ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation

Jer Yen Yang; Cong S. Zong; Weiya Xia; Hirohito Yamaguchi; Qingqing Ding; Xiaoming Xie; Jing Yu Lang; Chien Chen Lai; Chun Ju Chang; Wei Chien Huang; Hsin Huang; Hsu Ping Kuo; Dung Fang Lee; Long Yuan Li; Huang Chun Lien; Xiaoyun Cheng; King Jen Chang; Chwan Deng Hsiao; Fuu Jen Tsai; Chang Hai Tsai; Aysegul A. Sahin; William J. Muller; Gordon B. Mills; Dihua Yu; Gabriel N. Hortobagyi; Mien Chie Hung

doi:10.1038/ncb1676

ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation

Jer Yen Yang, Cong S. Zong, Weiya Xia, Hirohito Yamaguchi, Qingqing Ding, Xiaoming Xie, Jing Yu Lang, Chien Chen Lai, Chun Ju Chang, Wei Chien Huang, Hsin Huang, Hsu Ping Kuo, Dung Fang Lee, Long Yuan Li, Huang Chun Lien, Xiaoyun Cheng, King Jen Chang, Chwan Deng Hsiao, Fuu Jen Tsai, Chang Hai TsaiAysegul A. Sahin, William J. Muller, Gordon B. Mills, Dihua Yu, Gabriel N. Hortobagyi, Mien Chie Hung

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Abstract

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.

Original language	English (US)
Pages (from-to)	138-148
Number of pages	11
Journal	Nature Cell Biology
Volume	10
Issue number	2
DOIs	https://doi.org/10.1038/ncb1676
State	Published - Feb 2008
Externally published	Yes

ASJC Scopus subject areas

Cell Biology

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Yang, J. Y., Zong, C. S., Xia, W., Yamaguchi, H., Ding, Q., Xie, X., Lang, J. Y., Lai, C. C., Chang, C. J., Huang, W. C., Huang, H., Kuo, H. P., Lee, D. F., Li, L. Y., Lien, H. C., Cheng, X., Chang, K. J., Hsiao, C. D., Tsai, F. J., ... Hung, M. C. (2008). ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nature Cell Biology, 10(2), 138-148. https://doi.org/10.1038/ncb1676

Yang, JY, Zong, CS, Xia, W, Yamaguchi, H, Ding, Q, Xie, X, Lang, JY, Lai, CC, Chang, CJ, Huang, WC, Huang, H, Kuo, HP, Lee, DF, Li, LY, Lien, HC, Cheng, X, Chang, KJ, Hsiao, CD, Tsai, FJ, Tsai, CH, Sahin, AA, Muller, WJ, Mills, GB, Yu, D, Hortobagyi, GN & Hung, MC 2008, 'ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation', Nature Cell Biology, vol. 10, no. 2, pp. 138-148. https://doi.org/10.1038/ncb1676

@article{44c096fc6575403eadc9d056724859a6,

title = "ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation",

abstract = "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.",

author = "Yang, {Jer Yen} and Zong, {Cong S.} and Weiya Xia and Hirohito Yamaguchi and Qingqing Ding and Xiaoming Xie and Lang, {Jing Yu} and Lai, {Chien Chen} and Chang, {Chun Ju} and Huang, {Wei Chien} and Hsin Huang and Kuo, {Hsu Ping} and Lee, {Dung Fang} and Li, {Long Yuan} and Lien, {Huang Chun} and Xiaoyun Cheng and Chang, {King Jen} and Hsiao, {Chwan Deng} and Tsai, {Fuu Jen} and Tsai, {Chang Hai} and Sahin, {Aysegul A.} and Muller, {William J.} and Mills, {Gordon B.} and Dihua Yu and Hortobagyi, {Gabriel N.} and Hung, {Mien Chie}",

note = "Funding Information: We thank: P. P. Pandolfi, D.-H. Yan, J. Chen, T. Sakai, P. Coffer and A. Toker for providing expression plasmids; G. Lozano for the knockoutMEF cells; M. C.-H. Hu for the p-FOXO3a (644) antibodies; Y. Wei, J.-M. Hsu, S. Zhang, J.-F. Lee and C.-T. Chen for technical support; W. Kaelin, M. Van Dyke and D. Sarbasov for critical comments on the manuscript; and J. C. Cheng and the Department of Scientific Publications, M. D. Anderson Cancer Center for editing the manuscript. This work was supported by National Institutes of Health (NIH) grant P01 CA 099031, MDACC SPORE in Breast Cancer CA116199 and The University of Texas M. D. Anderson Cancer Center support grant CA16672, and was partially supported by the National Breast Cancer Foundation, Inc., Patel Memorial Breast Cancer Research Foundation, Breast Cancer Research Foundation grant and Kadoorie Charitable Foundations.",

year = "2008",

month = feb,

doi = "10.1038/ncb1676",

language = "English (US)",

volume = "10",

pages = "138--148",

journal = "Nature Cell Biology",

issn = "1465-7392",

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TY - JOUR

T1 - ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation

AU - Yang, Jer Yen

AU - Zong, Cong S.

AU - Xia, Weiya

AU - Yamaguchi, Hirohito

AU - Ding, Qingqing

AU - Xie, Xiaoming

AU - Lang, Jing Yu

AU - Lai, Chien Chen

AU - Chang, Chun Ju

AU - Huang, Wei Chien

AU - Huang, Hsin

AU - Kuo, Hsu Ping

AU - Lee, Dung Fang

AU - Li, Long Yuan

AU - Lien, Huang Chun

AU - Cheng, Xiaoyun

AU - Chang, King Jen

AU - Hsiao, Chwan Deng

AU - Tsai, Fuu Jen

AU - Tsai, Chang Hai

AU - Sahin, Aysegul A.

AU - Muller, William J.

AU - Mills, Gordon B.

AU - Yu, Dihua

AU - Hortobagyi, Gabriel N.

AU - Hung, Mien Chie

N1 - Funding Information: We thank: P. P. Pandolfi, D.-H. Yan, J. Chen, T. Sakai, P. Coffer and A. Toker for providing expression plasmids; G. Lozano for the knockoutMEF cells; M. C.-H. Hu for the p-FOXO3a (644) antibodies; Y. Wei, J.-M. Hsu, S. Zhang, J.-F. Lee and C.-T. Chen for technical support; W. Kaelin, M. Van Dyke and D. Sarbasov for critical comments on the manuscript; and J. C. Cheng and the Department of Scientific Publications, M. D. Anderson Cancer Center for editing the manuscript. This work was supported by National Institutes of Health (NIH) grant P01 CA 099031, MDACC SPORE in Breast Cancer CA116199 and The University of Texas M. D. Anderson Cancer Center support grant CA16672, and was partially supported by the National Breast Cancer Foundation, Inc., Patel Memorial Breast Cancer Research Foundation, Breast Cancer Research Foundation grant and Kadoorie Charitable Foundations.

PY - 2008/2

Y1 - 2008/2

N2 - 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.

AB - 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.

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DO - 10.1038/ncb1676

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C2 - 18204439

AN - SCOPUS:38849139580

SN - 1465-7392

VL - 10

SP - 138

EP - 148

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 2

ER -

ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation

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