The EYA Tyrosine Phosphatase Activity Is Pro-Angiogenic and Is Inhibited by Benzbromarone

Eyes Absents (EYA) are multifunctional proteins best known for their role in organogenesis. There is accumulating evidence that overexpression of EYAs in breast and ovarian cancers, and in malignant peripheral nerve sheath tumors, correlates with tumor growth and increased metastasis. The EYA protein is both a transcriptional activator and a tyrosine phosphatase, and the tyrosine phosphatase activity promotes single cell motility of mammary epithelial cells. Since EYAs are expressed in vascular endothelial cells and cell motility is a critical feature of angiogenesis we investigated the role of EYAs in this process. Using RNA interference techniques we show that EYA3 depletion in human umbilical vein endothelial cells inhibits transwell migration as well as Matrigel-induced tube formation. To specifically query the role of the EYA tyrosine phosphatase activity we employed a chemical biology approach. Through an experimental screen the uricosuric agents Benzbromarone and Benzarone were found to be potent EYA inhibitors, and Benzarone in particular exhibited selectivity towards EYA versus a representative classical protein tyrosine phosphatase, PTP1B. These compounds inhibit the motility of mammary epithelial cells over-expressing EYA2 as well as the motility of endothelial cells. Furthermore, they attenuate tubulogenesis in matrigel and sprouting angiogenesis in the ex vivo aortic ring assay in a dose-dependent fashion. The anti-angiogenic effect of the inhibitors was also demonstrated in vivo, as treatment of zebrafish embryos led to significant and dose-dependent defects in the developing vasculature. Taken together our results demonstrate that the EYA tyrosine phosphatase activity is pro-angiogenic and that Benzbromarone and Benzarone are attractive candidates for repurposing as drugs for the treatment of cancer metastasis, tumor angiogenesis, and vasculopathies

A copia-like element in Pisum demonstrates the uses of dispersed repeated sequences in genetic analysis

A DNA sequence between two legumin genes in Pisum is a member of the copia-like class of retrotransposons and represents one member of a polymorphic and heterogeneous dispersed repeated sequence family in Pisum. This sequence can be exploited in genetic studies either by RFLP analysis where several markers can be scored together, or the segregation of individual elements can be followed after PCR amplification of specific members

Gender specificity in the prediction of clinically diagnosed depression. Results of a large cohort of Belgian workers.

BACKGROUND: The recent increase in the incidence of clinical depression represents a major public health and socio-economical burden. Depression has its roots in both professional and private domains but few epidemiological studies have looked at predictors of long term clinical depression as defined by a sick-leave of 28 days or more and a diagnosis by a general practitioner in both genders. OBJECTIVES: To study baseline predictors of long term spells of clinical depression within the framework of a large prospective study, the Belstress Study, in 6,659 men and 2,737 women aged 35-59 years at baseline survey. METHODS: Kaplan-Meyer survival curves and Cox regression models were used in order to relate long term clinical depression defined by a sick-leave of 28 days or more to baseline socio-demographic and work and non-work variables. RESULTS AND CONCLUSIONS: Density incidence of long term clinical depression is 0.5 years and 1.1/1,000 persons/months for men and women respectively. In univariate analyses specific gender predictors were observed as for men predictors besides level of education, were work related: high job-strain OR 1.67 (CI 95% 1.03; 2.71) and work dissatisfaction OR 1.78 (CI 95% 1.09; 2.91) whereas for women baseline predictors are related to private life dissatisfaction OR 1.84 (CI 95% 1.16; 2.91) and to a lesser degree low social support from co-workers OR 1.50 (CI 95% 0.93; 2.40). In both genders baseline severe depression symptoms defined by a CES-D score of percentile 90 or above is a predictor of long term sick-leave for clinical depression. In multivariate analyses, in a model without baseline CES-D high job-strain and job dissatisfaction remain independent predictors for incident clinical depression in men whereas only private life dissatisfaction remains a significant predictor in women. When added to the model CES-D is the most powerful predictor of clinical depression in both genders. Together with level of education, work dissatisfaction remains borderline significant in men whereas private life dissatisfaction remains an independent predictor for clinical depression in women. In men baseline symptoms of depression alleviate the impact of high job-strain on incident clinical depression whereas in women, private life dissatisfaction remains an independent predictor of clinical depression.Comparative StudyJournal Articleinfo:eu-repo/semantics/publishe