Abstract
The p73 gene is capable of inducing cell cycle arrest, apoptosis, senescence, differentiation and to cooperate with oncogenic Ras in cellular transformation. Ras can be considered as a branch point in signal transduction, where diverse extracellular stimuli converge. The intensity of the mitogen-activated protein kinase (MAPK) cascade activation influences the cellular response to Ras. Despite the fundamental role of p53 in Ras-induced growth arrest and senescence, it remains unclear how the Ras/MEK/ERK pathway induces growth arrest in the absence of p53. We report here that oncogenic Ras stabilizes p73 resulting in p73 accumulation and enhancement of its activity. p73, in turn, induces a sustained activation of the MAP kinase cascade synergizing with oncogenic Ras. We also found that inhibition of p73 function modifies the cellular outcome to Ras activation inhibiting Ras-dependent differentiation. Here, we show for the first time that there is a signaling loop between Ras-dependent MAPK cascade activation and p73 function.
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Abbreviations
- MAPK:
-
mitogen-activated protein kinase
- ERK:
-
extracellular signal-regulated kinase
- pp-ERK:
-
phosphorylated ERK
- Dex:
-
dexamethasone
- CHX:
-
cycloheximide
- p53-DD:
-
dominant-negative p53
- p73-DD:
-
dominant-negative p73
- p73-DD-L371P:
-
inactive dominant-negative p73
- Ph:
-
phalloidin
- Ad:
-
adenovirus
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Acknowledgements
We thank all the people cited in the text for their generous gift of reagents. We are grateful to A Fernández y A Munoz for their helpful advice and discussion of the manuscript. We also thank NI Fernandez and B Jimenez-Cuenca for their help and advice. We are grateful to Pilar Frade for technical assistance. MCM is especially thankful to PFM y NFM for their love and support. BFG has a fellowship from Consejería de Educación y Cultura de la Junta de Castilla y León and Fondo Social Europeo. MHV and JPV are recipients of predoctoral fellowships from the Spanish Ministerio de Educación y Ciencia. FMG has a fellowship from the University of León, Spain. This work was supported by Grants SAF-4193CO2 and SAF-4193CO1 from the Spanish Ministerio de Educación y Ciencia to MCM and JLS, respectively.
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Fernandez-Garcia, B., Vaqué, J., Herreros-Villanueva, M. et al. p73 cooperates with Ras in the activation of MAP kinase signaling cascade. Cell Death Differ 14, 254–265 (2007). https://doi.org/10.1038/sj.cdd.4401945
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DOI: https://doi.org/10.1038/sj.cdd.4401945
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