole-chromosome paint probes (11 cases with 1p+) revealed a trend toward deletion of 1pter relative to 1 centromere (63%); intratumor heterogeneity; and the origin of 1p+ in 3/11 cases (27%) from chromosome 17 [t(1;17)(p36;?)]. The frequency of this specific breakpoint and its involvement in recurrent translocations suggest that these regions are loci for genes important in the pathogenesis of a subset of sporadic ovarian carcinomas.
• Nelson, M., & Nelson, M. A. (1992). A microscopic comparison of fresh and burned bone. Journal of forensic sciences, 37(4).
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  Examination of the microstructure of human bone is useful in estimating age at death in forensic science cases. This technique has been tested and is well accepted, however samples of burned bone may complicate analysis because of possible changes in the microstructure occurring during the burning process. In a comparison of fresh and burned ground thin sections taken from midshaft femorae of eight dissecting-room cadavers of known age and sex, this study finds significant shrinkage of microstructural elements through the burning process. These results are compared to previous work on the subject, which found the microstructural elements to increase through the burning process.

Others

• Nelson, M., Leibovitz, A., Wymer, J., Massey, K., Thompson, F. H., & Nelson, M. A. (1994, Jul). Establishment of a new lung sarcoma cell line from a human lung carcinosarcoma. Cancer letters.
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  A cell-line (UACC 2561), was established from a biopsy specimen of a lung carcinosarcoma. The patient had Stage III non-small cell lung cancer. Characterization of this cell line revealed highly aneuploid cells containing multiple clonal chromosome alterations with growth in nude mice within 3 weeks following subcutaneous injection. The cell line UACC 2561 stained positive for vimentin and displayed resistance to a variety of chemotherapeutic agents. Polymerase chain reaction followed by single-strand conformational polymorphism analysis revealed the presence of a K-ras 12 codon mutation. This mutation was confirmed by mutation specific PCR analysis for mutant K-ras alleles and direct DNA sequencing to be a GGT to GTT at codon 12 of the K-ras gene. Examination by PCR-SSCP for p53 mutations did not reveal any point mutations in exon 5-8 of the p53 gene. This relatively rare cell line may represent a useful model to investigate human lung sarcomas.