A genomic sequence comparison within and flanking the ERRbeta genes of eight species demonstrated that short-form hERRbeta lacks an F domain and is the matched homolog of mouse and rat ERRbeta proteins in humans. However, hERRbeta2-Delta10 and the previously reported hERRbeta2 isoforms are primate specific. RT-PCR analysis showed that short-form hERRbeta has a wide distribution in the 24 of 27 human tissues and cell lines tested, whereas hERRbeta2 and hERRbeta2-Delta10 were only expressed in testis and kidney. The three human ERRbeta-splicing isoforms have different transcriptional activities when measured on an estrogen response element-driven luciferase reporter in transfection assays. The localization of a nuclear localization signal of short-form hERRbeta was also determined. Interestingly, the F domain of hERRbeta2 alters the function of the nuclear localization signal. Therefore, the ERRbeta isoforms are likely to have diverse biological functions in vivo, and characterizing the three isoforms of ERRbeta will lead to an understanding of the multiple levels of gene regulation involved in steroid receptor-signaling pathways in humans and may provide novel therapeutic targets for human diseases.

Objective-We examined the impact of C-reactive protein (CRP) on vascular smooth muscle cell (VSMC) expression of tissue factor (TF) and TF pathway inhibitor (TFPI

BackgroundPlatelets play a fundamental role in maintaining hemostasis and have been shown to participate in hematogenous dissemination of tumor cells. Abundant platelets were detected in the tumor microenvironment outside of the blood vessel, thus, platelet -tumor cell interaction outside of the bloodstream may play a role in regulating primary tumor growth and metastasis initiation. However, it is unclear that platelet depletion affects tumor vessel structure and dynamics.MethodsUsing thrombocytopenia induction in two different tumor-bearing mouse models, tumor tissues were performed by Westernblotting and immunohistochemical staining. Vascular permeability was evaluated by determination of intratumoral Evans blue and Miles vascular permeability assay. Furthermore, microdialysis was used to examining the intratumoral extracellular angiogenic growth factors (VEGF, TGF-β) by ELISA.ResultsPlatelet depletion showed no change in tumor growth and reduced lung metastasis. Platelet depletion led to reduced tumor hypoxia and Met receptor activation and was associated with a decreased release of MMP-2, 9, PAI-1, VEGF, and TGF-β. Tumor vessels in platelet-depleted mice showed impaired vessel density and maturation.ConclusionsOur findings demonstrate that platelets within the primary tumor microenvironment play a critical role in the induction of vascular permeability and initiation of tumor metastasis.