Constitutive activation of JAK–STAT3 signaling by BRCA1 in human prostate cancer cells

AbstractGerm-line mutations of the breast cancer susceptibility gene 1 (BRCA1) confer a high risk for breast and ovarian cancer in women and prostate cancer in men. The BRCA1 protein contributes to cell proliferation, cell cycle regulation, DNA repair and apoptosis; however, the mechanisms underlying these functions of BRCA1 remain largely unknown. Here, we showed that, in Du-145 human prostate cancer cells, enhanced expression of BRCA1 resulted in constitutive activation of signal transducer and activator transcription factor 3 (STAT3) tyrosine and serine phosphorylation. Moreover, Janus kinase 1 (JAK1) and JAK2, the upstream activators of STAT3, were also activated by BRCA1. Immunoprecipitation assay showed that BRCA1 interacted with JAK1 and JAK2. Blocking STAT3 activation using antisense oligonucleotides significantly inhibited cell proliferation and triggered apoptosis in Du-145 cells with enhanced expression of BRCA1. These findings indicate that BRCA1 interacts with the components of the JAK–STAT signaling cascade and modulates its activation, which may provide a new critical survival signal for the growth of breast, ovarian and prostate cancers in the presence of normal BRCA1

An Improved Method for Estimating Renal Dimensions; Implications for Management of Kidney Disease

Changes in renal dimensions, including total kidney volume, not only inform ongoing renal disease but also disease progression. Determination of renal dimensions can inform drug efficacy, is important for matching recipients with potential donors, and to inform debulking of renal tumors. Imaging of kidney and application of the ellipse-based formula has become standard for estimating renal dimensions. Nevertheless, the existing ellipse-based formula underestimates renal dimensions including total kidney volume, regardless of the imaging modality used. Based on a model of murine kidney disease, this laboratory has previously proposed a modification to this formula which exhibits better estimation of renal dimensions. The present study sought to determine whether this modified formula is applicable to additional models of kidney disease. Kidneys were sourced from etiologically distinct murine and rat models of renal scarring. In each case, renal dimensions calculated using the existing ellipse-based formula was significantly lesser than the measured dimensions. By contrast, there was no difference between the measured dimensions and those calculated using the modified formula. In a model of polycystic kidney disease, total kidney volume calculated using the existing formula significantly underestimated measured kidney volume whereas use of the modified formula yielded a calculated kidney volume in excellent agreement with the measured volume. Use of this modified formula provides a better estimate of renal dimensions across a number of disease models

Strain and site dependence of polyploidization of cultured rat smooth muscle

Smooth muscle cell (SMC) growth may play an important role in the pathogenesis of vascular diseases such as atherosclerosis and hypertension. Recent studies have demonstrated that, under different growth stimuli in vivo, SMC may respond by proliferation of diploid cells, polyploidization to the tetraploid (or even octaploid) state, or both. In this study, we used flow cytometry to evaluate the intrinsic tendencies of aortic SMC and nonarterial cells from rats of different strains, ages, and blood pressures to polyploidize in response to in vitro growth stimulation. Significant strain‐related differences in polyploidization of aortic SMC were found (P \u3c 0.001): highest in WKY (normotensive inbred rat related to SHR), intermediate in SHR (genetically hypertensive rat), and lowest in Sprague‐Dawley and Fischer (normotensive outbred and inbred rats). Animal age had less or no effect on the degree of polyploidization. Nonarterial cells (venous SMC and lung cells) from WKY and SHR remained essentially diploid, suggesting tissue specificity of in vitro polyploidization. Studies of the growth kinetics of uncloned and clonal populations of aortic SMC revealed decreased proliferation as the ploidy increased in WKY, SHR, and Sprague‐Dawley, These findings suggest that genetic strain factors as well as cell type/site of origin significantly influence in vitro polyploidization, whereas animal age and blood pressure do not. The findings also emphasize the need to consider ploidy changes when evaluating in vitro SMC growth kinetics. Further studies will improve understanding of SMC growth regulation and the functional significance of vascular polyploidy