E1a Gene Expression Blocks the ERK1/2 Signaling Pathway by Promoting Nuclear Localization and MKP Up-regulation
In: Journal of Biological Chemistry, Jg. 283 (2008-05-01), S. 13450-13458
Online
unknown
Zugriff:
In response to oncogenic signals, cells have developed safe mechanisms to avoid transformation through activation of a senescence program. Upon v-H-Ras overexpression, normal cells undergo senescence through several cellular processes, including activation of the ERK1/2 pathway. Interestingly, the E1a gene from adenovirus 5 has been shown to rescue cells from senescence by a yet unknown mechanism. We investigated whether E1a was able to interfere with the ERK1/2 signaling pathway to rescue cells from v-H-Ras-mediated senescence. Our results show that, E1a overexpression blocks v-H-Ras-mediated ERK1/2 activation by two different and concomitant mechanisms. E1a through its ability to interfere with PKB/Akt activation induces the down-regulation of the PEA15 protein, an ERK1/2 nuclear export factor, leading to nuclear accumulation of ERK1/2. In addition to this, we show that E1a increases the expression of the inducible ERK1/2 nuclear phosphatases (MAPK phosphatases) MKP1/DUSP1 and DUSP5, which leads to ERK1/2 dephosphorylation. We confirmed our observations in the human normal diploid fibroblasts IMR90, in which we could also show that an E1a mutant, unable to bind retinoblastoma protein (pRb), cannot rescue cells from v-H-Ras-induced senescence. In conclusion, E1a is able to rescue from Ras-induced senescence by affecting ERK1/2 localization and phosphorylation.
Titel: |
E1a Gene Expression Blocks the ERK1/2 Signaling Pathway by Promoting Nuclear Localization and MKP Up-regulation
|
---|---|
Autor/in / Beteiligte Person: | Sánchez-Prieto, Ricardo ; Guinea-Viniegra, Juan ; Santiago Ramón y Cajal ; Eva María Galán-Moya ; Martínez, Natalia ; Juan Luis Callejas-Valera ; Ramírez-Castillejo, Carmen ; Recio, Juan A. ; Rojas, José M. |
Link: | |
Zeitschrift: | Journal of Biological Chemistry, Jg. 283 (2008-05-01), S. 13450-13458 |
Veröffentlichung: | Elsevier BV, 2008 |
Medientyp: | unknown |
ISSN: | 0021-9258 (print) |
DOI: | 10.1074/jbc.m709230200 |
Schlagwort: |
|
Sonstiges: |
|