Long-term and baseline recreational physical activity and risk of endometrial cancer: the California Teachers Study.

BACKGROUND: Physical activity may be associated with decreasing endometrial cancer risk; it remains unclear whether the association is modified by body size. METHODS: Among 93 888 eligible California Teachers Study participants, 976 were diagnosed with incident endometrial cancer between 1995-1996 and 2007. Cox proportional hazards regression methods were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for endometrial cancer associated with long-term (high school through age 54 years) and baseline (3 years prior to joining the cohort) strenuous and moderate recreational physical activity, overall and by body size. RESULTS: Increased baseline strenuous recreational physical activity was associated with decreased endometrial cancer risk (Ptrend=0.006) with approximately 25% lower risk among women exercising >3 h per week per year than among those exercising <1/2 h per week per year (RR, 0.76; 95% CI, 0.63-0.92). This inverse association was observed among overweight/obese women (body mass index ≥25 kg m(-2); Ptrend=0.006), but not among thinner women (Ptrend=0.12). Baseline moderate activity was associated with lower risk among overweight/obese women. CONCLUSION: Increasing physical activity, particularly strenuous activity, may be a lifestyle change that overweight and obese women can implement to reduce their endometrial cancer risk.

Salivary gland development in Drosophila melanogaster.

The Drosophila salivary gland is proving to be an excellent experimental system for understanding how cells commit to specific developmental programs and, once committed, how cells implement such decisions. Through genetic studies, the factors that determine where salivary glands will form, the number of cells committed to a salivary gland fate, and the distinction between the two major cell types (secretory cells and duct cells) have been discovered. Within the next few years, we will learn the molecular details of the interactions among the salivary gland regulators and salivary gland target genes. We will also learn how the early-expressed salivary gland genes coordinate their activities to mediate the morphogenetic movements required to form the salivary gland and the changes in cell physiology required for high secretory activity.

Regulation and function of Scr, exd, and hth in the Drosophila salivary gland.

Salivary gland formation in the Drosophila embryo is dependent on the homeotic gene Sex combs reduced (Scr). When Scr function is missing, salivary glands do not form, and when SCR is expressed everywhere in the embryo, salivary glands form in new places. Scr is normally expressed in all the cells that form the salivary gland. However, as the salivary gland invaginates, Scr mRNA and protein disappear. Homeotic genes, such as Scr, specify tissue identity by regulating the expression of downstream target genes. For many homeotic proteins, target gene specificity is achieved by cooperatively binding DNA with cofactors. Therefore, it is likely that SCR also requires a cofactor(s) to specifically bind to DNA and regulate salivary gland target gene expression. Here, we show that two homeodomain-containing proteins encoded by the extradenticle (exd) and homothorax (hth) genes are also required for salivary gland formation. exd and hth function at two levels: (1) exd and hth are required to maintain the expression of Scr in the salivary gland primordia prior to invagination and (2) exd and hth are required in parallel with Scr to regulate the expression of downstream salivary gland genes. We also show that Scr regulates the nuclear localization of EXD in the salivary gland primordia through repression of homothorax (hth) expression, linking the regulation of Scr activity to the disappearance of Scr expression in invaginating salivary glands.

Cell fate specification in the Drosophila salivary gland: the integration of homeotic gene function with the DPP signaling cascade.

Salivary gland formation in the Drosophila embryo is linked to the expression of the homeotic gene Sex combs reduced (Scr). When Scr function is missing, salivary glands do not form, and when SCR is expressed everywhere, salivary glands form in new places. However, not every cell that expresses Scr is recruited to a salivary gland fate. Along the anterior-posterior axis, the posteriorly expressed proteins encoded by the teashirt (tsh) and Abdominal-B (Abd-B) genes block SCR activation of salivary gland genes, and along the dorsal-ventral axis, the secreted signaling molecule encoded by decapentaplegic (dpp) prevents activation of salivary gland genes by SCR in dorsal regions of parasegment 2. We have identified five downstream components in the DPP signaling cascade required to block salivary gland gene activation. These components include two known receptors, the type I receptor encoded by the thick veins (tkv) gene and the type II receptor encoded by the punt (put) gene; two of the four known Drosophila members of the Smad family of proteins which transduce signals from the receptors to the nucleus, Mothers against dpp (Mad) and Medea (Med); and, finally, a large zinc-finger transcription factor encoded by the schnurri (shn) gene. These results reveal how anterior-posterior and dorsal-ventral patterning information is integrated at the level of organ-specific gene expression.

Identification of a novel Drosophila SMAD on the X chromosome.

TGF-beta signaling from the cell surface to the nucleus is mediated by the SMAD family of proteins, which have been grouped into three classes based upon sequence identity and function. Receptor-regulated, or pathway-restricted, SMADs (R-SMADs) are phosphorylated by ligand-specific serine/threonine kinase receptors. Phosphorylated R-SMADs oligomerize with the coactivating, or shared, SMAD (Co-SMAD) mediator and translocate to the nucleus where the complex directs transcription of downstream target genes. Inhibitory SMADs (I-SMADs) block receptor-mediated phosphorylation of R-SMADs. In Drosophila, one member of each class of SMAD has been reported: MAD, an R-SMAD, MEDEA, a Co-SMAD, and DAD, an I-SMAD. Here, we report the first identification of a novel Drosophila R-SMAD, which we have named Smox for Smad on X. We have localized the Smox gene to a specific interval on the X chromosome and shown that Smox is transcribed throughout development.

The Drosophila dCREB-A gene is required for dorsal/ventral patterning of the larval cuticle.

We report on the characterization of the first loss-of-function mutation in a Drosophila CREB gene, dCREB-A. In the epidermis, dCREB-A is required for patterning cuticular structures on both dorsal and ventral surfaces since dCREB-A mutant larvae have only lateral structures around the entire circumference of each segment. Based on results from epistasis tests with known dorsal/ventral patterning genes, we propose that dCREB-A encodes a transcription factor that functions near the end of both the DPP- and SPI-signaling cascades to translate the corresponding extracellular signals into changes in gene expression. The lateralizing phenotype of dCREB-A mutants reveals a much broader function for CREB proteins than previously thought.