Showing papers by "Christian Sell published in 2005"
TL;DR: An increase in extracellular signal-regulated kinase-2 phosphorylation suggests that the downstream effects on the tight junction may be due to changes in the mitogen-activated protein kinase signaling pathway, and selective changes in permeability may influence tumorigenesis by the types of solutes now able to cross the epithelial barrier.
Abstract: Although ras mutations have been shown to affect epithelial architecture and polarity, their role in altering tight junctions remains unclear. Transfection of a valine-12 mutated ras construct into LLC-PK1 renal epithelia produces leakiness of tight junctions to certain types of solutes. Transepithelial permeability of D-mannitol increases sixfold but transepithelial electrical resistance increases >40%. This indicates decreased paracellular permeability to NaCl but increased permeability to nonelectrolytes. Permeability increases to D-mannitol (Mr 182), polyethylene glycol (Mr 4000), and 10,000-Mr methylated dextran but not to 2,000,000-Mr methylated dextran. This implies a "ceiling" on the size of solutes that can cross a ras-mutated epithelial barrier and therefore that the increased permeability is not due to loss of cells or junctions. Although the abundance of claudin-2 declined to undetectable levels in the ras-overexpressing cells compared with vector controls, levels of occludin and claudins 1, 4, and 7 increased. The abundance of claudins-3 and -5 remained unchanged. An increase in extracellular signal-regulated kinase-2 phosphorylation suggests that the downstream effects on the tight junction may be due to changes in the mitogen-activated protein kinase signaling pathway. These selective changes in permeability may influence tumorigenesis by the types of solutes now able to cross the epithelial barrier.
42 citations
TL;DR: It is found that, in prostate epithelial cells, the introduction of an activated HRAS causes cells to produce VEGF in response to insulin-like growth factor I (IGF-I), and IGF-I produced locally for normal tissue homeostasis.
Abstract: Mutations in the three closely related RAS genes, HRAS, KRAS, and NRAS are among the most common mutations found in human cancer; reaching 50% in some types of cancer, such as colorectal carcinoma, and 10% in prostate cancers The activated Ras proteins produced by these mutations can, among other cellular changes, increase vascular endothelial growth factor (VEGF) production Moreover, tumors bearing RAS gene mutations are more vascular than tumors without RAS mutations We find that, in prostate epithelial cells, the introduction of an activated HRAS causes cells to produce VEGF in response to insulin-like growth factor I (IGF-I) In comparison, cells lacking an activated Ras are unable to produce VEGF in response to IGF-I This effect of Ras may occur through stabilization of a second messenger protein, insulin receptor substrate 1, that mediates PI 3-kinase-dependent signaling Because IGF-I is a paracrine/endocrine hormone that has been associated with increased risk for several types of cancer, these results suggest a novel interrelationship between oncogenic conversion of a cellular gene such as HRAS, and IGF-I produced locally for normal tissue homeostasis
26 citations