Glucocorticoid Receptor Counteracts Tumorigenic Activity of Akt in Skin through Interference with the Phosphatidylinositol 3-Kinase Signaling Pathway. Export

@article{citeulike:903843, abstract = {The skin-targeted overexpression of the glucocorticoid receptor (GR) in transgenic mice dramatically impairs the inflammatory responses to tumor promoter agents and suppresses skin tumor development. The antiinflammatory, rapid effects of corticosteroids are partially exerted through interference of GR with the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway in several tissues, a highly relevant pathway in the mouse skin tumor progression process. In this work, we aimed to elucidate whether a cross-talk mechanism between GR and PI3K/Akt occurred in intact skin as well as the biological relevance of this interaction during skin tumorigenesis. We report that, in transgenic mice overexpressing the receptor, GR physically associated with p85 alpha/PI3K in skin, resulting in decreased Akt and I kappa B kinase activity. GR activation by dexamethasone in normal mouse skin also decreased Akt activity within minutes, whereas cotreatment with the GR antagonist RU486 abolished dexamethasone action. Indeed, GR exerted a nongenomic action because keratinocyte transfection with a transcriptionally defective receptor mutant still decreased PI3K and Akt activity. Moreover, GR coexpression greatly reduced the accelerated growth of malignant tumors and increased Akt activity induced by Akt-transfected keratinocytes, as shown by in vivo tumorigenic assays. Overall, our data strongly indicate that GR/PI3K-Akt cross-talk constitutes a major mechanism underlying the antitumor effect of glucocorticoids in skin.}, address = {Instituto de Biomedicina de Valencia-Consejo Superior de Investigaciones Cientificas, E-46010 Valencia, Spain.}, author = {Leis, H. and Page, A. and Ram\'{\i}rez, A. and Bravo, A. and Segrelles, C. and Paramio, J. and Barettino, D. and Jorcano, J. L. and P\'{e}rez, P.}, citeulike-article-id = {903843}, citeulike-linkout-0 = {http://dx.doi.org/10.1210/me.2003-0350}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/14615607}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=14615607}, doi = {10.1210/me.2003-0350}, issn = {0888-8809}, journal = {Mol Endocrinol}, keywords = {akt, gr, pi3k}, month = {February}, number = {2}, pages = {303--311}, posted-at = {2006-10-18 18:35:26}, priority = {2}, title = {Glucocorticoid Receptor Counteracts Tumorigenic Activity of Akt in Skin through Interference with the Phosphatidylinositol 3-Kinase Signaling Pathway.}, url = {http://dx.doi.org/10.1210/me.2003-0350}, volume = {18}, year = {2004} }

TY - JOUR ID - citeulike:903843 L3 - citeulike-article-id:903843 N2 - The skin-targeted overexpression of the glucocorticoid receptor (GR) in transgenic mice dramatically impairs the inflammatory responses to tumor promoter agents and suppresses skin tumor development. The antiinflammatory, rapid effects of corticosteroids are partially exerted through interference of GR with the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway in several tissues, a highly relevant pathway in the mouse skin tumor progression process. In this work, we aimed to elucidate whether a cross-talk mechanism between GR and PI3K/Akt occurred in intact skin as well as the biological relevance of this interaction during skin tumorigenesis. We report that, in transgenic mice overexpressing the receptor, GR physically associated with p85 alpha/PI3K in skin, resulting in decreased Akt and I kappa B kinase activity. GR activation by dexamethasone in normal mouse skin also decreased Akt activity within minutes, whereas cotreatment with the GR antagonist RU486 abolished dexamethasone action. Indeed, GR exerted a nongenomic action because keratinocyte transfection with a transcriptionally defective receptor mutant still decreased PI3K and Akt activity. Moreover, GR coexpression greatly reduced the accelerated growth of malignant tumors and increased Akt activity induced by Akt-transfected keratinocytes, as shown by in vivo tumorigenic assays. Overall, our data strongly indicate that GR/PI3K-Akt cross-talk constitutes a major mechanism underlying the antitumor effect of glucocorticoids in skin. IS - 2 JF - Mol Endocrinol SN - 0888-8809 AD - Instituto de Biomedicina de Valencia-Consejo Superior de Investigaciones Cientificas, E-46010 Valencia, Spain. EP - 311 TI - Glucocorticoid Receptor Counteracts Tumorigenic Activity of Akt in Skin through Interference with the Phosphatidylinositol 3-Kinase Signaling Pathway. VL - 18 SP - 303 KW - akt KW - gr KW - pi3k AU - Leis, H AU - Page, A AU - Ramírez, A AU - Bravo, A AU - Segrelles, C AU - Paramio, J AU - Barettino, D AU - Jorcano, JL AU - Pérez, P PY - 2004/02// UR - http://dx.doi.org/10.1210/me.2003-0350 ER -