TY - JOUR
T1 - Opposing effects of RAS on p53
T2 - Transcriptional activation of mdm2 and induction of p19(ARF)
AU - Ries, Stefan
AU - Biederer, Carola
AU - Woods, Douglas
AU - Shifman, Ohad
AU - Shirasawa, Senji
AU - Sasazuki, Takehiko
AU - McMahon, Martin
AU - Oren, Moshe
AU - McCormick, Frank
N1 - Funding Information:
We are grateful to G. Zambetti for the generous gift of Mdm2 antibody 2A10 and P. Rodriguez-Viciana for H-Ras(G12V) expression vector. The p19 ARF null MEFs were generously provided by C. Sherr and M. Roussel. HCT116 p53 −/− cells were a kind gift of F. Bunz and B. Vogelstein. We thank J. Ghysadael and M. Karin for expression vectors encoding c-ets-1, c-ets-2, and c-jun, F. Zindy for helpful advice with the mouse p53 antibody Ab-7, and M. Humbert for DKO4 cells expressing ΔRaf:ER. We are indebted to C. Brandts for critically reading the manuscript and to A. Balmain for exciting discussions. We thank P. Sabbatini, H. Jiang, O. Tetsu, C. O'Shea, D. Stokoe, A. Bhat, and A. Mirza for fruitful discussions and all members of the McCormick lab for their support. S. Ries received a DAAD fellowship as part of the “Gemeinsames Hochschulsonderprogramm III von Bund und Laendern”. This study was supported by the David A. Wood Foundation.
PY - 2000/10/13
Y1 - 2000/10/13
N2 - Mdm2 acts as a major regulator of the tumor suppressor p53 by targeting its destruction. Here, we show that the mdm2 gene is also regulated by the Ras-driven Raf/MEK/MAP kinase pathway, in a p53-independent manner. Mdm2 induced by activated Raf degrades p53 in the absence of the Mdm2 inhibitor p19(ARF). This regulatory pathway accounts for the observation that cells transformed by oncogenic Ras are more resistant to p53-dependent apoptosis following exposure to DNA damage. Activation of the Ras-induced Raf/MEK/MAP kinase may therefore play a key role in suppressing p53 during tumor development and treatment. In primary cells, Raf also activates the Mdm2 inhibitor p19(ARF). Levels of p53 are therefore determined by opposing effects of Raf-induced p19(ARF) and Mdm2.
AB - Mdm2 acts as a major regulator of the tumor suppressor p53 by targeting its destruction. Here, we show that the mdm2 gene is also regulated by the Ras-driven Raf/MEK/MAP kinase pathway, in a p53-independent manner. Mdm2 induced by activated Raf degrades p53 in the absence of the Mdm2 inhibitor p19(ARF). This regulatory pathway accounts for the observation that cells transformed by oncogenic Ras are more resistant to p53-dependent apoptosis following exposure to DNA damage. Activation of the Ras-induced Raf/MEK/MAP kinase may therefore play a key role in suppressing p53 during tumor development and treatment. In primary cells, Raf also activates the Mdm2 inhibitor p19(ARF). Levels of p53 are therefore determined by opposing effects of Raf-induced p19(ARF) and Mdm2.
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U2 - 10.1016/S0092-8674(00)00123-9
DO - 10.1016/S0092-8674(00)00123-9
M3 - Article
C2 - 11057904
AN - SCOPUS:0034644506
SN - 0092-8674
VL - 103
SP - 321
EP - 330
JO - Cell
JF - Cell
IS - 2
ER -