Cell Detachment Triggers p38 Mitogen-activated Protein Kinase-dependent Overexpression of Fas Ligand

Many cell types undergo apoptosis when they are detached from the extracellular matrix (ECM). This phenomenon has been termed anoikis. Most epithelial cells, which are normally attached to a type of ECM called basement membrane, are particularly sensitive to anoikis. Conversely, carcinoma cells tend to be resistant to anoikis, and this resistance plays a critical role in tumor invasion and metastasis. We reported previously that detachment-induced down-regulation of the anti-apoptotic molecule Bcl-XLmakes a significant contribution to anoikis of intestinal epithelial cells. Here we demonstrate that exogenous Bcl-XL, no matter how highly expressed in these cells, can significantly attenuate anoikis but cannot completely prevent it, suggesting that at least another pro-apoptotic event is activated by the loss of cell-ECM contacts. Indeed, in this study we identified a novel mechanism of anoikis in intestinal epithelial cells that involves detachment-induced overexpression of Fas ligand. We also demonstrated that this elevation in Fas ligand expression requires a detachment-induced increase of p38 mitogen-activated protein kinase activity. We conclude that the activation of at least two different pro-apoptotic events is required for anoikis of intestinal epithelial cells. Many cell types undergo apoptosis when they are detached from the extracellular matrix (ECM). This phenomenon has been termed anoikis. Most epithelial cells, which are normally attached to a type of ECM called basement membrane, are particularly sensitive to anoikis. Conversely, carcinoma cells tend to be resistant to anoikis, and this resistance plays a critical role in tumor invasion and metastasis. We reported previously that detachment-induced down-regulation of the anti-apoptotic molecule Bcl-XLmakes a significant contribution to anoikis of intestinal epithelial cells. Here we demonstrate that exogenous Bcl-XL, no matter how highly expressed in these cells, can significantly attenuate anoikis but cannot completely prevent it, suggesting that at least another pro-apoptotic event is activated by the loss of cell-ECM contacts. Indeed, in this study we identified a novel mechanism of anoikis in intestinal epithelial cells that involves detachment-induced overexpression of Fas ligand. We also demonstrated that this elevation in Fas ligand expression requires a detachment-induced increase of p38 mitogen-activated protein kinase activity. We conclude that the activation of at least two different pro-apoptotic events is required for anoikis of intestinal epithelial cells. Survival of most normal epithelial cells requires adhesion to a type of extracellular matrix (ECM) 1The abbreviations used for: ECM, extracellular matrix; MAP, mitogen-activated protein; IEC, intestinal epithelial cells; FBS, fetal bovine serum; MEM, minimum Eagle's medium; ELISA, enzyme-linked immunosorbent assay; d.n., dominant negative; GFP, green fluorescent protein; IAPs, inhibitor of apoptosis proteins. 1The abbreviations used for: ECM, extracellular matrix; MAP, mitogen-activated protein; IEC, intestinal epithelial cells; FBS, fetal bovine serum; MEM, minimum Eagle's medium; ELISA, enzyme-linked immunosorbent assay; d.n., dominant negative; GFP, green fluorescent protein; IAPs, inhibitor of apoptosis proteins. called basement membrane. Loss of cell-ECM contacts results in death of such cells by apoptosis, a phenomenon known as anoikis (1Meredith J.E. Fazeli B. Schwartz M.A. Mol. Biol. Cell. 1993; 4: 953-961Crossref PubMed Scopus (1389) Google Scholar, 2Frisch S.M. Francis H. J. Cell Biol. 1994; 124: 619-626Crossref PubMed Scopus (2748) Google Scholar, 3Frisch S.M. Screaton R.A. Curr. Opin. Cell Biol. 2001; 13: 555-562Crossref PubMed Scopus (1157) Google Scholar). Induction of anoikis is now thought to play a critical role in several physiological processes such as cavitation during vertebrate development and mammary gland regression after weaning (4Meredith J.E. Schwartz M.A. Trends Cell Biol. 1997; 7: 147-150Abstract Full Text PDF Scopus (245) Google Scholar, 5Frisch S.M. Ruoslahti E. Curr. Opin. Cell Biol. 1997; 9: 701-706Crossref PubMed Scopus (979) Google Scholar, 6Grossmann J. Apoptosis. 2002; 7: 247-260Crossref PubMed Scopus (473) Google Scholar). The process of cavitation transforms the solid embryonic ectoderm into a basement membrane-attached columnar epithelium surrounding a cavity. The cavity is generated by the apoptosis of the cells that are not attached to the basement membrane (7Coucouvanis E. Martin G.R. Cell. 1995; 83: 279-287Abstract Full Text PDF PubMed Scopus (492) Google Scholar). In the mammary gland cessation of lactation induces the secretion of metalloproteases that destroy the basement membrane to which milk-producing mammary epithelial cells are attached. As a consequence such cells undergo apoptosis that leads to mammary gland regression (8Strange R. Li F. Saurer S. Burkhardt A. Friis R.R. Development. 1992; 115: 49-58Crossref PubMed Google Scholar, 9Wiesen J. Werb Z. Mol. Reprod. Dev. 2000; 56: 534-540Crossref PubMed Scopus (23) Google Scholar).Anoikis is also thought to play an important role in the elimination of intestinal epithelial cells shed into the intestinal lumen. The surface of the intestine is covered by a single layer of epithelial cells that differentiate as they migrate upwards along the intestinal crypts and villi to be eventually shed into the lumen. As these cells reach the top of the crypt or villi they detach from the basement membrane and undergo apoptosis (10Ikeda H. Suzuki Y. Suzuki M. Koike M. Tamura J. Tong J. Nomura M. Itoh G. Gut. 1998; 42: 530-537Crossref PubMed Scopus (273) Google Scholar, 11Strater J. Wedding U. Barth Full Text Full Text PDF PubMed Scopus Google Scholar, J. S. E. J. 1998; PubMed Google in the of anoikis has significantly during the as that resistance to anoikis is a critical for invasion and in from epithelial cells S.M. Screaton R.A. Curr. Opin. Cell Biol. 2001; 13: 555-562Crossref PubMed Scopus (1157) Google Scholar, 2001; PubMed Scopus Google Scholar). of anoikis an the development of novel for has been demonstrated that the of anoikis resistance tumor J. J. J. Cell Biol. 2000; PubMed Scopus Google J. J. J. Curr. Biol. 1998; Full Text Full Text PDF PubMed Google the in the study of anoikis, the of this phenomenon are cells are known to to the ECM called S.M. Ruoslahti E. Curr. Opin. Cell Biol. 1997; 9: 701-706Crossref PubMed Scopus (979) Google Scholar, M.A. J. Cell Biol. 1997; PubMed Scopus Google Scholar). The loss of cell-ECM adhesion results in as as in of the cell events are known to to in the expression of that are in the of As a consequence of these the activated and anoikis is J. Apoptosis. 2002; 7: 247-260Crossref PubMed Scopus (473) Google is now that cell death is by two of involves the of the into the this molecule in the activation of H. 2000; PubMed Scopus Google Scholar, J. 2000; Full Text Full Text PDF PubMed Google Scholar). are that activation a of critical for cell and apoptosis J. J. Cell 2000; PubMed Google Scholar, Martin Cell PubMed Scopus Google Scholar). The of is and by of the of this such as and are and are pro-apoptotic and B. Cell 2000; PubMed Scopus Google S. 1998; PubMed Scopus Google Scholar). The that cell death involves the activation of of the death such as tumor and Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, A. 2002; PubMed Scopus Google Scholar, H. Trends 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, H. Cell 2000; PubMed Scopus Google Scholar). In most these are activated by but of activation also been Y. G. B. J. Cell Biol. 1998; PubMed Scopus Google Scholar, E. A. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). The activation of the death induces the of the In to the this the and to these are and activated and the to apoptosis H. Trends 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, A. M. J. 1997; PubMed Scopus Google Scholar, A. Burkhardt Mol. Cell. Biol. 2002; PubMed Scopus Google of the death and been to be by cell The M. J. Curr. Biol. 9: Full Text Full Text PDF PubMed Scopus Google Scholar, S.M. Curr. Biol. 9: Full Text Full Text PDF PubMed Scopus Google in this the death in anoikis of types of epithelial and cells. In to death the has also been to in anoikis in that the pro-apoptotic molecule and to the of mammary epithelial cells J. Cell Biol. 2000; PubMed Scopus Google Scholar). study the in anoikis reported that the pro-apoptotic which is normally to the in attached cells, to the cell H. A. A. 2001; PubMed Scopus Google we another mechanism of anoikis. We that of intestinal epithelial cells results in a significant down-regulation of Bcl-XL, and that expression of this anti-apoptotic molecule induces a significant of anoikis J. J. J. Cell Biol. 2000; PubMed Scopus Google Scholar, M. Li A. J. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). We also that the detachment-induced down-regulation of is not of the intestinal is also in epithelial cells J. 2001; Google that the detachment-induced in of the in different cell types the as to these are cell or of these events in the cell We to this in intestinal epithelial cells, and we events by cell which in to the the death is also activated during anoikis M. Li A. J. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). this plays a role in this of apoptosis in intestinal epithelial cells, which are the of activation of the death in such cells are not we that Fas is required for anoikis of intestinal epithelial cells. we demonstrate that the activation of this of the detachment-induced overexpression of Fas and that this increase in Fas ligand expression is by an elevation in p38 kinase this study we demonstrated that anoikis of intestinal epithelial cells requires detachment-induced increase in p38 kinase and p38 overexpression of Fas of the death during anoikis has been by previously M. J. Curr. Biol. 9: Full Text Full Text PDF PubMed Scopus Google Scholar, S.M. Curr. Biol. 9: Full Text Full Text PDF PubMed Scopus Google Scholar, F. J. Cell Biol. 2001; PubMed Scopus Google and to cell anoikis of and epithelial cells can be by dominant but not by that Fas ligand or M. J. Curr. Biol. 9: Full Text Full Text PDF PubMed Scopus Google Scholar). that detachment-induced apoptosis of these types of cells is by of the death in a or that is by death Fas ligand and In cells has been that anoikis requires the Fas ligand and F. J. Cell Biol. 2001; PubMed Scopus Google Scholar). in these cells the events in the activation of the Fas in anoikis are the detachment-induced overexpression of Fas and the detachment-induced down-regulation of an inhibitor of apoptosis that the and and can be that the activation of the Fas plays an important role in anoikis but that the mechanism of activation of this of the death the cell important of this study is the of p38 kinase in anoikis. to detachment-induced elevation in p38 kinase is by an increase in p38 kinase this is known to be activated by such as M. 2001; PubMed Scopus Google Scholar). expression of p38 is for the p38 during anoikis, or to be to such to be activation of the p38 kinase has not been previously anoikis. another has been to play a role in anoikis of epithelial cells G. S.M. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google this is A. J. J. Cell Biol. 1997; PubMed Scopus Google Scholar). We reported previously J. J. PubMed Scopus Google that kinase activation is not in anoikis of intestinal epithelial that p38 kinase plays a role in the of Fas ligand expression during anoikis is this kinase in the of Fas ligand expression in and cells E. A. J. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, J. M. J. 2000; PubMed Scopus Google Scholar, J. J. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). in of these J. J. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google has been demonstrated that p38 kinase can expression by the Fas ligand the results in this study and in J. J. J. Cell Biol. 2000; PubMed Scopus Google Scholar, J. J. J. Curr. Biol. 1998; Full Text Full Text PDF PubMed Google we conclude that anoikis of intestinal epithelial cells is by at least two events that are by cell and which the overexpression of Fas and down-regulation of at the we cannot the that pro-apoptotic events are by of intestinal epithelial cells, such events been in cell types J. Cell Biol. 2000; PubMed Scopus Google H. A. A. 2001; PubMed Scopus Google Fas be to a of cells in the type at apoptosis of cells in the to be to study this of this study is that in intestinal epithelial cells. is to that this plays a significant role in the of anoikis. In several cell types of the been to be to from death apoptosis J. J. Biol. 2001; Full Text Full Text PDF Scopus Google Scholar, S. Cell Biol. PubMed Scopus Google Scholar). is now that in such cells the Fas is to of the to activation by pro-apoptotic such as and S. Cell Biol. PubMed Scopus Google Scholar, S. Y. H. J. J. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, M. M. J. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). The is known to apoptosis by the of the IAPs, which are of J. J. Cell Biol. 2001; PubMed Scopus Google Scholar). The pro-apoptotic role of is critical for the of apoptosis in cells that of S. Y. H. J. J. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). has been reported J. 2002; PubMed Scopus Google that in intestinal epithelial cells to apoptosis by Fas ligand can be by is that in such cells the and is by and plays a critical role in anoikis. Survival of most normal epithelial cells requires adhesion to a type of extracellular matrix (ECM) 1The abbreviations used for: ECM, extracellular matrix; MAP, mitogen-activated protein; IEC, intestinal epithelial cells; FBS, fetal bovine serum; MEM, minimum Eagle's medium; ELISA, enzyme-linked immunosorbent assay; d.n., dominant negative; GFP, green fluorescent protein; IAPs, inhibitor of apoptosis proteins. 1The abbreviations used for: ECM, extracellular matrix; MAP, mitogen-activated protein; IEC, intestinal epithelial cells; FBS, fetal bovine serum; MEM, minimum Eagle's medium; ELISA, enzyme-linked immunosorbent assay; d.n., dominant negative; GFP, green fluorescent protein; IAPs, inhibitor of apoptosis proteins. called basement membrane. Loss of cell-ECM contacts results in death of such cells by apoptosis, a phenomenon known as anoikis (1Meredith J.E. Fazeli B. Schwartz M.A. Mol. Biol. Cell. 1993; 4: 953-961Crossref PubMed Scopus (1389) Google Scholar, 2Frisch S.M. Francis H. J. Cell Biol. 1994; 124: 619-626Crossref PubMed Scopus (2748) Google Scholar, 3Frisch S.M. Screaton R.A. Curr. Opin. Cell Biol. 2001; 13: 555-562Crossref PubMed Scopus (1157) Google Scholar). Induction of anoikis is now thought to play a critical role in several physiological processes such as cavitation during vertebrate development and mammary gland regression after weaning (4Meredith J.E. Schwartz M.A. Trends Cell Biol. 1997; 7: 147-150Abstract Full Text PDF Scopus (245) Google Scholar, 5Frisch S.M. Ruoslahti E. Curr. Opin. Cell Biol. 1997; 9: 701-706Crossref PubMed Scopus (979) Google Scholar, 6Grossmann J. Apoptosis. 2002; 7: 247-260Crossref PubMed Scopus (473) Google Scholar). The process of cavitation transforms the solid embryonic ectoderm into a basement membrane-attached columnar epithelium surrounding a cavity. The cavity is generated by the apoptosis of the cells that are not attached to the basement membrane (7Coucouvanis E. Martin G.R. Cell. 1995; 83: 279-287Abstract Full Text PDF PubMed Scopus (492) Google Scholar). In the mammary gland cessation of lactation induces the secretion of metalloproteases that destroy the basement membrane to which milk-producing mammary epithelial cells are attached. As a consequence such cells undergo apoptosis that leads to mammary gland regression (8Strange R. Li F. Saurer S. Burkhardt A. Friis R.R. Development. 1992; 115: 49-58Crossref PubMed Google Scholar, 9Wiesen J. Werb Z. Mol. Reprod. Dev. 2000; 56: 534-540Crossref PubMed Scopus (23) Google Scholar). is also thought to play an important role in the elimination of intestinal epithelial cells shed into the intestinal lumen. The surface of the intestine is covered by a single layer of epithelial cells that differentiate as they migrate upwards along the intestinal crypts and villi to be eventually shed into the lumen. As these cells reach the top of the crypt or villi they detach from the basement membrane and undergo apoptosis (10Ikeda H. Suzuki Y. Suzuki M. Koike M. Tamura J. Tong J. Nomura M. Itoh G. Gut. 1998; 42: 530-537Crossref PubMed Scopus (273) Google Scholar, 11Strater J. Wedding U. Barth Full Text Full Text PDF PubMed Scopus Google Scholar, J. S. E. J. 1998; PubMed Google Scholar). The in the of anoikis has significantly during the as that resistance to anoikis is a critical for invasion and in from epithelial cells S.M. Screaton R.A. Curr. Opin. Cell Biol. 2001; 13: 555-562Crossref PubMed Scopus (1157) Google Scholar, 2001; PubMed Scopus Google Scholar). of anoikis an the development of novel for has been demonstrated that the of anoikis resistance tumor J. J. J. Cell Biol. 2000; PubMed Scopus Google J. J. J. Curr. Biol. 1998; Full Text Full Text PDF PubMed Google Scholar). the in the study of anoikis, the of this phenomenon are cells are known to to the ECM called S.M. Ruoslahti E. Curr. Opin. Cell Biol. 1997; 9: 701-706Crossref PubMed Scopus (979) Google Scholar, M.A. J. Cell Biol. 1997; PubMed Scopus Google Scholar). The loss of cell-ECM adhesion results in as as in of the cell events are known to to in the expression of that are in the of As a consequence of these the activated and anoikis is J. Apoptosis. 2002; 7: 247-260Crossref PubMed Scopus (473) Google Scholar). is now that cell death is by two of involves the of the into the this molecule in the activation of H. 2000; PubMed Scopus Google Scholar, J. 2000; Full Text Full Text PDF PubMed Google Scholar). are that activation a of critical for cell and apoptosis J. J. Cell 2000; PubMed Google Scholar, Martin Cell PubMed Scopus Google Scholar). The of is and by of the of this such as and are and are pro-apoptotic and B. Cell 2000; PubMed Scopus Google S. 1998; PubMed Scopus Google Scholar). The that cell death involves the activation of of the death such as tumor and Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, A. 2002; PubMed Scopus Google Scholar, H. Trends 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, H. Cell 2000; PubMed Scopus Google Scholar). In most these are activated by but of activation also been Y. G. B. J. Cell Biol. 1998; PubMed Scopus Google Scholar, E. A. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). The activation of the death induces the of the In to the this the and to these are and activated and the to apoptosis H. Trends 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, A. M. J. 1997; PubMed Scopus Google Scholar, A. Burkhardt Mol. Cell. Biol. 2002; PubMed Scopus Google Scholar). of the death and been to be by cell The M. J. Curr. Biol. 9: Full Text Full Text PDF PubMed Scopus Google Scholar, S.M. Curr. Biol. 9: Full Text Full Text PDF PubMed Scopus Google in this the death in anoikis of types of epithelial and cells. In to death the has also been to in anoikis in that the pro-apoptotic molecule and to the of mammary epithelial cells J. Cell Biol. 2000; PubMed Scopus Google Scholar). study the in anoikis reported that the pro-apoptotic which is normally to the in attached cells, to the cell H. A. A. 2001; PubMed Scopus Google Scholar). we another mechanism of anoikis. We that of intestinal epithelial cells results in a significant down-regulation of Bcl-XL, and that expression of this anti-apoptotic molecule induces a significant of anoikis J. J. J. Cell Biol. 2000; PubMed Scopus Google Scholar, M. Li A. J. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). We also that the detachment-induced down-regulation of is not of the intestinal is also in epithelial cells J. 2001; Google Scholar). The that the detachment-induced in of the in different cell types the as to these are cell or of these events in the cell We to this in intestinal epithelial cells, and we events by cell which in to the the death is also activated during anoikis M. Li A. J. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). this plays a role in this of apoptosis in intestinal epithelial cells, which are the of activation of the death in such cells are not Here we that Fas is required for anoikis of intestinal epithelial cells. we demonstrate that the activation of this of the detachment-induced overexpression of Fas and that this increase in Fas ligand expression is by an elevation in p38 kinase activity. this study we demonstrated that anoikis of intestinal epithelial cells requires detachment-induced increase in p38 kinase and p38 overexpression of Fas of the death during anoikis has been by previously M. J. Curr. Biol. 9: Full Text Full Text PDF PubMed Scopus Google Scholar, S.M. Curr. Biol. 9: Full Text Full Text PDF PubMed Scopus Google Scholar, F. J. Cell Biol. 2001; PubMed Scopus Google and to cell anoikis of and epithelial cells can be by dominant but not by that Fas ligand or M. J. Curr. Biol. 9: Full Text Full Text PDF PubMed Scopus Google Scholar). that detachment-induced apoptosis of these types of cells is by of the death in a or that is by death Fas ligand and In cells has been that anoikis requires the Fas ligand and F. J. Cell Biol. 2001; PubMed Scopus Google Scholar). in these cells the events in the activation of the Fas in anoikis are the detachment-induced overexpression of Fas and the detachment-induced down-regulation of an inhibitor of apoptosis that the and and can be that the activation of the Fas plays an important role in anoikis but that the mechanism of activation of this of the death the cell important of this study is the of p38 kinase in anoikis. to detachment-induced elevation in p38 kinase is by an increase in p38 kinase this is known to be activated by such as M. 2001; PubMed Scopus Google Scholar). expression of p38 is for the p38 during anoikis, or to be to such to be activation of the p38 kinase has not been previously anoikis. another has been to play a role in anoikis of epithelial cells G. S.M. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google this is A. J. J. Cell Biol. 1997; PubMed Scopus Google Scholar). We reported previously J. J. PubMed Scopus Google that kinase activation is not in anoikis of intestinal epithelial that p38 kinase plays a role in the of Fas ligand expression during anoikis is this kinase in the of Fas ligand expression in and cells E. A. J. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, J. M. J. 2000; PubMed Scopus Google Scholar, J. J. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). in of these J. J. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google has been demonstrated that p38 kinase can expression by the Fas ligand the results in this study and in J. J. J. Cell Biol. 2000; PubMed Scopus Google Scholar, J. J. J. Curr. Biol. 1998; Full Text Full Text PDF PubMed Google we conclude that anoikis of intestinal epithelial cells is by at least two events that are by cell and which the overexpression of Fas and down-regulation of at the we cannot the that pro-apoptotic events are by of intestinal epithelial cells, such events been in cell types J. Cell Biol. 2000; PubMed Scopus Google H. A. A. 2001; PubMed Scopus Google Fas be to a of cells in the type at apoptosis of cells in the to be to study this of this study is that in intestinal epithelial cells. is to that this plays a significant role in the of anoikis. In several cell types of the been to be to from death apoptosis J. J. Biol. 2001; Full Text Full Text PDF Scopus Google Scholar, S. Cell Biol. PubMed Scopus Google Scholar). is now that in such cells the Fas is to of the to activation by pro-apoptotic such as and S. Cell Biol. PubMed Scopus Google Scholar, S. Y. H. J. J. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, M. M. J. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). The is known to apoptosis by the of the IAPs, which are of J. J. Cell Biol. 2001; PubMed Scopus Google Scholar). The pro-apoptotic role of is critical for the of apoptosis in cells that of S. Y. H. J. J. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). has been reported J. 2002; PubMed Scopus Google that in intestinal epithelial cells to apoptosis by Fas ligand can be by is that in such cells the and is by and plays a critical role in anoikis. In this study we demonstrated that anoikis of intestinal epithelial cells requires detachment-induced increase in p38 kinase and p38 overexpression of Fas ligand. of the death during anoikis has been by previously M. J. Curr. Biol. 9: Full Text Full Text PDF PubMed Scopus Google Scholar, S.M. Curr. Biol. 9: Full Text Full Text PDF PubMed Scopus Google Scholar, F. J. Cell Biol. 2001; PubMed Scopus Google and to cell anoikis of and epithelial cells can be by dominant but not by that Fas ligand or M. J. Curr. Biol. 9: Full Text Full Text PDF PubMed Scopus Google Scholar). that detachment-induced apoptosis of these types of cells is by of the death in a or that is by death Fas ligand and In cells has been that anoikis requires the Fas ligand and F. J. Cell Biol. 2001; PubMed Scopus Google Scholar). in these cells the events in the activation of the Fas in anoikis are the detachment-induced overexpression of Fas and the detachment-induced down-regulation of an inhibitor of apoptosis that the and and can be that the activation of the Fas plays an important role in anoikis but that the mechanism of activation of this of the death the cell important of this study is the of p38 kinase in anoikis. to detachment-induced elevation in p38 kinase is by an increase in p38 kinase this is known to be activated by such as M. 2001; PubMed Scopus Google Scholar). expression of p38 is for the p38 during anoikis, or to be to such to be activation of the p38 kinase has not been previously anoikis. another has been to play a role in anoikis of epithelial cells G. S.M. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google this is A. J. J. Cell Biol. 1997; PubMed Scopus Google Scholar). We reported previously J. J. PubMed Scopus Google that kinase activation is not in anoikis of intestinal epithelial cells. that p38 kinase plays a role in the of Fas ligand expression during anoikis is this kinase in the of Fas ligand expression in and cells E. A. J. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, J. M. J. 2000; PubMed Scopus Google Scholar, J. J. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). in of these J. J. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google has been demonstrated that p38 kinase can expression by the Fas ligand the results in this study and in J. J. J. Cell Biol. 2000; PubMed Scopus Google Scholar, J. J. J. Curr. Biol. 1998; Full Text Full Text PDF PubMed Google we conclude that anoikis of intestinal epithelial cells is by at least two events that are by cell and which the overexpression of Fas and down-regulation of at the we cannot the that pro-apoptotic events are by of intestinal epithelial cells, such events been in cell types J. Cell Biol. 2000; PubMed Scopus Google H. A. A. 2001; PubMed Scopus Google Scholar). Fas be to a of cells in the type at apoptosis of cells in the to be to study this of this study is that in intestinal epithelial cells. is to that this plays a significant role in the of anoikis. In several cell types of the been to be to from death apoptosis J. J. Biol. 2001; Full Text Full Text PDF Scopus Google Scholar, S. Cell Biol. PubMed Scopus Google Scholar). is now that in such cells the Fas is to of the to activation by pro-apoptotic such as and S. Cell Biol. PubMed Scopus Google Scholar, S. Y. H. J. J. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, M. M. J. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). The is known to apoptosis by the of the IAPs, which are of J. J. Cell Biol. 2001; PubMed Scopus Google Scholar). The pro-apoptotic role of is critical for the of apoptosis in cells that of S. Y. H. J. J. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). has been reported J. 2002; PubMed Scopus Google that in intestinal epithelial cells to apoptosis by Fas ligand can be by is that in such cells the and is by and plays a critical role in anoikis. We for in the of this and for

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