Fbxw7 contributes to tumor suppression by targeting multiple proteins for ubiquitin-dependent degradation
Yo Fujii
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, and
CREST, Japan Science and Technology Corporation, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
Search for more papers by this authorMasayoshi Yada
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, and
CREST, Japan Science and Technology Corporation, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
Search for more papers by this authorMasaaki Nishiyama
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, and
CREST, Japan Science and Technology Corporation, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
Search for more papers by this authorTakumi Kamura
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, and
CREST, Japan Science and Technology Corporation, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
Search for more papers by this authorHidehisa Takahashi
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, and
CREST, Japan Science and Technology Corporation, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
Search for more papers by this authorRyosuke Tsunematsu
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, and
CREST, Japan Science and Technology Corporation, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
Search for more papers by this authorEtsuo Susaki
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, and
CREST, Japan Science and Technology Corporation, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
Search for more papers by this authorTadashi Nakagawa
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, and
CREST, Japan Science and Technology Corporation, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
Search for more papers by this authorAkinobu Matsumoto
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, and
CREST, Japan Science and Technology Corporation, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
Search for more papers by this authorCorresponding Author
Keiichi I. Nakayama
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, and
CREST, Japan Science and Technology Corporation, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
To whom correspondence should be addressed. E-mail: [email protected]Search for more papers by this authorYo Fujii
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, and
CREST, Japan Science and Technology Corporation, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
Search for more papers by this authorMasayoshi Yada
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, and
CREST, Japan Science and Technology Corporation, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
Search for more papers by this authorMasaaki Nishiyama
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, and
CREST, Japan Science and Technology Corporation, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
Search for more papers by this authorTakumi Kamura
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, and
CREST, Japan Science and Technology Corporation, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
Search for more papers by this authorHidehisa Takahashi
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, and
CREST, Japan Science and Technology Corporation, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
Search for more papers by this authorRyosuke Tsunematsu
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, and
CREST, Japan Science and Technology Corporation, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
Search for more papers by this authorEtsuo Susaki
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, and
CREST, Japan Science and Technology Corporation, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
Search for more papers by this authorTadashi Nakagawa
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, and
CREST, Japan Science and Technology Corporation, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
Search for more papers by this authorAkinobu Matsumoto
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, and
CREST, Japan Science and Technology Corporation, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
Search for more papers by this authorCorresponding Author
Keiichi I. Nakayama
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, and
CREST, Japan Science and Technology Corporation, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
To whom correspondence should be addressed. E-mail: [email protected]Search for more papers by this authorAbstract
Fbxw7 (also known as Sel-10, hCdc4 or hAgo) is the F-box protein component of a Skp1–Cul1–F-box protein (SCF) ubiquitin ligase. Fbxw7 contributes to the ubiquitin-mediated degradation of cyclin E, c-Myc, Aurora-A, Notch and c-Jun, all of which appear to function as cell-cycle promoters and oncogenic proteins. Loss of Fbxw7 results in elevated expression of its substrates, which may lead to oncogenesis. However, it remains largely unclear which accumulating substrate is most related to cancer development in Fbxw7-mutant cancer cells. In the present study, we examined the abundance of cyclin E, c-Myc and Aurora-A in seven cancer cell lines, which harbor wild-type (three lines) or mutant (four lines) Fbxw7. Although these three substrates accumulated in the Fbxw7-mutant cells, the extent of increase in the expression of these proteins varied in each line. Forced expression of Fbxw7 reduced the levels of cyclin E, c-Myc and Aurora-A in the Fbxw7-mutant cells. In contrast, a decrease in the expression of cyclin E, c-Myc or Aurora-A by RNA interference significantly suppressed the rate of proliferation and anchorage-independent growth of the Fbxw7-mutant cells. These findings thus suggest that the loss of Fbxw7 results in accumulation of cyclin E, c-Myc and Aurora-A, all of which appear to be required for growth promotion of cancer cells. Fbxw7 seems to regulate the levels of multiple targets to suppress cancer development. (Cancer Sci 2006; 97: 729–736)
References
- 1 Nakayama KI, Nakayama K. Ubiquitin ligases: cell cycle control and cancer. Nat Rev Cancer 2006; 6: 369–81.
- 2 Hershko A, Ciechanover A. The ubiquitin system. Annu Rev Biochem 1998; 67: 425–79.
- 3 Bai C, Sen P, Hofmann K et al. SKP1 connects cell cycle regulators to the ubiquitin proteolysis machinery through a novel motif, the F-box. Cell 1996; 86: 263–74.
- 4 Feldman RM, Correll CC, Kaplan KB, Deshaies RJ. A complex of Cdc4p, Skp1p, and Cdc53p/cullin catalyzes ubiquitination of the phosphorylated CDK inhibitor Sic1p. Cell 1997; 91: 221–30.
- 5 Skowyra D, Craig KL, Tyers M, Elledge SJ, Harper JW. F-box proteins are receptors that recruit phosphorylated substrates to the SCF ubiquitin-ligase complex. Cell 1997; 91: 209–19.
- 6 King RW, Peters JM, Tugendreich S, Rolfe M, Hieter P, Kirschner MW. A 20S complex containing CDC27 and CDC16 catalyzes the mitosis-specific conjugation of ubiquitin to cyclin B. Cell 1995; 81: 279–88.
- 7 Sudakin V, Ganoth D, Dahan A et al. The cyclosome, a large complex containing cyclin-selective ubiquitin ligase activity, targets cyclins for destruction at the end of mitosis. Mol Biol Cell 1995; 6: 185–97.
- 8 Harper JW, Burton JL, Solomon MJ. The anaphase-promoting complex: it's not just for mitosis any more. Genes Dev 2002; 16: 2179–206.
- 9 Nakayama KI, Nakayama K. Regulation of the cell cycle by SCF-type ubiquitin ligases. Semin Cell Dev Biol 2005; 16: 323–33.
- 10 Bornstein G, Bloom J, Sitry-Shevah D, Nakayama K, Pagano M, Hershko A. Role of the SCFSkp2 ubiquitin ligase in the degradation of p21Cip1 in S phase. J Biol Chem 2003; 278: 25 752–7.
- 11 Carrano AC, Eytan E, Hershko A, Pagano M. SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Nat Cell Biol 1999; 1: 193–9.
- 12 Sutterluty H, Chatelain E, Marti A et al. p45SKP2 promotes p27Kip1 degradation and induces S phase in quiescent cells. Nat Cell Biol 1999; 1: 207–14.
- 13 Tsvetkov LM, Yeh KH, Lee SJ, Sun H, Zhang H. p27Kip1 ubiquitination and degradation is regulated by the SCFSkp2 complex through phosphorylated Thr187 in p27. Curr Biol 1999; 9: 661–4.
- 14 Kamura T, Hara T, Kotoshiba S et al. Degradation of p57Kip2 mediated by SCFSkp2-dependent ubiquitylation. Proc Natl Acad Sci USA 2003; 100: 10 231–6.
- 15 Koepp DM, Schaefer LK, Ye X et al. Phosphorylation-dependent ubiquitination of cyclin E by the SCFFbw7 ubiquitin ligase. Science 2001; 294: 173–7.
- 16 Moberg KH, Bell DW, Wahrer DC, Haber DA, Hariharan IK. Archipelago regulates Cyclin E levels in Drosophila and is mutated in human cancer cell lines. Nature 2001; 413: 311–16.
- 17 Strohmaier H, Spruck CH, Kaiser P, Won KA, Sangfelt O, Reed SI. Human F-box protein hCdc4 targets cyclin E for proteolysis and is mutated in a breast cancer cell line. Nature 2001; 413: 316–22.
- 18 Yada M, Hatakeyama S, Kamura T et al. Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7. EMBO J 2004; 23: 2116–25.
- 19 Welcker M, Orian A, Jin J et al. The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation. Proc Natl Acad Sci USA 2004; 101: 9085–90.
- 20 Mao JH, Perez-Losada J, Wu D et al. Fbxw7/Cdc4 is a p53-dependent, haploin sufficient tumour suppressor gene. Nature 2004; 432: 775–9.
- 21 Hubbard EJ, Wu G, Kitajewski J, Greenwald I. Sel-10, a negative regulator of lin-12 activity in Caenorhabditis elegans, encodes a member of the CDC4 family of proteins. Genes Dev 1997; 11: 3182–93.
- 22
Gupta-Rossi N,
Le Bail O,
Gonen H et al.
Functional interaction between SEL-10, an F-box protein, and the nuclear form of activated Notch1 receptor.
J Biol Chem
2001; 276: 34 371–8.
10.1074/jbc.M101343200 Google Scholar
- 23 Oberg C, Li J, Pauley A, Wolf E, Gurney M, Lendahl U. The Notch intracellular domain is ubiquitinated and negatively regulated by the mammalian Sel-10 homolog. J Biol Chem 2001; 276: 35 847–53.
- 24 Wu G, Lyapina S, Das I et al. SEL-10 is an inhibitor of notch signaling that targets notch for ubiquitin-mediated protein degradation. Mol Cell Biol 2001; 21: 7403–15.
- 25 Nateri AS, Riera-Sans L, Da Costa C, Behrens A. The ubiquitin ligase SCFFbw7 antagonizes apoptotic JNK signaling. Science 2004; 303: 1374–8.
- 26 Kwak EL, Moberg KH, Wahrer DC et al. Infrequent mutations of Archipelago (hAGO, hCDC4, Fbw7) in primary ovarian cancer. Gynecol Oncol 2005; 98: 124–8.
- 27 Ekholm-Reed S, Spruck CH, Sangfelt O et al. Mutation of hCDC4 leads to cell cycle deregulation of cyclin E in cancer. Cancer Res 2004; 64: 795–800.
- 28 Cassia R, Moreno-Bueno G, Rodriguez-Perales S, Hardisson D, Cigudosa JC, Palacios J. Cyclin E gene (CCNE) amplification and hCDC4 mutations in endometrial carcinoma. J Pathol 2003; 201: 589–95.
- 29 Spruck CH, Strohmaier H, Sangfelt O et al. hCDC4 gene mutations in endometrial cancer. Cancer Res 2002; 62: 4535–9.
- 30 Rajagopalan H, Jallepalli PV, Rago C et al. Inactivation of hCDC4 can cause chromosomal instability. Nature 2004; 428: 77–81.
- 31 Spruck CH, Won KA, Reed SI. Deregulated cyclin E induces chromosome instability. Nature 1999; 401: 297–300.
- 32 Tsunematsu R, Nakayama K, Oike Y et al. Mouse Fbw7/Sel-10/Cdc4 is required for notch degradation during vascular development. J Biol Chem 2004; 279: 9417–23.
- 33 Nakayama K, Nagahama H, Minamishima YA et al. Targeted disruption of Skp2 results in accumulation of cyclin E and p27Kip1, polyploidy and centrosome overduplication. EMBO J 2000; 19: 2069–81.
- 34 Nakayama K, Nagahama H, Minamishima YA et al. Skp2-mediated degradation of p27 regulates progression into mitosis. Dev Cell 2004; 6: 661–72.
- 35 Kossatz U, Dietrich N, Zender L, Buer J, Manns MP, Malek NP. Skp2-dependent degradation of p27kip1 is essential for cell cycle progression. Genes Dev 2004; 18: 2602–7.
- 36 Nakayama K, Ishida N, Shirane M et al. Mice lacking p27Kip1 display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell 1996; 85: 707–20.
- 37 Hatakeyama S, Kitagawa M, Nakayama K et al. Ubiquitin-dependent degradation of IκBα is mediated by a ubiquitin ligase Skp1/Cul 1/F-box protein FWD1. Proc Natl Acad Sci USA 1999; 96: 3859–63.
- 38 Morita S, Kojima T, Kitamura T. Plat-E: an efficient and stable system for transient packaging of retroviruses. Gene Ther 2000; 7: 1063–6.
- 39 Kamura T, Maenaka K, Kotoshiba S et al. VHL-box and SOCS-box domains determine binding specificity for Cul2-Rbx1 and Cul5-Rbx2 modules of ubiquitin ligases. Genes Dev 2004; 18: 3055–65.
- 40 Kamura T, Hara T, Matsumoto M et al. Cytoplasmic ubiquitin ligase KPC regulates proteolysis of p27Kip1 at G1 phase. Nat Cell Biol 2004; 6: 1229–35.
- 41 Hatakeyama S, Watanabe M, Fujii Y, Nakayama KI. Targeted destruction of c-Myc by an engineered ubiquitin ligase suppresses cell transformation and tumor formation. Cancer Res 2005; 65: 7874–9.
- 42 Tetzlaff MT, Yu W, Li M et al. Defective cardiovascular development and elevated cyclin E and Notch proteins in mice lacking the Fbw7 F-box protein. Proc Natl Acad Sci USA 2004; 101: 3338–45.
- 43 Adhikary S, Eilers M. Transcriptional regulation and transformation by Myc proteins. Nature Rev Mol Cell Biol 2005; 6: 635–45.
- 44 Giet R, Petretti C, Prigent C. Aurora kinases, aneuploidy and cancer, a coincidence or a real link? Trends Cell Biol 2005; 15: 241–50.
- 45 Weng AP, Aster JC. Multiple niches for Notch in cancer: context is everything. Curr Opin Genet Dev 2004; 14: 48–54.
- 46 Callahan R, Raafat A. Notch signaling in mammary gland tumorigenesis. J Mammary Gland Biol Neoplasia 2001; 6: 23–36.
- 47 Capobianco AJ, Zagouras P, Blaumueller CM, Artavanis-Tsakonas S, Bishop JM. Neoplastic transformation by truncated alleles of human NOTCH1/TAN1 and NOTCH2. Mol Cell Biol 1997; 17: 6265–73.
- 48 Hoemann CD, Beaulieu N, Girard L, Rebai N, Jolicoeur P. Two distinct Notch1 mutant alleles are involved in the induction of T-cell leukemia in c-myc transgenic mice. Mol Cell Biol 2000; 20: 3831–42.
- 49 Pear WS, Aster JC, Scott ML et al. Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles. J Exp Med 1996; 183: 2283–91.
- 50 Gallahan D, Callahan R. The mouse mammary tumor associated gene INT3 is a unique member of the NOTCH gene family (NOTCH4). Oncogene 1997; 14: 1883–90.
- 51 Hartl M, Bader AG, Bister K. Molecular targets of the oncogenic transcription factor jun. Curr Cancer Drug Targets 2003; 3: 41–55.
- 52 Li K, Lin SY, Brunicardi FC, Seu P. Use of RNA interference to target cyclin E-overexpressing hepatocellular carcinoma. Cancer Res 2003; 63: 3593–7.
- 53 Williams NS, Gaynor RB, Scoggin S et al. Identification and validation of genes involved in the pathogenesis of colorectal cancer using cDNA microarrays and RNA interference. Clin Cancer Res 2003; 9: 931–46.
- 54 Du J, Hannon GJ. Suppression of p160ROCK bypasses cell cycle arrest after Aurora-A/STK15 depletion. Proc Natl Acad Sci USA 2004; 101: 8975–80.
- 55 Hata T, Furukawa T, Sunamura M et al. RNA interference targeting aurora kinase A suppresses tumor growth and enhances the taxane chemosensitivity in human pancreatic cancer cells. Cancer Res 2005; 65: 2899–905.
