Cyr61 protects against hyperoxia-induced cell death via Akt pathway in pulmonary epithelial cells.
We have used gene expression profiling approaches to identify new molecular targets in various models of lung injury and human lung diseases. Among the many genes that are significantly induced in these studies, cysteine-rich61 (Cyr61) consistently ranks as one of the most significant genes. Here, we use the well-established model of hyperoxia to better understand the function of Cyr61 in acute lung injury. Cyr61, a stress-related immediate-early response gene, has known diverse functions involving angiogenesis, tumorigenesis, and wound repair. It belongs to the newly discovered "CCN" family containing six growth and regulatory factors. We showed that hyperoxia induces Cyr61 expression in a variety of pulmonary cells and in lung tissue in vivo. Loss of function studies, by suppressing Cyr61 expression by siRNA, accelerated lung epithelial cell death after hyperoxia. Gain of function studies, by overexpressing Cyr61, significantly conferred increased resistance to hyperoxia-induced cell death. Moreover, cells overexpressing Cyr61 induce Akt activation. Inhibition of Akt by siRNA abrogated the protective effects of Cyr61-overexpressing cells in response to hyperoxia. Taken together, our data demonstrate that Cyr61 expression provides cytoprotection in hyperoxia-induced pulmonary epithelial cell death and that this effect was in part mediated via the Akt signaling pathway.
Jin
Yang
Y
Division of Pulmonary, Allergy and Critical Care Medicine, 628 NW MUH, University of Pittsburgh Medical Center, 3459 5th Ave., Pittsburgh, PA 15213, USA.
Kim
Hong Pyo
HP
Ifedigbo
Emeka
E
Lau
Lester F
LF
Choi
Augustine M K
AM
D000818:Animals; D016923:Cell Death / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D055515:Cysteine-Rich Protein 61; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D018496:Hyperoxia / Q000473:pathology / Q000503:physiopathology*; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D012128:Respiratory Distress Syndrome / Q000473:pathology / Q000503:physiopathology; D020545:Respiratory Mucosa / Q000473:pathology / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology
C501848:CCN1 protein, human; C491850:CCN1 protein, mouse; D055515:Cysteine-Rich Protein 61; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt