Thioredoxin and Jab1 control estrogen- and antiestrogen-mediated progression of the cell cycle through p27 interactions

A major problem with breast cancer treatment is the prevalence of antiestrogen resistance, be it de novo or acquired after continued use. Many of the underlying mechanisms of antiestrogen resistance are not clear, although estrogen receptor-mediated actions have been identified as a pathway that is blocked by antiestrogens. Selective estrogen receptor modulators (SERMs), such as tamoxifen, are capable of producing reactive oxygen species (ROS) through metabolic activation, and these ROS, at high levels, can induce irreversible growth arrest that is similar to the growth arrest incurred by SERMs. This suggests that SERM-mediated growth arrest may also be through ROS accumulation. Breast cancer receiving long-term antiestrogen treatment appears to adapt to this increased, persistent level of ROS. This, in turn, leads to the disruption of reversible redox signaling that involves redox-sensitive phosphatases and protein kinases and transcription factors. This has downstream consequences for apoptosis, cell cycle progression, and cell metabolism. For this dissertation, we explored if altering the ROS formed by tamoxifen also alters sensitivity of the drug in resistant cells. We explored an association with a thioredoxin/Jab1/p27 pathway, and a possible role of dysregulation of thioredoxin-mediated redox regulation contributing to the development of antiestrogen resistance in breast cancer. We used standard laboratory techniques to perform proteomic assays that showed cell proliferation, protein concentrations, redox states, and protein-protein interactions. We found that increasing thioredoxin reductase levels, and thus increasing the amount of reduced thioredoxin, increased tamoxifen sensitivity in previously resistant cells, as well as altered estrogen and tamoxifen-induced ROS. We also found that decreasing levels of Jab1 protein also increased tamoxifen sensitivity, and that the downstream effects showed a decrease p27 phosphorylation in both cases. We conclude that the chronic use of tamoxifen can lead to an increase in ROS that alters cell signaling and causing cell growth in the presence of tamoxifen, and that this resistant cell growth can be reversed with an alteration to the thioredoxin/Jab1 pathway.

Control of MNC environmental performance and the challenges of subsidiary network dimensions

The trend of green consumerism and increased standardization of environmental regulations has driven multinational corporations (MNCs) to seek standardization of environmental practices or at least seek to be associated with such behavior. In fact, many firms are seeking to free ride on this global green movement, without having the actual ecological footprint to substantiate their environmental claims. While scholars have articulated the benefits from such optimization of uniform global green operations, the challenges for MNCs to control and implement such operations are understudied. For firms to translate environmental commitment to actual performance, the obstacles are substantial, particularly for the MNC. This is attributed to headquarters' (HQ) control challenges (1) in managing core elements of the corporate environmental management (CEM) process and specifically matching verbal commitment and policy with ecological performance and by (2) the fact that the MNC operates in multiple markets and the HQ is required to implement policy across complex subsidiary networks consisting of diverse and distant units. Drawing from the literature on HQ challenges of MNC management and control, this study examines (1) how core components of the CEM process impact optimization of global environmental performance (GEP) and then uses network theory to examine how (2) a subsidiary network's dimensions can present challenges to the implementation of green management policies. It presents a framework for CEM which includes (1) MNCs' Verbal environmental commitment, (2) green policy Management which guides standards for operations, (3) actual environmental Performance reflected in a firm's ecological footprint and (4) corporate environmental Reputation (VMPR). Then it explains how an MNC's key subsidiary network dimensions (density, diversity, and dispersion) create challenges that hinder the relationship between green policy management and actual environmental performance. It combines content analysis, multiple regression, and post-hoc hierarchal cluster analysis to study US manufacturing MNCs. The findings support a positive significant effect of verbal environmental commitment and green policy management on actual global environmental performance and environmental reputation, as well as a direct impact of verbal environmental commitment on green policy management. Unexpectedly, network dimensions were not found to moderate the relationship between green management policy and GEP.

Hydrological Conditions Control P Loading and Aquatic Metabolism in an Oligotrophic, Subtropical Estuary

Using high-resolution measures of aquatic ecosystem metabolism and water quality, we investigated the importance of hydrological inputs of phosphorus (P) on ecosystem dynamics in the oligotrophic, P-limited coastal Everglades. Due to low nutrient status and relatively large inputs of terrestrial organic matter, we hypothesized that the ponds in this region would be strongly net heterotrophic and that pond gross primary production (GPP) and respiration (R) would be the greatest during the “dry,” euhaline estuarine season that coincides with increased P availability. Results indicated that metabolism rates were consistently associated with elevated upstream total phosphorus and salinity concentrations. Pulses in aquatic metabolism rates were coupled to the timing of P supply from groundwater upwelling as well as a potential suite of hydrobiogeochemical interactions. We provide evidence that freshwater discharge has observable impacts on aquatic ecosystem function in the oligotrophic estuaries of the Florida Everglades by controlling the availability of P to the ecosystem. Future water management decisions in South Florida must include the impact of changes in water delivery on downstream estuaries.