K. Woodson

The orphan nuclear receptor steroidogenic factor 1 (SF-1) is expressed in the adrenal cortex and gonads and regulates the expression of several P450 steroid hydroxylases in vitro. We examined the role of SF-1 in the adrenal glands and gonads in vivo by a targeted disruption of the mouse SF-1 gene. All SF-1-deficient mice died shortly after delivery. Their adrenal glands and gonads were absent, and persistent Mullerian structures were found in all genotypic males. While serum levels of corticosterone in SF-1-deficient mice were diminished, levels of adrenocorticotropic hormone (ACTH) were elevated, consistent with intact pituitary corticotrophs. Intrauterine survival of SF-1-deficient mice appeared normal, and they had normal serum level of corticosterone and ACTH, probably reflecting transplacental passage of maternal steroids. We tested whether SF-1 is required for P450 side-chain-cleavage enzyme (P450scc) expression in the placenta, which expresses both SF-1 and P450scc, and found that in contrast to its strong activation of the P450scc gene promoter in vitro, the absence of SF-1 had no effect on P450scc mRNA levels in vivo. Although the region targeted by our disruption is shared by SF-1 and by embryonal long terminal repeat-binding protein (ELP), a hypothesized alternatively spliced product, we believe that the observed phenotype reflects absent SF-1 alone, as PCR analysis failed to detect ELP transcripts in any mouse tissue, and sequences corresponding to ELP are not conserved across species. These results confirm that SF-1 is an important regulator of adrenal and gonadal development, but its regulation of steroid hydroxylase expression in vivo remains to be established.

BACKGROUND: Higher blood levels of alpha-tocopherol, the predominant form of vitamin E, have been associated in some studies with a reduced risk of lung cancer, but other studies have yielded conflicting results. To clarify this association, we examined the relationship between prospectively collected serum alpha-tocopherol and lung cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study cohort. METHODS: The ATBC Study was a randomized, clinical trial of 29 133 white male smokers from Finland who were 50-69 years old and who had received alpha-tocopherol (50 mg), beta-carotene (20 mg), both, or neither daily for 5-8 years. Data regarding medical histories, smoking, and dietary factors were obtained at study entry, as was a serum specimen for baseline alpha-tocopherol determination. alpha-Tocopherol measurements were available for 29 102 of the men, among whom 1144 incident cases of lung cancer were diagnosed during a median observation period of 7.7 years. The association between alpha-tocopherol and lung cancer was evaluated with the use of multivariate proportional hazards regression. RESULTS: A 19% reduction in lung cancer incidence was observed in the highest versus lowest quintile of serum alpha-tocopherol (relative risk = 0.81; 95% confidence interval = 0. 67-0.97). There was a stronger inverse association among younger men (<60 years), among men with less cumulative tobacco exposure (<40 years of smoking), and possibly among men receiving alpha-tocopherol supplementation. CONCLUSIONS: In the ATBC Study cohort, higher serum alpha-tocopherol status is associated with lower lung cancer risk; this relationship appears stronger among younger persons and among those with less cumulative smoke exposure. These findings suggest that high levels of alpha-tocopherol, if present during the early critical stages of tumorigenesis, may inhibit lung cancer development.

Loss of imprinting (LOI) of insulin-like growth factor-II (IGF-II) may be an inherited epigenetic trait that is polymorphic in the population, and its presence may predispose an individual to the development of colorectal cancer. We evaluated the association between LOI of IGF-II in normal colonic mucosal samples and adenomas in women participating in a colonoscopy screening study. Among 40 participants, 11 (27.5%) had LOI of IGF-II in their normal colonic mucosal tissue. After adjusting for body mass index and family history of colorectal cancer, LOI status was associated with a fivefold increased risk of adenoma formation (odds ratio = 5.2, 95% confidence interval = 1.0 to 26.7). On average, IGF-II expression was more than threefold higher among women with LOI of IGF-II than among women with normal imprinting status. Our findings support the hypothesis that LOI of IGF-II is an epigenetic trait polymorphic in the population and suggest that LOI of IGF-II may play a role in colorectal cancer. These findings are intriguing and need to be confirmed in larger studies.

Alterations in DNA methylation have been associated with cancers at almost all tumor sites and represent one of the most consistent changes in neoplastic cells. The underlying etiological mechanisms for alteration of DNA methylation patterns are not understood, but experimental studies in animals suggest potential environmental and genetic influences. The purpose of this study was to investigate whether DNA hypomethylation in peripheral blood DNA (potentially representing status at the lung) was associated with increased risk for the development of lung cancer. We evaluated genome-wide and p53 gene-specific hypomethylation in 100 lung cancer cases and controls selected from a large clinical trial of male smokers, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Genome-wide methylation status was assessed using the in vitro methyl acceptance capacity assay and p53 gene-specific methylation status using the HpaII quantitative PCR assay. Hypomethylation was evaluated as a risk factor using multivariate conditional logistic regression analyses. Genome-wide methylation status was unrelated to lung cancer risk; the odds ratio was 1.25 and the 95% confidence interval was 0.48-3.21 for those in the highest versus lowest quartile of hypomethylation status. Hypomethylation of the p53 gene in exons 5-8, the hypermutable region, was associated with a 2-fold increased risk for lung cancer (odds ratio, 2.20; 95% confidence interval, 1.04-4.65), whereas there was no risk increase for hypomethylation at exons 2-4, a region of the gene not known for its mutability or functional significance in cancer. Our results indicate that hypomethylation status within exons 5-8 of p53 from peripheral lymphocyte DNA may be a relevant predictor of lung cancer among male smokers.

The csa-15 locus of Bacillus subtilis corresponds to an operon encoding proteins which display features characteristic of the ABC group of transporters. Sequence analysis reveals a very high level of identity to the ribose transport operon of Escherichia coli. This hypothesis is supported by the observation that strains carrying mutagenic insertions in this operon are unable to grow on ribose as sole carbon source. Expression of this operon is directed by a single SigA-type promoter which is negatively regulated by Spo0A during the late-exponential/transition state of the growth cycle. Expression is also subject to catabolite repression and this mode of regulation is dominant to control of expression by Spo0A.