Ligand-Induced Tyrosine Phosphorylation of Cysteinyl Leukotriene Receptor 1 Triggers Internalization and Signaling in Intestinal Epithelial Cells

Leukotriene D(4) (LTD(4)) belongs to the bioactive lipid group known as eicosanoids and has implications in pathological processes such as inflammation and cancer. Leukotriene D(4) exerts its effects mainly through two different G-protein-coupled receptors, CysLT(1) and CysLT(2). The high affinity LTD(4) receptor CysLT(1)R exhibits tumor-promoting properties by triggering cell proliferation, survival, and migration in intestinal epithelial cells. In addition, increased expression and nuclear localization of CysLT(1)R correlates with a poorer prognosis for patients with colon cancer

Hormone-replacement therapy influences gene expression profiles and is associated with breast-cancer prognosis: a cohort study

BACKGROUND: Postmenopausal hormone-replacement therapy (HRT) increases breast-cancer risk. The influence of HRT on the biology of the primary tumor, however, is not well understood. METHODS: We obtained breast-cancer gene expression profiles using Affymetrix human genome U133A arrays. We examined the relationship between HRT-regulated gene profiles, tumor characteristics, and recurrence-free survival in 72 postmenopausal women. RESULTS: HRT use in patients with estrogen receptor (ER) protein positive tumors (n = 72) was associated with an altered regulation of 276 genes. Expression profiles based on these genes clustered ER-positive tumors into two molecular subclasses, one of which was associated with HRT use and had significantly better recurrence free survival despite lower ER levels. A comparison with external data suggested that gene regulation in tumors associated with HRT was negatively correlated with gene regulation induced by short-term estrogen exposure, but positively correlated with the effect of tamoxifen. CONCLUSION: Our findings suggest that post-menopausal HRT use is associated with a distinct gene expression profile related to better recurrence-free survival and lower ER protein levels. Tentatively, HRT-associated gene expression in tumors resembles the effect of tamoxifen exposure on MCF-7 cells

Involvement of Eicosanoid Signaling in Intestinal Epithelial Cell Survival

Eicosanoids are known to be involved in many different aspects of eukaryotic physiology and pathology. Notably, over the past 10 years much attention has been given to cyclooxygenase-2 (COX-2) due to its involvement in colorectal cancer. Less is known about the other major branch of arachidonic acid metabolism, namely the lipoxygenases (LO). The cysteinyl leukotrienes (CysLTs) are a family of metabolites derived from 5-LO, and they are fairly well known because they play a pathogenic role in asthmatic disease. One member of this family, LTD4 , aggravates asthma by exerting a powerful mitogenic effect on bronchiolar smooth muscle. In light of this observation and the fact that tissue levels of leukotrienes are high in the precancerous inflammatory bowel disease known as ulcerative colitis, the present studies focused mainly on the influence of leukotrienes in general, and LTD4 in particular, on the survival of intestinal epithelial cells. Stimulation of intestinal epithelial cells with leukotrienes heightened the expression of colorectal oncogenic factors, such as COX-2, b-catenin, and Bcl-2, and simultaneously boosted the resistance of the cells to death induced by non-steroidal anti-inflammatory drugs. In analogy with this, levels of the LTD4 receptor CysLT1 R were significantly increased in roughly 50% of 84 colorectal cancer specimens, and this was accompanied by a markedly poorer disease outcome. Interestingly, in addition to the plasma membrane, the CysLT1 R receptor was specifically found in cell nuclei, possibly because this protein contains a putative nuclear-localizing sequence. This finding indicates that leukotrienes may even act as intracellular messengers

Bildandet av företagssamarbete : en studie av svensk-sydafrikanska småföretagssamarbeten

Background: The Background of this thesis dates back to November of 1999 when Sweden arranged its largest manifestation ever in a developing country, namely South Africa. The origin of this study lies within the frame of Trade&Industry, more specifically a seminar on small business partnership. At the seminar companies with less than 20 employees from both countries were introduced to each other with the long term goal of establishing partnerships between the two countries. These companies awoke our interest in the process of creating a partnership. Purpose: With this thesis, we hope to contribute to a higher level of knowledge about small business partnership creation. We also intend to give normative guidelines as for what may be important to have in mind when creating a partnership. We will do this by describing the initial stage of collaboration between small companies and by discussing how initial conditions may affect the parties’ collaboration. Delimitation: Our focus is on the strategic objectives and context of collaboration, and we have looked upon these factors without taking corporate culture or external factors, such as political environment, business climate etc., into account. Proceed of the Study: As well as participating in the manifestation and at the seminar we have conducted interviews with representatives from 8 companies. Results: In creating a small business partnership companies often heavily depends on one key-person. Communication between companies will contribute to a clearer value-creation scenario - and misunderstandings can be avioded. Furthermore, flexibility, openness and equality between partners will substantially ease the process of creating a partnership

Bildandet av företagssamarbete : en studie av svensk-sydafrikanska småföretagssamarbeten

Background: The Background of this thesis dates back to November of 1999 when Sweden arranged its largest manifestation ever in a developing country, namely South Africa. The origin of this study lies within the frame of Trade&Industry, more specifically a seminar on small business partnership. At the seminar companies with less than 20 employees from both countries were introduced to each other with the long term goal of establishing partnerships between the two countries. These companies awoke our interest in the process of creating a partnership. Purpose: With this thesis, we hope to contribute to a higher level of knowledge about small business partnership creation. We also intend to give normative guidelines as for what may be important to have in mind when creating a partnership. We will do this by describing the initial stage of collaboration between small companies and by discussing how initial conditions may affect the parties’ collaboration. Delimitation: Our focus is on the strategic objectives and context of collaboration, and we have looked upon these factors without taking corporate culture or external factors, such as political environment, business climate etc., into account. Proceed of the Study: As well as participating in the manifestation and at the seminar we have conducted interviews with representatives from 8 companies. Results: In creating a small business partnership companies often heavily depends on one key-person. Communication between companies will contribute to a clearer value-creation scenario - and misunderstandings can be avioded. Furthermore, flexibility, openness and equality between partners will substantially ease the process of creating a partnership

Leukotrienes induce cell-survival signaling in intestinal epithelial cells

BACKGROUND & AIMS: Inflammatory bowel conditions, particularly ulcerative colitis, are associated with an increased incidence of neoplastic transformation. High levels of proinflammatory leukotrienes (LTs) and up-regulated expression of cyclooxygenase (COX)-2 are characteristic of inflammation. Moreover, COX-2 has been implicated in cell survival and early colon carcinogenesis. Other aspects of interest for intestinal cell viability are the levels of beta-catenin and the antiapoptotic protein Bcl-2. We investigated the possibility that LTs participate in the regulation of these survival factors. METHODS: We used the human intestinal epithelial cell line Int 407 and the rat intestinal epithelial cell line IEC-6. Immunoblotting was applied to ascertain protein expression and distribution, and enzyme immunoassay methodology was used to measure prostaglandin E(2) (PGE(2)) production. Apoptotic ability was assessed by trypan blue exclusion, Hoechst staining, DNA fragmentation, and a caspase-3 activity assay. RESULTS: LTD(4) and LTB(4), but not LTC(4), caused a time- and dose-dependent increase in expression and/or membrane accumulation of COX-2, beta-catenin, and Bcl-2, as well as PGE(2) production. Apoptosis assays showed that the effects of LTs on these transformation-associated proteins correlated well with the ability of these LTs to reduce programmed cell death. CONCLUSIONS: The results suggest that inflammatory conditions are associated with the expression and distribution of proteins that are characteristic of transformed cells; such conditions may involve a signaling mechanism comprising an altered rate of apoptosis

Do leukotrienes increase cell viability in human intestinal epithelial cells?

In this preliminary report we present data showing that leukotrienes increase the baseline cell viability in human intestinal epithelial cells and that LTB4 partially reverses the morphological hallmarks of non-necrotic cell death induced by the COX-2 specific inhibitor NS-398. The proposed signaling mechanisms regulating these events are summarized in fig. 3. Please view the work on LT signal transduction in these cells by Thodeti et al. in this volume