Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Science 321 (5895): 1499-1502

Copyright © 2008 by the American Association for the Advancement of Science

FBXW7 Targets mTOR for Degradation and Cooperates with PTEN in Tumor Suppression

Jian-Hua Mao,1* Il-Jin Kim,1* Di Wu,1 Joan Climent,1 Hio Chung Kang,1 Reyno DelRosario,1 Allan Balmain1,2{dagger}

Abstract: The enzyme mTOR (mammalian target of rapamycin) is a major target for therapeutic intervention to treat many human diseases, including cancer, but very little is known about the processes that control levels of mTOR protein. Here, we show that mTOR is targeted for ubiquitination and consequent degradation by binding to the tumor suppressor protein FBXW7. Human breast cancer cell lines and primary tumors showed a reciprocal relation between loss of FBXW7 and deletion or mutation of PTEN (phosphatase and tensin homolog), which also activates mTOR. Tumor cell lines harboring deletions or mutations in FBXW7 are particularly sensitive to rapamycin treatment, which suggests that loss of FBXW7 may be a biomarker for human cancers susceptible to treatment with inhibitors of the mTOR pathway.

1 Cancer Research Institute, University of California at San Francisco, 2340 Sutter Street, San Francisco, CA 94143, USA.
2 Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, CA 94143, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: abalmain{at}cc.ucsf.edu


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Circadian Regulation of mTOR by the Ubiquitin Pathway in Renal Cell Carcinoma.
H. Okazaki, N. Matsunaga, T. Fujioka, F. Okazaki, Y. Akagawa, Y. Tsurudome, M. Ono, M. Kuwano, S. Koyanagi, and S. Ohdo (2014)
Cancer Res. 74, 543-551
   Abstract »    Full Text »    PDF »
Prolyl-isomerase Pin1 controls normal and cancer stem cells of the breast.
A. Rustighi, A. Zannini, L. Tiberi, R. Sommaggio, S. Piazza, G. Sorrentino, S. Nuzzo, A. Tuscano, V. Eterno, F. Benvenuti, et al. (2014)
EMBO Mol Med. 6, 99-119
   Abstract »    Full Text »    PDF »
FBXW7 Mediates Chemotherapeutic Sensitivity and Prognosis in NSCLCs.
T. Yokobori, Y. Yokoyama, A. Mogi, H. Endoh, B. Altan, T. Kosaka, E. Yamaki, T. Yajima, K. Tomizawa, Y. Azuma, et al. (2014)
Mol. Cancer Res. 12, 32-37
   Abstract »    Full Text »    PDF »
Role of Ubiquitin Ligases and the Proteasome in Oncogenesis: Novel Targets for Anticancer Therapies.
L. N. Micel, J. J. Tentler, P. G. Smith, and G. S. Eckhardt (2013)
J. Clin. Oncol. 31, 1231-1238
   Abstract »    Full Text »    PDF »
Transforming Growth Factor {beta} Integrates Smad 3 to Mechanistic Target of Rapamycin Complexes to Arrest Deptor Abundance for Glomerular Mesangial Cell Hypertrophy.
F. Das, N. Ghosh-Choudhury, A. Bera, N. Dey, H. E. Abboud, B. S. Kasinath, and G. G. Choudhury (2013)
J. Biol. Chem. 288, 7756-7768
   Abstract »    Full Text »    PDF »
Phosphoinositide 3-Kinase (PI3K) Pathway Alterations Are Associated with Histologic Subtypes and Are Predictive of Sensitivity to PI3K Inhibitors in Lung Cancer Preclinical Models.
J. M. Spoerke, C. O'Brien, L. Huw, H. Koeppen, J. Fridlyand, R. K. Brachmann, P. M. Haverty, A. Pandita, S. Mohan, D. Sampath, et al. (2012)
Clin. Cancer Res. 18, 6771-6783
   Abstract »    Full Text »    PDF »
Human Molecular Genetic and Functional Studies Identify TRIM63, Encoding Muscle RING Finger Protein 1, as a Novel Gene for Human Hypertrophic Cardiomyopathy.
S. N. Chen, G. Czernuszewicz, Y. Tan, R. Lombardi, J. Jin, J. T. Willerson, and A. J. Marian (2012)
Circ. Res. 111, 907-919
   Abstract »    Full Text »    PDF »
DEPTOR ubiquitination and destruction by SCF{beta}-TrCP.
Z. Wang, J. Zhong, D. Gao, H. Inuzuka, P. Liu, and W. Wei (2012)
Am J Physiol Endocrinol Metab 303, E163-E169
   Abstract »    Full Text »    PDF »
Pten Regulates Aurora-A and Cooperates with Fbxw7 in Modulating Radiation-Induced Tumor Development.
Y.-W. Kwon, I.-J. Kim, D. Wu, J. Lu, W. A. Stock Jr, Y. Liu, Y. Huang, H. C. Kang, R. DelRosario, K.-Y. Jen, et al. (2012)
Mol. Cancer Res. 10, 834-844
   Abstract »    Full Text »    PDF »
Triggering Fbw7-Mediated Proteasomal Degradation of c-Myc by Oridonin Induces Cell Growth Inhibition and Apoptosis.
H.-L. Huang, H.-Y. Weng, L.-Q. Wang, C.-H. Yu, Q.-J. Huang, P.-P. Zhao, J.-Z. Wen, H. Zhou, and L.-H. Qu (2012)
Mol. Cancer Ther. 11, 1155-1165
   Abstract »    Full Text »    PDF »
ROR{alpha} Suppresses Breast Tumor Invasion by Inducing SEMA3F Expression.
G. Xiong, C. Wang, B. M. Evers, B. P. Zhou, and R. Xu (2012)
Cancer Res. 72, 1728-1739
   Abstract »    Full Text »    PDF »
Sequential mutations in Notch1, Fbxw7, and Tp53 in radiation-induced mouse thymic lymphomas.
K.-Y. Jen, I. Y. Song, K. L. Banta, D. Wu, J.-H. Mao, and A. Balmain (2012)
Blood 119, 805-809
   Abstract »    Full Text »    PDF »
Paracrine Signaling Through MYCN Enhances Tumor-Vascular Interactions in Neuroblastoma.
Y. H. Chanthery, W. C. Gustafson, M. Itsara, A. Persson, C. S. Hackett, M. Grimmer, E. Charron, S. Yakovenko, G. Kim, K. K. Matthay, et al. (2012)
Science Translational Medicine 4, 115ra3
   Abstract »    Full Text »    PDF »
Emerging roles of the FBW7 tumour suppressor in stem cell differentiation.
Z. Wang, H. Inuzuka, H. Fukushima, L. Wan, D. Gao, S. Shaik, F. H. Sarkar, and W. Wei (2012)
EMBO Rep. 13, 36-43
   Abstract »    Full Text »    PDF »
Control of mTORC1 signaling by the Opitz syndrome protein MID1.
E. Liu, C. A. Knutzen, S. Krauss, S. Schweiger, and G. G. Chiang (2011)
PNAS 108, 8680-8685
   Abstract »    Full Text »    PDF »
Fbxw7-dependent Degradation of Notch Is Required for Control of "Stemness" and Neuronal-Glial Differentiation in Neural Stem Cells.
A. Matsumoto, I. Onoyama, T. Sunabori, R. Kageyama, H. Okano, and K. I. Nakayama (2011)
J. Biol. Chem. 286, 13754-13764
   Abstract »    Full Text »    PDF »
mTOR Signaling, Function, Novel Inhibitors, and Therapeutic Targets.
R. Watanabe, L. Wei, and J. Huang (2011)
J. Nucl. Med. 52, 497-500
   Abstract »    Full Text »    PDF »
Ex vivo maintenance of hematopoietic stem cells by quiescence induction through Fbxw7{alpha} overexpression.
H. Iriuchishima, K. Takubo, S. Matsuoka, I. Onoyama, K. I. Nakayama, Y. Nojima, and T. Suda (2011)
Blood 117, 2373-2377
   Abstract »    Full Text »    PDF »
FBXW7 influences murine intestinal homeostasis and cancer, targeting Notch, Jun, and DEK for degradation.
R. Babaei-Jadidi, N. Li, A. Saadeddin, B. Spencer-Dene, A. Jandke, B. Muhammad, E. E. Ibrahim, R. Muraleedharan, M. Abuzinadah, H. Davis, et al. (2011)
J. Exp. Med. 208, 295-312
   Abstract »    Full Text »    PDF »
Notch-dependent expression of the archipelago ubiquitin ligase subunit in the Drosophila eye.
S. C. Nicholson, B. N. Nicolay, M. V. Frolov, and K. H. Moberg (2011)
Development 138, 251-260
   Abstract »    Full Text »    PDF »
C/EBP{delta}: friend or foe? A novel role for C/EBP{delta} in metastasis.
F. G. Pelorosso and A. Balmain (2010)
EMBO J. 29, 4063-4065
   Abstract »    Full Text »    PDF »
The tumour suppressor C/EBP{delta} inhibits FBXW7 expression and promotes mammary tumour metastasis.
K. Balamurugan, J.-M. Wang, H.-H. Tsai, S. Sharan, M. Anver, R. Leighty, and E. Sterneck (2010)
EMBO J. 29, 4106-4117
   Abstract »    Full Text »    PDF »
mTOR attenuates the inflammatory response in cardiomyocytes and prevents cardiac dysfunction in pathological hypertrophy.
X. Song, Y. Kusakari, C.-Y. Xiao, S. D. Kinsella, M. A. Rosenberg, M. Scherrer-Crosbie, K. Hara, A. Rosenzweig, and T. Matsui (2010)
Am J Physiol Cell Physiol 299, C1256-C1266
   Abstract »    Full Text »    PDF »
MicroRNA-223 Regulates Cyclin E Activity by Modulating Expression of F-box and WD-40 Domain Protein 7.
Y. Xu, T. Sengupta, L. Kukreja, and A. C. Minella (2010)
J. Biol. Chem. 285, 34439-34446
   Abstract »    Full Text »    PDF »
Monitoring the Outside: Cell Wall-Sensing Mechanisms.
C. Ringli (2010)
Plant Physiology 153, 1445-1452
   Full Text »    PDF »
The NEDD8 Conjugation Pathway and Its Relevance in Cancer Biology and Therapy.
T. A. Soucy, L. R. Dick, P. G. Smith, M. A. Milhollen, and J. E. Brownell (2010)
Genes & Cancer 1, 708-716
   Abstract »    Full Text »    PDF »
The Fbw7/Human CDC4 Tumor Suppressor Targets Proproliferative Factor KLF5 for Ubiquitination and Degradation through Multiple Phosphodegron Motifs.
N. Liu, H. Li, S. Li, M. Shen, N. Xiao, Y. Chen, Y. Wang, W. Wang, R. Wang, Q. Wang, et al. (2010)
J. Biol. Chem. 285, 18858-18867
   Abstract »    Full Text »    PDF »
The Fbw7 Tumor Suppressor Targets KLF5 for Ubiquitin-Mediated Degradation and Suppresses Breast Cell Proliferation.
D. Zhao, H.-Q. Zheng, Z. Zhou, and C. Chen (2010)
Cancer Res. 70, 4728-4738
   Abstract »    Full Text »    PDF »
Validation of SAG/RBX2/ROC2 E3 Ubiquitin Ligase as an Anticancer and Radiosensitizing Target.
L. Jia, J. Yang, X. Hao, M. Zheng, H. He, X. Xiong, L. Xu, and Y. Sun (2010)
Clin. Cancer Res. 16, 814-824
   Abstract »    Full Text »    PDF »
Perifosine Inhibits Mammalian Target of Rapamycin Signaling through Facilitating Degradation of Major Components in the mTOR Axis and Induces Autophagy.
L. Fu, Y.-A. Kim, X. Wang, X. Wu, P. Yue, S. Lonial, F. R. Khuri, and S.-Y. Sun (2009)
Cancer Res. 69, 8967-8976
   Abstract »    Full Text »    PDF »
Combined epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A and the histone deacetylase inhibitor panobinostat against human AML cells.
W. Fiskus, Y. Wang, A. Sreekumar, K. M. Buckley, H. Shi, A. Jillella, C. Ustun, R. Rao, P. Fernandez, J. Chen, et al. (2009)
Blood 114, 2733-2743
   Abstract »    Full Text »    PDF »
REDD1, an inhibitor of mTOR signalling, is regulated by the CUL4A-DDB1 ubiquitin ligase.
S. Katiyar, E. Liu, C. A. Knutzen, E. S. Lang, C. R. Lombardo, S. Sankar, J. I. Toth, M. D. Petroski, Z. Ronai, and G. G. Chiang (2009)
EMBO Rep. 10, 866-872
   Abstract »    Full Text »    PDF »
Targeting the PI3K/AKT Pathway for the Treatment of Prostate Cancer.
D. Sarker, A. H.M. Reid, T. A. Yap, and J. S. de Bono (2009)
Clin. Cancer Res. 15, 4799-4805
   Abstract »    Full Text »    PDF »
Targeting NEDD8-Activated Cullin-RING Ligases for the Treatment of Cancer.
T. A. Soucy, P. G. Smith, and M. Rolfe (2009)
Clin. Cancer Res. 15, 3912-3916
   Abstract »    Full Text »    PDF »
A Phosphorylation Cascade Controls the Degradation of Active SREBP1.
M. T. Bengoechea-Alonso and J. Ericsson (2009)
J. Biol. Chem. 284, 5885-5895
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882