Flowchart: Preparation: Collagen
 

 


Text Box: Integren                  

                                                    

          

Arthritis

Type 2 Diabetes

                                                

Text Box: Collagen
 


                                                    

                                                             

                                              

Text Box: NfkbText Box: PTHrP                                   

Text Box: IL8Text Box: IL6                                                                               

                                                     

 

   5/6/2007/-17                                            

 

Circ Res. 2006 May 25; [Epub ahead of print]

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Integrin-Mediated Transcriptional Activation of Inhibitor of Apoptosis Proteins Protects Smooth Muscle Cells Against Apoptosis Induced by Degraded Collagen.

von Wnuck Lipinski K, Keul P, Ferri N, Lucke S, Heusch G, Fischer JW, Levkau B.

Institute of Pathophysiology, Center of Internal Medicine, University Hospital, Essen, Germany; Department of Pharmacological Sciences, University of Milan, Italy; and Molecular Pharmacology, Institute of Pharmacology and Clinical Pharmacology, Heinrich-Heine University Dusseldorf, Germany.

Apoptosis of smooth muscle cells (SMC) and degradation of the extracellular matrix (ECM) have both been implicated in atherosclerotic plaque rupture. We have previously reported that degraded type I collagen fragments induce a rapid but transient apoptotic burst initiated by calpains in SMC. The aim of the current study was to identify the pathway responsible for consecutive SMC survival. We show that exposure of SMC to collagen fragments resulted in a sustained activation of nuclear factor (NF)-kappaB via phosphorylation and degradation of IkappaBalpha. Its prevention through retroviral expression of superrepressor IkappaBalpha or proteasome inhibition potently induced apoptosis. In the presence of blocking antibodies to alphavbeta3 integrin and RGD peptides, collagen fragments no longer activated NF-kappaB and apoptosis was enhanced. The mechanism by which NF-kappaB was protecting SMC against collagen fragment-induced apoptosis was a transcriptional activation of several endogenous caspase inhibitors of the inhibitor of apoptosis protein (IAP) family as: (1) the expression of xIAP, c-IAP2, and survivin was potently induced by collagen fragments; (2) IAP expression was abrogated by superrepressor IkappaBalpha; and (3) knockdown of each of the 3 IAPs by small interfering RNA (siRNA) resulted in enhanced apoptosis after collagen fragment treatment. Our data suggest that SMC exposed to degraded collagen are protected against apoptosis by a mechanism involving alphavbeta3-dependent NF-kappaB activation with consequent activation of IAPs. This may constitute a novel antiapoptotic pathway ensuring SMC survival in settings of enhanced ECM degradation such as cell migration, vascular remodeling, and atherosclerotic plaque rupture.

PMID: 16728660 [PubMed - as supplied by publisher]

 

 

Int J Gastrointest Cancer. 2005;36(3):131-46.

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Type I Collagen and Divalent Cation Shifts Disrupt Cell-Cell Adhesion, Increase Migration, and Decrease PTHrP, IL-6, and IL-8 Expression in Pancreatic Cancer Cells.

Grzesiak JJ, Smith KC, Chalberg C, Burton DW, Deftos LJ, Bouvet M.

Department of Surgery, University of California, San Diego and Veterans Affairs, San Diego Healthcare System, San Diego, CA 92161.

Background:We have shown in FG pancreatic cancer cells that alpha2beta1 integrin-mediated type I collagen adhesion decreases parathyroid hormone-related protein (PTHrP), interleukin-6 (IL-6), and interleukin-8 (IL-8) expression, decreases the localization of E-cadherin and beta-catenin in cell-cell contacts, increases cell migration, and increases glycogen synthase kinase 3 (GSK3) and protein kinase B (PKB/Akt) phosphorylation states relative to alpha5beta1 integrin-mediated fibronectin (Fn) adhesion. Aim of the Study: To extend our observations in FG cells to other pancreatic cancer cell lines, and to determine whether E-cadherin-mediated cell-cell adhesion and its downstream effectors were functionally involved in the ECM-mediated regulation of PTHrP, IL-6, and IL-8. Methods: We used standard biochemical techniques to determine ECM-specific differences in E-cadherin and beta-catenin localization, GSK3 and PKB/Akt phosphorylation, haptokinetic cell migration, and cytokine expression in pancreatic cancer cells. We also conducted functional studies using pharmacological inhibitors for GSK3 and PKB/Akt, as well as elevated Mg2+/Ca2+ ratios similar to pancreatic juice, and examined their effects on cytokine expression. Results: Differences in E-cadherin and beta-catenin localization along with GSK3 and PKB/Akt phosphorylation occur in multiple pancreatic cancer cell lines, resulting in differences in ECM-mediated haptokinesis and cytokine expression that are generally consistent with previous observations in FG cells. Our functional studies also suggest that E-cadherin-mediated cell-cell adhesion and downstream effectors are involved in PTHrP, IL-6, and IL-8 expression. Conclusions: These data indicate that alpha2beta1 integrin-mediated type I collagen adhesion disrupts cell-cell adhesion architecture, resulting in increased migration and decreased PTHrP, IL-6, and IL-8 expression in pancreatic cancer cells.

PMID: 16720909 [PubMed - in process]