Thrombospondin-1 C-terminal-derived peptide protects thyroid cells from ceramide-induced apoptosis through the adenylyl cyclase pathway.
Thrombospondin-1, a multi-modular matrix protein is able to interact with a variety of matrix proteins and cell-surface receptors. Thus it is multifunctional. In this work, we examined the role of thrombospondin-1 in ceramide-induced thyroid apoptosis. We focused on the VVM containing sequence localized in the C-terminal domain of the molecule. Primary cultured thyroid cells synthesize thrombospondin-1 depending on their morphological organization. As it leads thyrocytes to organize into monolayers before inducing apoptosis ceramide can modulate this organization. Here, we established that C(2)-ceramide treatment decreased thrombospondin-1 expression by interfering with the adenylyl cyclase pathway, thus leading to apoptosis. Furthermore, we demonstrated that the thrombospondin-1-derived peptide 4N1 (RFYVVMWK) abolished ceramide-induced thyroid cell death by preventing intracellular cAMP levels from dropping. Finally, we reported that 4N1-mediated inhibition of ceramide-induced apoptosis was consistently associated with a down-regulation of the caspase-3 processing. Integrin-associated protein receptor (IAP or CD47) was identified as a molecular relay mediating the observed 4N1 effects. Taken together, our results shed light for the first time on anti-apoptotic activities of the thrombospondin-1-derived peptide 4N1 and provide new information on how thrombospondin-1 may control apoptosis of non-tumoral cells.
Rath
G M
GM
UMR-CNRS 6198 Matrice Extracellulaire et Régulation Cellulaire, UFR Sciences de Reims, IFR 53, 51687 Reims Cedex 2, France. geraldine.rath@univ-reims.fr
Schneider
C
C
Dedieu
S
S
Sartelet
H
H
Morjani
H
H
Martiny
L
L
El Btaouri
H
H
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D002518:Ceramides / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D013552:Swine; D019700:Thrombospondin 1 / Q000737:chemistry*; D013961:Thyroid Gland / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology
D002518:Ceramides; C064769:N-acetylsphingosine; D010455:Peptides; D012333:RNA, Messenger; D019700:Thrombospondin 1; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D053148:Caspase 3; D000262:Adenylyl Cyclases; D013110:Sphingosine