Thrombin stimulates RPE cell proliferation by promoting c-Fos-mediated cyclin D1 expression.
The retinal pigment epithelium (RPE) plays an essential role in the maintenance and normal functioning of the neural retina. Alterations in RPE function are involved in several ocular pathologies involving the breakdown of the blood-retina barrier (BRB), which exposes RPE to serum components, thrombin among them. Our previous work has shown that thrombin stimulates the proliferation of RPE cells. We here analyzed the molecular pathways leading to this outcome, in order to support thrombin involvement in proliferative vitreoretinopathy (PVR), a major cause of retinal surgery failure. We demonstrated that thrombin activation of PAR-1 promotes cyclin D1 expression at the transcriptional level by stimulating c-Fos expression, mediated by PI3K, MAPK ERK1/2, and conventional PKC activity. Our results show that ERK activation is necessary but not sufficient for the induction of cyclin D1 expression and proliferation, since the inhibition of PI3K or cPKC prevents this outcome. Analysis of thrombin-activated PAR-1 downstream effectors demonstrated that c-Fos expression by the sustained activation of ERK and c-fos transcription triggers the expression and nuclear translocation of cyclin D1, a key regulator of cell cycle G1/S phase progression leading to proliferation. Evidence here provided contributes to the understanding of the mechanisms involved in proliferative eye diseases and enhances the possibility of controlling pathologies such as proliferative PVR, which eventually lead to blindness.
Parrales
Alejandro
A
Departamento de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México, DF, Mexico.
Palma-Nicolás
José Prisco
JP
López
Edith
E
López-Colomé
Ana María
AM
D021581:Active Transport, Cell Nucleus; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D054799:Phospholipase C beta / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D044463:Receptor, PAR-1 / Q000819:agonists / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D013917:Thrombin / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation; D018630:Vitreoretinopathy, Proliferative / Q000378:metabolism* / Q000473:pathology
C530106:Ccnd1 protein, rat; D047428:Protein Kinase Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D044463:Receptor, PAR-1; D019938:Cyclin D1; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054799:Phospholipase C beta; D013917:Thrombin