Structure of the FoxM1 DNA-recognition domain bound to a promoter sequence.

FoxM1 is a member of the Forkhead family of transcription factors and is implicated in inducing cell proliferation and some forms of tumorigenesis. It binds promoter regions with a preference for tandem repeats of a consensus 'TAAACA' recognition sequence. The affinity of the isolated FoxM1 DNA-binding domain for this site is in the micromolar range, lower than observed for other Forkhead proteins. To explain these FoxM1 features, we determined the crystal structure of its DNA-binding domain in complex with a tandem recognition sequence. FoxM1 adopts the winged-helix fold, typical of the Forkhead family. Neither 'wing' of the fold however, makes significant contacts with the DNA, while the second, C-terminal, wing adopts an unusual ordered conformation across the back of the molecule. The lack of standard DNA-'wing' interactions may be a reason for FoxM1's relatively low affinity. The role of the 'wings' is possibly undertaken by other FoxM1 regions outside the DBD, that could interact with the target DNA directly or mediate interactions with other binding partners. Finally, we were unable to show a clear preference for tandem consensus site recognition in DNA-binding, transcription activation or bioinformatics analysis; FoxM1's moniker, 'Trident', is not supported by our data.

The ubiquitin ligase Triad1 inhibits myelopoiesis through UbcH7 and Ubc13 interacting domains.

Ubiquitination plays a major role in many aspects of hematopoiesis. Alterations in ubiquitination have been implicated in hematological cancer. The ubiquitin ligase Triad1 controls the proliferation of myeloid cells. Here, we show that two RING (really interesting new gene) domains in Triad1 differentially bind ubiquitin-conjugating enzymes, UbcH7 and Ubc13. UbcH7 and Ubc13 are known to catalyze the formation of different poly-ubiquitin chains. These chains mark proteins for proteasomal degradation or serve crucial non-proteolytic functions, respectively. In line with the dual Ubc interactions, we observed that Triad1 catalyzes the formation of both types of ubiquitin chains. The biological relevance of this finding was studied by testing Triad1 mutants in myeloid clonogenic assays. Full-length Triad1 and three mutants lacking conserved domains inhibited myeloid colony formation by over 50%. Strikingly, deletion of either RING finger completely abrogated the inhibitory effect of Triad1 in clonogenic growth. We conclude that Triad1 exhibits dual ubiquitin ligase activity and that both of its RING domains are crucial to inhibit myeloid cell proliferation. The differential interaction of the RINGs with Ubcs strongly suggests that the ubiquitination mediated through UbcH7 as well as Ubc13 plays a major role in myelopoiesis.

High lead exposures resulting from pottery production in a village in Michoacán State, Mexico.

This paper reports findings from a screening study conducted to examine potential lead (Pb) exposures in residents of a Mexican village where Pb oxide continues to be used in ceramic pottery production. Extremely high Pb concentrations were measured in personal and indoor air samples, household surface dust samples, and household soil samples. Personal air Pb concentrations for workers performing pottery firing and glazing were up to 454 microg/m3. Results from indoor air samples indicate that airborne Pb concentrations were lower during nonglazing period compared to the glazing period. Soil Pb concentrations measured in 17 homes ranged from 0.39 to 19.8 mg/g. Dust Pb loading on surfaces of household items, hands, and clothes of a worker ranged from 172 to 33,060 microg/ft2. Pb content as high as 2.4 microg/g was found in a bean stew cooked in a pot made in the village. Based on these Pb concentrations measured in multiple media and data adapted for exposure contact rates, we have made rough estimates of Pb exposures via inhalation, soil/dust ingestion, and food ingestion. Estimated total daily Pb intake, on average, is 4.0 mg for adults and 3.4 mg for children living in the village. In the total daily intake, a greatest fraction may be contributed by food ingestion and another significant fraction may come from soil/dust ingestion for the children. Although the sample size is small, these measurements indicate a very significant public health problem for the village residents and a large number of other similar communities in Mexico. (It was estimated that there are approximately 1.5 million glaze potters.) The Pb exposure is implicated in a number of pervasive health problems in the region, and is the cause for national and international attention. Several recommended solutions to this problem range from personal protection and behavioral changes to introduction of alternative glazes.

United States Department of Agriculture's requirements for markers.

The U.S. Department of Agriculture's regulation of food and food ingredients is essentially limited to meat and poultry products. Within this area, there do not appear to be any overriding general problems associated with the concept of the use of adherence markers that are deemed to be both safe and effective. Although present regulations do not specifically authorize such a practice, they could be amended through utilization of standard rule-making procedures. There also appears to be sufficient basis, under current regulation, for some controlled, experimental evaluation of the concept. The Department's inspection and label approval systems for meat and poultry products may serve to facilitate such an approach, while providing a relatively high level of regulatory control. Practical problems, in areas such as the scope and applicability of inspection coverage and appropriate labeling, can and should be identified and resolved at a relatively early stage of the project, if the introduction of these substances into meat and poultry products is deemed to be a viable option.