Papel de e1a en las rutas de erk1/2 y 5. Implicaciones en la senescencia asociada al oncogén v-h-ras

Resumen

In response to different stimuli, including oncogenic stimuli, cells trigger different mechanisms to avoid transformation, being one of the most important the induction of senescence. This process is characterized by an irreversible block in the cellular growth. Upon v-H-Ras over expression, human normal cells undergo senescence through several cellular processes, including the activation of ERK1/2 pathway. Interestingly, the E1a gene from Adenovirus 5 has been shown to rescue cells from senescence by a yet unknown mechanism. In the present thesis, we study the role of several members of the MAPKs superfamily (ERK1/2 and ERK5) in the ability of E1a to suppress v-H-Ras mediated senescence. Our results show how E1a is able to block the activation of ERK1/2 by v-H-Ras through two different and complementary mechanisms. On the one hand, across AKT's inactivation, this in turns mediates in the stability of PEA15, a nuclear export factor of ERK1/2, allowing the nuclear accumulation of ERK1/2. On the other hand, increasing the expression, at the transcriptional level, of two inducible nuclear phosphates (MKP1 and DUSP5), which leads ERK1/2 desphosphorylation. Furthermore, we demonstrate that the blockade of ERK1/2 signaling pathway could happen in response to v-H-ras over expression but also in the presence of serum, indicating the general character of our observation. This data have been obtained in transient transfection approaches as well as in human normal diploid fibroblast (IMR90). In addition, our results demonstrate how ERK5, a MAPK related to ERK1/2, is not a target of E1a protein and has no effect, or if so marginal, onto the suppression of cellular senescence. In summary, we show that the inhibitory effect of E1a on the ERK1/2 signaling pathway is a critical event to suppress the senescence program associated to v-H-Ras over expression. Our observation supports the role of E1a as an oncogene in the context of none transformed cells and demonstrates the critical role of ERK1/2 signaling pathway in the v-H-Ras associated transformation.