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Establishment and maintenance of tissue polarity is a functional property of epithelial cells and loss of this property is a hallmark of the breast cancer phenotype. We have used a 3-dimensional culture assay in which malignant human breast cells can be phenotypically reverted to a non- malignant phenotype when P13 kinase (Pl3K) activity is inhibited. We show here that Akt and Raci act as downstream effectors of Pl3K and function as control points of cellular proliferation and tissue polarity respectively. Signaling through these two effectors is sufficient to prevent restoration of a normal phenotype. We reveal key events downstream of Pl3K that act synergistically to maintain tissue polarity and when disrupted result in malignant phenotype. We also find that activation of Akti can prevent invasive behavior in vitro. Activated Aktl in human breast cancer cells affects cell motility and invasiveness by targeting the tumor suppressor tuberous sclerosis complex 2 (TSC2) for degradation leading to reduced Rho-GTPase activity. TSC2 thus acts as a downstream target of Aktl to regulate breast cancer cell motility and invasion suggesting the need for caution in designing therapies targeting the fundtion of individual genes in epithelial tissues.

Myopia, or nearsightedness, is the most common eye disorder, resulting primarily from excess elongation of the eye. The etiology of myopia, although known to be complex, is poorly understood. Here we report the largest ever genome-wide association study (43,360 participants) on myopia in Europeans. We performed a survival analysis on age of myopia onset and identified 19 significant associations (p < 5e-8), two of which are replications of earlier associations with refractive error. These 19 associations in total explain 2.7% of the variance in myopia age of onset, and point towards a number of different mechanisms behind the development of myopia. One association is in the gene PRSS56, which has previously been linked to abnormally small eyes; one is in a gene that forms part of the extracellular matrix (LAMA2); two are in or near genes involved in the regeneration of 11-cis-retinal (RGR and RDH5); two are near genes known to be involved in the growth and guidance of retinal ganglion cells (ZIC2, SFRP1); and five are in or near genes involved in neuronal signaling or development. These novel findings point towards multiple genetic factors involved in the development of myopia and suggest that complex interactions between extracellular matrix remodeling, neuronal development, and visual signals from the retina may underlie the development of myopia in humans.

This article is from BMC Nephrology , volume 13 . Abstract Background: Polycystic Kidney Disease (PKD) kidneys exhibit increased extracellular matrix (ECM) collagen expression and metalloproteinases (MMPs) activity. We investigated the role of these increases on cystic disease progression in PKD kidneys. Methods: We examined the role of type I collagen (collagen I) and membrane bound type 1 MMP (MT1-MMP) on cyst development using both in vitro 3 dimensional (3D) collagen gel culture and in vivo PCK rat model of PKD. Results: We found that collagen concentration is critical in controlling the morphogenesis of MDCK cells cultured in 3D gels. MDCK cells did not form 3D structures at collagen I concentrations lower than 1 mg/ml but began forming tubules when the concentration reaches 1 mg/ml. Significantly, these cells began to form cyst when collagen I concentration reached to 1.2 mg/ml, and the ratios of cyst to tubule structures increased as the collagen I concentration increased. These cells exclusively formed cyst structures at a collagen I concentration of 1.8 mg/ml or higher. Overexpression of MT1-MMP in MDCK cells significantly induced cyst growth in 3D collagen gel culture. Conversely, inhibition of MMPs activity with doxycycline, a FDA approved pan-MMPs inhibitor, dramatically slowed cyst growth. More importantly, the treatment of PCK rats with doxycycline significantly decreased renal tubule cell proliferation and markedly inhibited the cystic disease progression. Conclusions: Our data suggest that increased collagen expression and MMP activity in PKD kidneys may induce cyst formation and expansion. Our findings also suggest that MMPs may serve as a therapeutic target for the treatment of human PKD.