ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation.
The RAS-ERK pathway is known to play a pivotal role in differentiation, proliferation and tumour progression. Here, we show that Erk downregulates Forkhead box O 3a (FOXO3a) by directly interacting with and phosphorylating FOXO3a at Ser 294, Ser 344 and Ser 425, which consequently promotes cell proliferation and tumorigenesis. The ERK-phosphorylated FOXO3a degrades via an MDM2-mediated ubiquitin-proteasome pathway. However, the non-phosphorylated FOXO3a mutant is resistant to the interaction and degradation by murine double minute 2 (MDM2), thereby resulting in a strong inhibition of cell proliferation and tumorigenicity. Taken together, our study elucidates a novel pathway in cell growth and tumorigenesis through negative regulation of FOXO3a by RAS-ERK and MDM2.
Yang
Jer-Yen
JY
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Zong
Cong S
CS
Xia
Weiya
W
Yamaguchi
Hirohito
H
Ding
Qingqing
Q
Xie
Xiaoming
X
Lang
Jing-Yu
JY
Lai
Chien-Chen
CC
Chang
Chun-Ju
CJ
Huang
Wei-Chien
WC
Huang
Hsin
H
Kuo
Hsu-Ping
HP
Lee
Dung-Fang
DF
Li
Long-Yuan
LY
Lien
Huang-Chun
HC
Cheng
Xiaoyun
X
Chang
King-Jen
KJ
Hsiao
Chwan-Deng
CD
Tsai
Fuu-Jen
FJ
Tsai
Chang-Hai
CH
Sahin
Aysegul A
AA
Muller
William J
WJ
Mills
Gordon B
GB
Yu
Dihua
D
Hortobagyi
Gabriel N
GN
Hung
Mien-Chie
MC
D000595:Amino Acid Sequence; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000096:biosynthesis / Q000502:physiology*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D014183:Transplantation, Heterologous
C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D012694:Serine; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D048049:Extracellular Signal-Regulated MAP Kinases