Sprouty 2 Regulates DNA Damage-induced Apoptosis in Ras-transformed Human Fibroblasts*
| Autor: | Veronica M. Maher, Bryan D. Mets, Piro Lito, Daniel M. Appledorn, J. Justin McCormick |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
rac1 GTP-Binding Protein
endocrine system DNA damage Down-Regulation Apoptosis Biology Oncogene Protein p21(ras) Biochemistry Cell Line medicine Gene silencing Humans Transgenes Molecular Biology Protein kinase B Cisplatin Mechanisms of Signal Transduction Intracellular Signaling Peptides and Proteins Membrane Proteins Cell Biology Fibroblasts Cell biology Enzyme Activation Cell culture SPRY2 Cancer research Signal transduction medicine.drug DNA Damage Signal Transduction |
| Popis: | We have reported that expression of Sprouty 2 (Spry2) is necessary for tumor formation by HRasV12-transformed fibroblasts. We now report on the role of Spry2 in the inhibition of UV254 nm radiation-induced apoptosis in HRasV12-transformed human fibroblasts. Silencing Spry2 in this context resulted in increased apoptosis, associated with decreased Akt activation and decreased phosphorylation of HDM2 at Ser-166, which has been shown to stabilize HDM2. As a consequence, when cells with silenced Spry2 were UV-irradiated, they exhibited diminished levels of HDM2 and elevated levels of p53. In agreement with these findings, overexpression of Spry2 in the parental non-transformed fibroblasts led to increased Akt activation and to the stabilization of HDM2. It also led to diminished expression of p53 and decreased apoptosis following UV irradiation. Silencing Spry2 in HRas-transformed cells decreased Rac1 activation, but independent expression of Spry2 in the non-transformed parental cells had no effect on Rac1, suggesting a specific involvement in the activation of Rac1 by Ras. Silencing Spry2 in HRasV12-transformed cells resulted in diminished interaction between HRas and Tiam1, a Rac1-specific nucleotide exchange factor. Expression of constitutively active Rac1 in cells with silenced Spry2 partly reversed the effect of Spry2 down-regulation. Furthermore, loss of Spry2 expression in HRasV12-transformed cells augmented the cytotoxicity of the DNA-damaging, chemotherapeutic agent cisplatin, a process that was also reversed by active Rac1. Together, these data show that Spry2 inhibits apoptosis in response to DNA damage by regulating Akt, HDM2, and p53, by a process mediated partly by Rac1. |
| Databáze: | OpenAIRE |
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