Thu, 21 Aug 2008 07:07:14 BST CiteULike: gambarde's Paterson http://www.citeulike.org/user/gambarde/author/Paterson CiteULike.org en-gb Copyright © 2004-2008 citeulike.org http://www.citeulike.org/user/gambarde/article/404685 <i>Cancer Cell, Vol. 7, No. 3. (March 2005), pp. 219-226.</i><br /><br />To investigate the role of signaling by the small GTPase Ral, we have generated mice deficient for RalGDS, a guanine nucleotide exchange factor that activates Ral. We show that RalGDS is dispensable for mouse development but plays a substantial role in Ras-induced oncogenesis. Lack of RalGDS results in reduced tumor incidence, size, and progression to malignancy in multistage skin carcinogenesis, and reduced transformation by Ras in tissue culture. RalGDS does not appear to participate in the regulation of cell proliferation, but instead controls survival of transformed cells. Experiments performed in cells isolated from skin tumors suggest that RalGDS mediates cell survival through the activation of the JNK/SAPK pathway. These studies identify RalGDS as a key component in Ras-dependent carcinogenesis in vivo. RalGDS is required for tumor formation in a model of skin carcinogenesis. A González-García CA Pritchard HF Paterson G Mavria G Stamp CJ Marshall doi:10.1016/j.ccr.2005.01.029 Cancer Cell, Vol. 7, No. 3. (March 2005), pp. 219-226. 2005-11-22T16:06:22-00:00 2005 Cancer Cell 1535-6108 7 3 219 226 carcinogenesis skin http://www.citeulike.org/user/gambarde/article/2718963 <i>Cancer Cell, Vol. 9, No. 1. (January 2006), pp. 33-44.</i><br /><br />Summary Inhibition of ERK-MAPK signaling by expression of dominant-negative MEK1 in the tumor vasculature suppresses angiogenesis and tumor growth. In an organotypic tissue culture angiogenesis assay, ERK-MAPK inhibition during the migratory phase results in loss of bipolarity, detachment, and cell death of isolated endothelial cells and retraction of sprouting tubules. These effects are the consequence of upregulated Rho-kinase signaling. Transient inhibition of Rho-kinase rescues the effects of ERK-MAPK inhibition in vitro and in vivo, promotes sprouting, and increases vessel length in tumors. We propose a regulatory role of Rho-kinase by ERK-MAPK during angiogenesis that acts through the control of actomyosin contractility. Our data delineate a mechanism by which ERK-MAPK promotes endothelial cell survival and sprouting by downregulating Rho-kinase signaling. ERK-MAPK signaling opposes Rho-kinase to promote endothelial cell survival and sprouting during angiogenesis Georgia Mavria Yvonne Vercoulen Maggie Yeo Hugh Paterson Maria Karasarides Richard Marais Demelza Bird Christopher Marshall doi:10.1016/j.ccr.2005.12.021 Cancer Cell, Vol. 9, No. 1. (January 2006), pp. 33-44. 2008-04-25T16:27:56-00:00 2006 Cancer Cell 9 1 33 44 angiogenesis endothelial_cell rho