p73 cooperates with Ras in the activation of MAP kinase signaling cascade.
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.
Fernandez-Garcia
B
B
Instituto de Biomedicina, Universidad de León, Campus de Vegazana, León 24071, Spain.
Vaqué
J P
JP
Herreros-Villanueva
M
M
Marques-Garcia
F
F
Castrillo
F
F
Fernandez-Medarde
A
A
León
J
J
Marín
M C
MC
D000818:Animals; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D011905:Genes, ras; D045325:HCT116 Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D009687:Nuclear Proteins / Q000378:metabolism*; D015689:Oncogene Protein p21(ras) / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D015689:Oncogene Protein p21(ras)