The Link Between Selenium and Chemoprevention: A Case for Selenoproteins1
Selenium is effective in reducing cancer incidence in animal models, and epidemiologic data, as well as supplementation trials, have indicated that selenium is likely to be effective in humans. The mechanism by which selenium prevents cancer remains unknown. The mammalian genome encodes 25 selenoprotein genes, each containing one or more molecules of selenium in the form of the amino acid selenocysteine, translationally inserted into the growing peptide in response to the UGA codon. There is evidence that several of these proteins may be involved with the mechanism by which selenium provides its anti-cancer effects. Data are reviewed indicating that genetic variants of the cytosolic glutathione peroxidase are associated with increased cancer risk, and that loss of one of the copies of this same gene may be involved with malignant progression. Similarly, allelic differences in the gene for a second selenoprotein, Sep15, may be relevant to the protection provided by selenium, and allelic loss at this locus have been reported as well. These data, along with the differential expression patterns reported for other selenoproteins in tumor vs. normal tissues, support the role of selenoproteins in the chemoprotection by selenium. J. Nutr. 134: 2899-2902, 2004.
KEY WORDS: * selenium * selenoproteins * glutathione peroxidase * chemoprevention
Selenium is an intriguing essential trace element due to its potential role in influencing cancer incidence. A wealth of published experimental evidence exists indicating that selenium supplementation is effective in the reduction of cancer incidence when nontoxic doses are provided to the diet of several rodent species (1). Remarkably, selenium is effective in these animal models against a diverse group of cancer-causing agents, including irradiation, and carcinogens that form DNA adducts, and efficacy has been demonstrated in most organs examined (1). In humans, studies identified an inverse correlation between selenium intake and cancer incidence at several sites, including prostate, colon, lung, and breast (2-7). Although several large selenium supplementation trials are in progress, previous reports have suggested that selenium supplementation at doses of 200 g/d is effective in reducing the incidence of prostate, lung, colon, and liver cancers (8,9). Collectively, studies in both animals and humans have pointed toward a role for selenium in cancer prevention, yet the mechanism of action remains to be resolved. The mammalian genome encodes 25 selenoproteins, each containing selenium in the form of the amino acid selenocysteine (Sec)3 (10). Several of these selenoproteins have antioxidant activities, although the functions of most have not been determined. However, the effect of selenium on modulating the activity of these proteins is one possible means by which selenium might suppress carcinogenesis. Evidence in support of this possibility is accumulating.
Selenoproteins and their synthesis. Throughout evolution, the translation of selenoproteins has involved the incorporation of Sec into the elongating peptide in response to a UGA codon, a triplet otherwise used to signal the termination of protein synthesis (11). Recognition of the UGA triplet as Sec requires an RNA signal sequence, referred to as the Selenocysteine Insertion Sequence (SECIS), located 3′ and proximal to the UGA in prokaryotes (12), and in the 3′ untranslated region of eukaryotic selenoprotein mRNAs (13). Mammalian cells contain several dedicated molecules involved in the synthesis and regulation of selenoprotein synthesis (11), and data implicating selenoprotein levels as modifiers of cancer risk and therefore also as the mediators of the anticarcinogenic effects of selenium are now only beginning to emerge.
GPx-1. The cytosolic glutathione peroxidase (GPx-1) is the first and best-characterized mammalian selenoprotein, capable of using reducing equivalents from glutathione to detoxify hydrogen and lipid peroxides (14). GPx-1 is ubiquitously expressed, and knock-out mice are generally without phenotype unless challenged chemically or with pathogens (15-17).
Genetic variants of GPx-1 in the human population have been described, including a single nucleotide polymorphism that results in either a proline (Pro) or leucine (Leu) at codon 198 (18). GPx-1 was implicated in cancer risk when. GPx-1 allele frequencies were evaluated in a case-control study involving lung cancer (19). It was determined that the frequency of the leu allele was greater in individuals with lung cancer than controls (P
In addition to the polymorphism at codon 198, there is an additional common polymorphism in which there are a variable number of tandem alanine (Ala) codons, 4, 5, or 6 repeats, in GPx-1 exon 1 (18,23). Two case-control studies have indicated an association of a particular variant with the risk of cancer, i.e., 4 repeats were associated with breast cancer risk (24), whereas 6 repeats were associated with young onset prostate cancer (25).
In addition to the genetic data implicating GPx-1 allelic identity in cancer risk, other results have suggested that the loss of 1 of 2 GPx-1 copies may be an important event in tumor progression. Frequent loss of heterozygosity (LOH) in the DNA of lung cancer and lung cancer-derived cell lines have been reported (18). These data were extended to demonstrate reduced GPx-1 activity and increased levels of the DNA oxidative lesion 8- hydroxydeoxyguanosine in lung cancers exhibiting GPx-1 LOH (26).
Other studies have been published implicating the leu allele in breast cancer risk, as well as demonstrating fewer heterozygotes at the GPx-1 locus in tumor tissues compared a DNA obtained from cancer- free individuals. Using the polyalanine repeat polymorphism located in the GPx-1 coding sequence, genotype analysis revealed that the heterozygosity frequency in breast tumors was significantly lower than that in the cancer-free population (39% vs. 75%), indicating the likely frequent loss of this genetic locus (21).
The data on GPx-1 allelic variants and LOH were recently extended to another type of cancer, squamous cell carcinomas (SQCC) of the head and neck (27). These results indicated a difference in allele frequency between DNAs obtained from cancers of this type vs. controls, with fewer heterozygotes in tumors, as observed for breast cancer. To identify GPx-1 allelic loss in tissues obtained from the same individuals, peripheral lymphocytes, tumor tissue, and when available, microscopically nonmalignant tissues from the resected sites were examined. Three such sets were obtained from patients diagnosed with SQCC of the tongue, vocal cord, or oropharynx, and genotyping indicated LQH in tumor DNA from all 3 sample sets. It is relevant that GPX-1 LOH also occurred in the microscopically normal margins adjacent to the tumors in 2 of the 3 sample sets examined. These data raise the possibility that the loss of GPx-1 was an early event in tumor development because LOH occurred in the precancerous field that surrounds this type of cancer. It is noteworthy that a single polynucleotide polymorphism with functional consequences was also reported for another glutathione peroxidase family member, the phospholipid glutathione peroxidase GPx-4 (28), and it remains to be seen whether this variant is associated with cancer risk.
Sep15. Sep15 was initially characterized in 1998 as a major ^sup 75^Se-labeled protein detected in human T cells (29). It is expressed at relatively high levels in the prostate, liver, brain, kidney, and testis, whereas it is low or not detectable in muscle, trachea, and the mammary gland. Although its function remains unknown, it was shown to reside in the endoplasmic reticulum in a tight complex with UDP-glucose:glycoprotein glucosyltransferase (UGTR) (30). Given the known UGTR role in the quality control of protein folding, this might imply that Sep15 also functions in this process. In addition, recent data have indicated that Sep15 may have an antioxidant function as well (31).
The Sep15 gene is polymorphic in the human population, existing as 2 allelic variants differing at positions 811 and 1125 in the cDNA sequence (29). These 2 haplotypes, C^sup 811^/G^sup 1125^ and T^sup 811^/A^sup 1125^, are exclusive in the human genome, and the polymorphic positions are located within the SEC\IS element located within the 3′-untranslated region of the gene (32). Several lines of evidence have indicated a functional consequence to these sequence variations. Using a specialized reporter vector, it was shown that the T^sup 811^/A^sup 112^-containing SECIS element was more effective in supporting UGA translation than C^sup 811^/G^sup 1125^, but was less responsive to the addition of selenium to the culture media (32,33). The nucleotide identity at the polymorphic positions in the Sep 15 gene has also been shown to influence the ability of high doses of selenium to induce apoptosis and inhibit the growth of human mesothelioma cells (34).
Genetic data have supported a role for Sep15 in cancer etiology. A survey of the frequency of Sep15 alleles in human DNA samples indicated a dramatically different allele distribution between Caucasians and African Americans, with the T^sup 811^/A^sup 1125^ allele being represented 4 times more often among African Americans (33). In this population, there was a significant difference in allele frequency in DNA obtained from either breast cancers or cancers of the head and neck compared with DNA obtained from cancer- free individuals. LOH at the Sep15 locus is likely to account for much, if not all of the differences in Sep15 allele frequency. Indeed, LOH was observed when DNA from a head and neck tumor was compared with that obtained from lymphocytes from the same individual (33). In a detailed analysis of LOH at Sep15 in breast cancer, significantly fewer (28%) heterozygotes were observed at a genetic marker tightly linked to Sep15 (35). An analysis of other microsatellite markers along human chromosome 1p did not detect a significant difference in the heterozygosity indices for these markers between breast tumor and control DNA. These data indicate that the loss of either Sep15, or perhaps another very tightly linked gene, is a common and important event in breast cancer development.
Expression of selenoproteins and cancer? Polymorphisms associated with cancer risk may indicate that these genes are involved with cancer etiology. Allelic loss during tumor development, although possibly indicative of tumor suppressor activity of a linked gene, also offers support for the notion that either a recessive mutation in the remaining allele or haplo-insufficiency at that locus is promoting cancer development. In addition to the selenoproteins referred to above, others may be involved with the protection offered by selenium, and there are several candidates based on expression patterns or in vitro studies. Among these, thioredoxin reductase 1 (TR1) is the best-characterized isoform of the TR family of selenium-containing proteins. Much of the biological function of TR1 is attributed to its role as a reductant of the protein thioredoxin (TRx). Both TR and TRx are critical for redox control at the cellular level; together, they are involved in several biologic processes including antioxidant defense, cell proliferation, and inhibition of apoptosis (36). Although the components of the TR-TRx system have been reported to be overexpressed in cancer vs. normal cells (37-40), they may also play an important regulatory role in the function of p53 (41-43), a tumor suppressor gene that is either deleted or suppressed in several human cancers. In this regard, it may also be significant that elevated p53 expression was correlated with lower TR positivity in breast tumor tissue (44).
FIGURE 1 A model for the role of selenoproteins in cancer risk and development.
Selenoprotein P (SelP) is a selenoprotein that contains multiple selenocysteine residues, and constitutes ~60% of the selenium in plasma (45). To date, its best-charactetized function is its role in selenium transport from the liver (46,47). With regard to a possible role in cancer etiology, reduced mRNA expression for SelP, but a variable increase for gastrointestinal-Gpx was observed in colorectal adenoma polyps compared with adjacent normal mucosa (48). The same investigators recently reported a dramatic decrease in SelP transcript levels in colorectal cancer tissues compared with normal colonic mucosa (49). In 4 of 11 cancers tissues examined, SelP mRNA was undetectable. Additional studies will be required to determine the importance of different expression patterns of selenoprotein genes and whether these changes are a consequence or participant in the transformation process.
The growing argument for the role of selenoproteins in cancer risk and development. That selenium supplementation can reduce cancer incidence in animals is now established, and mounting evidence supports a similar role in humans. It remains likely that at least some of the 25 mammalian selenoproteins are involved in the mechanism of protection by selenium. Genetic data indicating functional polymorphisms in the genes for several selenoproteins, and more significantly, the association of allelic variants with cancer risk, are a compelling argument for the involvement of those genes, and by logical extension, the mediators of the benefits of selenium. Similarly, allelic loss of selenoprotein genes during tumor evolution, along with other data, supports the possibility that the deletion of these genes promotes cancer development. What is emerging, therefore, is a model of chemoprevention by selenium, summarized in Figure 1. The model does not exclude the involvement of small selenium-containing metabolites in cancer prevention, for which there is considerable evidence [reviewed in (50)]. It suggests that reduced levels of 1 or more selenoproteins increase the likelihood of cancer development. Three possible ways this could happen are indicated in the figure: 1) reduced dietary selenium intake; 2) genetic polymorphisms that result in an increased selenium requirement for baseline levels of protection; and 3) allelic loss of 1 of 2 gene copies during tumor development. Clearly, these possibilities are not exclusive and in fact may be additive. An additional possibility raised by this hypothesis is that targeted selenium supplementation may be useful in returning selenoproteins to that level at which they can provide the maximum benefit. Individuals with lower selenium intake, attenuating polymorphisms, or haploinsufficiency may be those who will benefit most from additional dietary selenium intake, and individuals in each of these categories could be identified by a variety of cost- effective procedures.
1 Manuscript received 5 August 2004.
3 Abbreviations used: GPx-1, glutathione peroxidase; LOH, loss of heterozygosity; Sec, selenocysteine; SECIS, Selenocysteine Insertion Sequence; SelP, selenoprotein P; SQCC, squamous cell carcinomas; TR1, thioredoxin reductase 1; TRx, thioredoxin; UGTR, UDP- glucose:glycoprotein glucosyltransferase.
1. El-Bayoumy, K. (1991) The role of selenium in cancer prevention. In: Cancer Prevention (DeVita, V. T., Hellman, S. & Rosenberg, S. A., eds.), pp. 1-15. J. B. Lippincott, Philadelphia, PA.
2. Yoshizawa, K., Willett, W. C., Morris, S. J., Stampfer, M. J., Spiegelman, D., Rimm, E. B. & Giovannucci, E. (1998) Study of prediagnostic selenium level in toenails and the risk of advanced prostate cancer. J. Natl. Cancer Inst. 90: 1219-1224.
3. Ghadirian, P., Maisonneuve, P., Perret, C., Kennedy, G., Boyle, P., Krewski, D. & Lacroix, A. (2000) A case-control study of toenail selenium and cancer of the breast, colon, and prostate. Cancer Detect. Prev. 24: 305-313.
4. Brooks, J. D., Metter, E. J., Chan, D. W., Sokoll, L. J., Landis, P., Nelson, W. G., Muller, D., Andres, R. & Carter, H. B. (2001) Plasma selenium level before diagnosis and the risk of prostate cancer development. J. Urol. 166: 2034-2038.
5. Fernandez-Banares, F., Cabre, E., Esteve, M., Mingorance, M. D., Abad-Lacruz, A., Lachica, M., Gil, A. & Gassull, M. A. (2002) Serum selenium and risk of large size colorectal adenomas in a geographical area with a low selenium status. Am. J. Gastroenterol. 97: 2103-2108.
6. Knekt, P., Marniemi, J., Teppo, L., Heliovaara, M. & Aromaa, A. (1998) Is low selenium status a risk factor for lung cancer? Am. J. Epidemiol. 148: 975-982.
7. Garland, M., Morris, J. S., Stampfer, M. J., Colditz, G. A., Spate, V. L., Baskett, C. K., Rosner, B., Speizer, F. E., Willett, W. C. & Hunter, D. J. (1995) Prospective study of toenail selenium levels and cancer among women. J. Natl. Cancer lnst. 87: 497-505.
8. Clark, L. C., Combs, G.F.J., Turnbull, B. W., Slate, E. H., Chalker, E. H., Chow, J., Davis, L. S., Glover, R. A., Graham, G. F., Gross, E. G., Krongrad, A., Lesher, J.L.J., Park, H. K., Sanders, B.B.J., Smith, C. L. & Taylor, J. R. (1996) Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. J. Am. Med. Assoc. 276: 1957-1963.
9. Yu, S. Y., Zhu, Y. J. & Li, W. G. (1997) Protective role of selenium against hepatitis B virus and primary liver cancer in Qidong. Biol. Trace Elem. Res. 56: 117-124.
10. Kryukov, G. V., Castellano, S., Novoselov, S. V., Lobanov, A. V., Zehtab, O., Guigo, R. & Gladyshev, V. N. (2003) Characterization of mammalian selenoproteomes. Science (Washington, DC) 300: 1439- 1443.
11. Hatfield, D. L. & Gladyshev, V. N. (2002) How selenium has altered our understanding of the genetic code. Mol. Cell Biol. 22: 3565-3576.
12. Zinoni, F., Birkmann, A., Leinfelder, W. & Bock, A. (1987) Cotranslational insertion of selenocysteine into formate dehydrogenase from Escherichia coli directed by a UGA codon. Proc. Natl. Acad. Sci. U.S.A. 84: 3156-3160.
13. Berry, M. J., Banu, L., Harney, J. W. & Larsen, P. R. (1993) Functional characterization of the eukaryotic SECIS elements which direct selenocysteine insertion at UGA codons. EMBO J. 12: 3315- 3322.
14. Brigelius-Flohe, R. (1999) Tissue-specific functions of individual glutathione peroxidases. Free Radic. Biol. Med. 27: 951- 965.
15. Ho, Y. S., Magnenat, J. L., Bronson\, R. T., Cao, J., Gargano, M., Sugawara, M. & Funk, C. D. (1997) Mice deficient in cellular glutathione peroxidase develop normally and show no increased sensitivity to hyperoxia. J. Biol. Chem. 272: 16644- 16651.
16. Ho, Y. S., Gargano, M., Cao, J., Bronson, R. T., Heimler, I. & Hutz, R. J. (1998) Reduced fertility in female mice lacking copper- zinc Superoxide dismutase. J. Biol. Chem. 273: 7765-7769.
17. Esworthy, R. S., Binder, S. W., Doroshow, J. H. & Chu, F. F. (2003) Microflora trigger colitis in mice deficient in selenium- dependent glutathione peroxidase and induce Gpx2 gene expression. Biol. Chem. 384: 597-607.
18. Moscow, J. A., Schmidt, L., Ingram, D. T., Gnarra, J., Johnson, B. & Cowan, K. H. (1994) Loss of heterozygosity of the human cytosolic glutathione peroxidase I gene in lung cancer. Carcinogenesis 15: 2769-2773.
19. Ratnasinghe, D., Tangrea, J. A., Andersen, M. R., Barrett, M. J., Virtamo, J., Taylor, P. R. & Albanes, D. (2000) Glutathione peroxidase codon 198 polymorphism variant increases lung cancer risk. Cancer Res. 60: 6381-6383.
20. Ichimura, Y., Habuchi, T., Tsuchiya, N., Wang, L., Oyama, C., Sato, K., Nishiyama, H., Ogawa, O. & Kato, T. (2004) Increased risk of bladder cancer associated with a glutathione peroxidase 1 codon 198 variant. J. Ural. 172: 728-732.
21. Hu, Y. J. & Diamond, A. M. (2003) Role of glutathione peroxidase 1 in breast cancer: loss of heterozygosity and allelic differences in the response to selenium. Cancer Res. 63: 3347-3351.
22. Forsberg, L., de Faire, U., Marklund, S. L., Andersson, P. M., Stegmayr, B. & Morgenstern, R. (2000) Phenotype determination of a common Pro-Leu polymorphism in human glutathione peroxidase 1. Blood Cells Mol. Dis. 26: 423-426.
23. Shen, Q., Townes, P. L., Padden, C. & Newburger, P. E. (1994) An in-frame trinucleotide repeat in the coding region of the human cellular glutathione peroxidase (GPX1) gene: in vivo polymorphism and in vitro instability. Genomics 23: 292-294.
24. Knight, J. A., Onay, U. V., Wells, S., Li, H., Shi, E. J., Andrulis, I. L. & Ozcelik, H. (2004) Genetic variants of GPX1 and SOD2 and breast cancer risk at the Ontario site of the Breast Cancer Family Registry. Cancer Epidemiol. Biomark. Prev. 13: 146-149.
25. Kote-Jarai, Z., Durocher, F., Edwards, S. M., Hamoudi, R., Jackson, R. A., Ardern-Jones, A., Murkin, A., Dearnaley, D. P., Kirby, R., Houlston, R., Easton, D. F. & Eeles, R. (2002) Association between the GCG polymorphism of the selenium dependent GPX1 gene and the risk of young onset prostate cancer. Prostate Cancer Prostatic Dis. 5: 189-192.
26. Hardie, L. J., Briggs, J. E., Davidson, L. Y., Allan, J. M., King, R. F., Williams, G. I. & Wild, C. P. (2000) The effect of hOGG1 and glutathione peroxidase I genotypes and 3p chromosomal loss on 8-hydroxydeoxyguanosine levels in lung cancer. Carcinogenesis 21: 167-172.
27. Hu, Y. J., Dolan, M. E., Bae, R., Yee, Y., Roy, M., Glickman, R., Kiremidjian-Schumacher, L. & Diamond, A. M. (2004) Allelic loss at the GPx-1 locus and the risk for cancer of the head and neck. Biol. Trace Elements Res. (in press).
28. Villette, S., Kyle, J. A., Brown, K. M., Pickard, K., Milne, J. S., Nicol, F., Arthur, J. R. & Hesketh, J. E. (2002) A novel single nucleotide polymorphism in the 3′ untranslated region of human glutathione peroxidase 4 influences lipoxygenase metabolism. Blood Cells Mol. Dis. 29: 174-178.
29. Gladyshev, V. N., Jeang, K., Wootton, J. C. & Hatfield, D. L. (1998) A new human selenium-containing protein. J. Biol. Chem. 273: 8910-8915.
30. Korotkov, K. V., Kumaraswamy, E., Zhou, Y., Hatfield, D. L. & Gladyshev, V. N. (2001) Association between the 15-kDa selenoprotein and UDP-glucose: glycoprotein glucosyltransferase in the endoplasmic reticulum of mammalian cells. J. Biol. Chem. 276: 15330-15336.
31. Wu, H. J., Lin, C., Zha, Y. Y., Yang, J. G., Zhang, M. C., Zhang, X. Y., Liang.X., Fu, M. & Wu, M. (2003) Redox reactions of Sep15 and its relationship with tumor development. Ai Zheng. 22: 119- 122.
32. Kumaraswamy, E., Korotkov, K. V., Diamond, A. M., Gladyshev, V. N. & Hatfield, D. L. (2002) Genetic and functional analysis of mammalian Sep15 selenoprotein. Methods Enzymol. 347: 187-197.
33. Hu, Y. J., Korotkov, K. V., Mehta, R., Hatfield, D. L., Rotimi, C. N., Luke, A., Prewitt, T. E., Cooper, R. S., Stock, W., Vokes, E. E., Dolan, M. E., Gladyshev, V. N. & Diamond, A. M. (2001) Distribution and functional consequences of nucleotide polymorphisms in the 3′-untranslated region of the human Sep15 gene. Cancer Res. 61: 2307-2310.
34. Apostolou, S., Klein, J. O., Mitsuuchi, Y., Shetler, J. N., Poulikakos, P. I., Jhanwar, S. C., Kruger, W. D., Testa, J. R., Wu, H. J., Lin, C., Zha, Y. Y., Yang, J. G., Zhang, M. C., Zhang, X. Y., Liang, X., Fu, M. & Wu, M. (2004) Growth inhibition and induction of apoptosis in mesothelioma cells by selenium and dependence on selenoprotein SEP15 genotype. Oncogene 23: 5032-5040.
35. Nasr, M. A., Hu, Y. J. & Diamond, A. M. (2004) Allelic loss at the Sep15 locus in breast cancer. Cancer Ther. 1: 307-312.
36. Mustacich, D. & Powis, G. (2000) Thioredoxin reductase. Biochem. J. 346: 1-8.
37. Rundlof, A. & Arner, E.S.J. (2004) Regulation of the mammalian selenoprotein thioredoxin reductase 1 in relation to cellular phenotype, growth, and signaling events. Antioxid. Redox Signal. 6: 41-52.
38. Gladyshev, V. N., Factor, V. M., Housseau, F. & Hatfield, D. L. (1998) Contrasting patterns of regulation of the antioxidant selenoproteins thioredoxin reductase and glutathione peroxidase, in cancer cells. Biochem. Biophys. Res. Commun. 251: 488-49.
39. Lincoln, D. T., Ali Emadi, E. M., Tonissen, K. F. & Clarke, F. M. (2003) The thioredoxin-thioredoxin reductase system: over- expression in human cancer. Anticancer Res. 23: 2425-2433.
40. Kim, H. J., Chae, H. Z., Kim, Y. J., Hwangs, T. S., Park, E. M. & Park, Y. M. (2003) Preferential elevation of Prx I and Trx expression in lung cancer cells following hypoxia and in human lung cancer tissues. Cell Biol. Toxicol. 19: 285-298.
41. Pearson, G. D. & Merrill, G. F. (1997) Deletion of the Saccharomyces cerevisiae TRR1 gene encoding thioredoxin reductase inhibits p53-dependent reporter gene expression. J. Biol. Chem. 273: 5431-5434.
42. Ueno, M., Masutani, H., Arai, R. J., Yamauchi, A., Hirota, K., Sakai, T., Inamoto, T., Yamaoka, Y., Yodoi, J. & Nikaido, T. (1999) Thioredoxin-dependent redox regulation of p53-mediated p21 activation. J. Biol. Chem. 274: 35809-35815.
43. Moos, P. J., Edes, K., Cassidy, P., Massuda, E. & Fitzpatrick, F. A. (2003) Electrophilic prostaglandins and lipid aldehydes repress redox-senstive transcription factors p53 and hypoxia-inducible factor by impairing the selenoprotein thioredoxin reductase. J. Biol. Chem. 278: 745-750.
44. Turunen, N., Karihtala, P., Mantyniemi, A., Sormunen, R., Holmgren, A., Kinnula, V. L. & Soini, Y. (2004) Thioredoxin is associated with proliferation, p53 expression and negative estrogen and progesterone receptor status in breast carcinoma. APMIS 112: 123- 132.
45. Burk, R. F., Hill, K. E. & Motley, A. K. (2003) Selenoprotein metabolism and function: evidence for more than one function for selenoprotein P. J. Nutr. 133: 1517S-1520S.
46. Schomburg, L., Schweizer, U., Holtmann, B., Flohe, L., Sendtner, M. & Kohrle, J. (2003) Gene disruption discloses role of selenoprotein P in selenium delivery to target tissues. Biochem. J. 370: 397-402.
47. Hill, K. E., Zhou, J., McMahan, W. J., Motley, A. K., Atkins, J. F., Gesteland, R. F. & Burk, R. F. (2003) Deletion of selenoprotein P alters distribution of selenium in mouse. J. Biol. Chem. 278: 13640-13646.
48. Mork, H., Al-Taie, O. H., Bahr, K., Zierer, A., Beck, C., Scheurlen, M., Jakob, F. & Kohrle, J. (2000) Inverse mRNA expression of the selenocysteine-containing proteins GI-GPx and SeP in colorectal adenomas compared with adjacent normal mucosa. Nutr. Cancer 37: 108-116.
49. Al-Taie, O. H., Uceyler, N., Euβner, U., Jakob, F., Mork, H., Scheurlen, M., Brigelius-Flohe, R., Schottker, K., Able, J., Thalheimer, A., Katzenberger, T., Illert, B., Melcher, R. & Kohrle, J. (2004) Expression profiling and genetic alterations of the selenoproteins Gl-GPx and SePP in colorectal carcinogenesis. Nutr. Cancer 48: 6-14.
50. Clement, I. (1998) Lessons from basic research in selenium and cancer prevention. J. Nutr. 128: 1845-1854.
Veda Diwadkar-Navsariwala and Alan M. Diamond2
Department of Human Nutrition, University of Illinois at Chicago, Chicago, IL 60612
2 To whom correspondence and reprint requests should be addressed. E-mail: firstname.lastname@example.org.
Copyright American Institute of Nutrition Nov 2004