This Article Abstract Full Text (PDF) Supplementary Data Correction (v68,p1245) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Akhoondi, S. Articles by Spruck, C. Search for Related Content PubMed PubMed Citation Articles by Akhoondi, S. Articles by Spruck, C.

FBXW7/hCDC4 Is a General Tumor Suppressor in Human Cancer

¹ Cancer Center Karolinska, Karolinska Hospital, Stockholm, Sweden; ² Department of Tumor Cell Biology, Sidney Kimmel Cancer Center, San Diego, California; ³ Department of Gynaecological Oncology, Institute for Women's Health, University College London, London, United Kingdom; ⁴ Department of Obstetrics and Gynecology, Medical University Innsbruck, Innsbruck, Austria; ⁵ Research Center for Gastrointestinal and Liver Disease, Taleghani Hospital, Tehran, Iran; ⁶ Department of Medical Sciences, Pathology, and Gastroenterology, Uppsala University Hospital, Uppsala, Sweden; and ⁷ Department of Molecular Biology, The Scripps Research Institute, La Jolla, California

Requests for reprints: Charles Spruck, Sidney Kimmel Cancer Center, 10905 Road to the Cure, San Diego, CA 92121. Phone: 858-450-5990; Fax: 858-450-3251; E-mail: cspruck{at}skcc.org.

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion References

 
The ubiquitin-proteasome system is a major regulatory pathway of protein degradation and plays an important role in cellular division. Fbxw7 (or hCdc4), a member of the F-box family of proteins, which are substrate recognition components of the multisubunit ubiquitin ligase SCF (Skp1-Cdc53/Cullin-F-box-protein), has been shown to mediate the ubiquitin-dependent proteolysis of several oncoproteins including cyclin E1, c-Myc, c-Jun, and Notch. The oncogenic potential of Fbxw7 substrates, frequent allelic loss in human cancers, and demonstration that mutation of FBXW7 cooperates with p53 in mouse tumorigenesis have suggested that Fbxw7 could function as a tumor suppressor in human cancer. Here, we carry out an extensive genetic screen of primary tumors to evaluate the role of FBXW7 as a tumor suppressor in human tumorigenesis. Our results indicate that FBXW7 is inactivated by mutation in diverse human cancer types with an overall mutation frequency of 6%. The highest mutation frequencies were found in tumors of the bile duct (cholangiocarcinomas, 35%), blood (T-cell acute lymphocytic leukemia, 31%), endometrium (9%), colon (9%), and stomach (6%). Approximately 43% of all mutations occur at two mutational "hotspots," which alter Arg residues (Arg⁴⁶⁵ and Arg⁴⁷⁹) that are critical for substrate recognition. Furthermore, we show that Fbxw7^Arg465 hotspot mutant can abrogate wild-type Fbxw7 function through a dominant negative mechanism. Our study is the first comprehensive screen of FBXW7 mutations in various human malignancies and shows that FBXW7 is a general tumor suppressor in human cancer. [Cancer Res 2007;67(19):9006–12]

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References

 
The ubiquitin-proteasome system regulates important cellular processes including differentiation and development, apoptosis, protein trafficking, the immune and inflammatory responses, cell cycle progression, and cellular division (1). The latter processes are primarily regulated by two ubiquitin ligases known as the anaphase-promoting complex (APC) and SCF. SCF ubiquitin ligases are composed of Cul1, Rbx1 (also called Roc1 or Hrt1), and Skp1 bound to a member of the F-box protein family, which provide substrate specificity. Approximately 65 F-box proteins exist in humans, each characterized by an 40-amino-acid F-box motif that associates with the SCF complex through Skp1 (1).

In S. cerevisiae, the F-box protein Cdc4 plays a critical role in cell cycle control by mediating the ubiquitin-dependent proteolysis of DNA replication protein Cdc6 and cyclin-dependent kinase (Cdk) inhibitors Far1 and Sic1 (2, 3). Similarly, the orthologue of Cdc4 in humans, designated Fbxw7 (also known as hCdc4, Fbw7, or SEL-10), mediates the ubiquitin-dependent proteolysis of several key regulatory proteins involved in cell division and cell fate determination, including cyclin E1, c-Myc, c-Jun, Notch, and Aurora-A (2). Furthermore, FBXW7 deficiency in mice has been shown to result in early embryonic lethality (day 10.5) with embryos exhibiting abnormalities in hematopoietic and vascular development (2).

Several lines of evidence suggest that Fbxw7 is a putative tumor suppressor in human tumorigenesis, including (a) the well-defined oncogenic potential of its putative substrates (described above); (b) localization of FBXW7 to chromosome 4q31.3, which is deleted in 30% of human cancers; (c) the finding that allelic loss of FBXW7 cooperates with p53 in tumorigenesis in mice (4); and (d) demonstration that targeted disruption of FBXW7 in cultured cells leads to an increase in genetic instability (5), a hallmark of human cancers.

In this study, we carry out an extensive genetic analysis of FBXW7 in primary human tumors of diverse tissue origin to determine its role as a putative tumor suppressor. We find that FBXW7 is mutated in a variety of human tumor types with an overall mutation frequency of 6%. Furthermore, we show that expression of an Fbxw7 mutant corresponding to one of the major mutational hotspots in primary tumors interferes with wild-type Fbxw7 function, suggesting a potential dominant negative mechanism of Fbxw7 inactivation. Our results show that FBXW7 is a general tumor suppressor in human tumorigenesis and provide insight into how Fbxw7 function is inactivated during tumorigenesis.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results Discussion References

 
Tumor specimens. Primary tumor specimens (534 in total) were obtained from (a) Department of Obstetrics and Gynecology, Innsbruck Medical University, Innsbruck, Austria (breast and ovarian tumor specimens); (b) Sidney Kimmel Cancer Center, San Diego, CA (lung and prostate); (c) Department of Pathology and Gastroenterology, Uppsala University Hospital, Uppsala, Sweden (bile duct and liver); (d) Department of Oncology/Pathology, Karolinska Hospital, Stockholm, Sweden (hematologic malignancies and melanomas); and (e) Research Center for Gastrointestinal and Liver Disease, Talghani Hospital, Tehran, Iran (stomach, bladder, colon, and esophagus). This project was approved by the research ethics committees at the Karolinska Institute, Uppsala University Hospital, and Shahid Beheshti University of Medical Sciences. A total of 1,556 primary tumor specimens (our results pooled with previously published data) are included in our final analysis.

FBXW7 mutation screening. Screening for FBXW7 mutations was done as previously described (6).

Methylation analysis. Methylation status of mutational hotspot 1435-6 was determined by bisulfite sequencing as described (7). PCR amplifications were done with primers 5'-TGTGGAATGTAGAGATTGGAGAATGTATA-3' and 5'-AAAAAATCCCAACCATAACAAAATTT-3'.

Antibodies. Antibodies used in this study include anti-Flag (Sigma), anti-Skp1 (Lab Vision), anti–cyclin E1 (HE12, Santa Cruz Biotechnology), anti–phospho-T380 cyclin E1 (Santa Cruz Biotechnology), anti-Myc (9E10, Santa Cruz Biotechnology), anti–glutathione S-transferase (GST; Santa Cruz Biotechnology), anti-actin (Santa Cruz Biotechnology), anti-p53 (DO-1, Santa Cruz Biotechnology), and anti-p21 (Ab-1, Calbiochem). Precipitation experiments were done using anti-Flag agarose (Sigma) or Glutathione-Sepharose (GE Healthcare). Immunohistochemical analysis of p21 and p53 was done as described (8). Analysis of ploidy was determined by Feulgen staining of histopathologic sections and image cytometry.

Plasmids and transfection. The full-length -Fbxw7 cDNA was cloned into pFlag-CMV2 (Sigma) and GST expression vector pEBG. Expression plasmids for all FBXW7 mutants were generated using the GeneTailor Site-Directed Mutagenesis System (Invitrogen). Expression plasmid for 3x Myc-cyclin E1 was generated by cloning the full-length cyclin E1 cDNA into pcDNA3.1 (Invitrogen). Transfections were done using Lipofectamine 2000 (Invitrogen).

Molecular modeling. The molecular structure of -Fbxw7 was created using the SWISS-MODEL program and viewed using the DeepView-SwissPDB-Viewer.

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
FBXW7 is mutated in a variety of primary human tumor types. To determine the role of FBXW7 as a tumor suppressor in human tumorigenesis, we genetically analyzed the complete coding region, including sequences unique to the three alternatively spliced Fbxw7 isoforms (, ß, and ), in a variety of human tumor types. The results of this analysis, combined with previously reported data (9–17) for FBXW7 in primary tumors (1,556 specimens in total), are presented in Table 1 . FBXW7 mutations were detected in tumors of diverse tissue origin, including those of the blood, breast, bile duct, colon, endometrium, stomach, lung, bone, ovary, pancreas, and prostate. The highest frequencies of mutations were observed in tumors of the bile duct (cholangiocarcinomas, 35%), blood (T-cell acute lymphocytic leukemia, 31%), colon (9%), endometrium (9%), and stomach (6%). Overall, the frequency of FBXW7 mutations in all primary human cancers analyzed was 6% (87 of 1,556). DNA sequencing of matching negative biopsies from patients with stomach cancers showed that the FBXW7 mutations were exclusively in the tumor specimens, indicating that the mutations were somatic in nature.

View larger version (30K): [in this window] [in a new window]   Figure 1. FBXW7 mutations in primary human tumors. A, spectra of FBXW7 mutations. Three 5'-exons (, ß, and ) encoding the Fbxw7 isoforms are alternatively spliced to 10 common exons that encode the F-box domain (hatched box) and WD40 repeats (boxes I–VII). Each triangle represents an FBXW7 mutation found in a primary human tumor. Mutation type is indicated by color (dark gray, point mutations; light gray, deletions/insertions; black, CT or GA point mutations at CG dinucleotides). Mutational hotspots are observed at nucleotides 670, 832, 1,177, 1,393, 1,394, 1,436, and 1,745. *, chain terminating mutations (nonsense). B, molecular structure of Fbxw7 diagramming mutational hotspots in human tumors. The seven WD40 repeats of Fbxw7 form a ß-propeller structure that is involved in substrate recognition. Amino acids that correspond to mutational hotspots are highlighted in yellow. Arg465, Arg479, Arg505, and Ser582 are localized to the surface or lumen of the ß-propeller structure; Arg393 is located on the rear-face of the ß-propeller; and Arg278 is located proximal to the F-box domain.

Functional analysis of Fbxw7 mutants reveals defects in localization and substrate binding. Substrate recognition by Fbxw7 is mediated through the interaction of the ß-propeller surface formed by the WD40 repeats with the phosphodegron of the substrate protein (2, 3). To examine the consequence on substrate binding of the hotspot mutations, we expressed -Fbxw7^Arg465 and -Fbxw7^Arg479 in HEK 293T cells and assessed their ability to bind substrate cyclin E1. Whereas wild-type -Fbxw7 readily bound cyclin E1 in vivo, mutants -Fbxw7^Arg465 and -Fbxw7^Arg479 did not (Fig. 2 ), despite their proper localization as assessed by immunofluorescence (data not shown). Interestingly, many FBXW7 mutations fall outside of the WD40 repeats and the effect of these on Fbxw7 function is unclear. To analyze this in more detail, we functionally tested mutant FBXW7^+p16 identified in a prostate tumor specimen that contains a proline residue inserted at amino acid 16 of the -isoform (Table 1). Expression of -Fbxw7^+p16 in HEK 293T cells showed that it was incapable of binding cyclin E1 substrate in vivo, although it could readily associate with the SCF core components (Fig. 2). Because residue 16 is in close proximity to the proposed nuclear localization signal of the -isoform (2), we next tested whether -Fbxw7^+p16 is properly localized in cells. Immunofluorescence analysis showed that whereas wild-type -Fbxw7 is almost exclusively localized to the nucleus in HEK 293T cells, -Fbxw7^+p16 is restricted to the cytoplasm (Fig. 2). These results show that the insertion of proline at residue 16 abolished the nuclear localization signal, preventing interaction with cyclin E1 substrate in the nucleus.

View larger version (13K): [in this window] [in a new window]   Figure 2. Functional analysis of Fbxw7 mutants. A, effect of hotspot mutants Arg465 and Arg479 on binding to cyclin E1 substrate. HEK 293T cells were cotransfected with plasmids that express Myc-cyclin E1 and GST--Fbxw7 or mutants GST--Fbxw7R465C or GST--Fbxw7R479Q, and complexes precipitated and analyzed by Western blot analysis. B, functional analysis of -isoform–specific mutant -Fbxw7+p16 isolated from a prostate tumor specimen. HEK 293T cells were cotransfected with Myc-cyclin E1 and Flag--Fbxw7 or Flag--Fbxw7+p16 and extracts immunoprecipitated with anti-Flag antibodies. C, -Fbxw7+p16 mutant mislocalizes to the cytoplasm. HEK 293T cells were transfected with plasmids that express Flag--Fbxw7 (left) or Flag--Fbxw7+p16 (right) and protein location was assessed by immunofluorescence with anti-Flag-FITC antibodies.

View larger version (14K): [in this window] [in a new window]   Figure 3. Hotspot mutant Fbxw7R465C acts dominant negatively to inactivate wild-type Fbxw7 function. A, expression of -Fbxw7R465C interferes with degradation of cyclin E1 by wild-type -Fbxw7. HCT116Fbxw7–/– cells were cotransfected with plasmids that express Myc-cyclin E1, Cdk2, wild-type GST--Fbxw7, and increasing amounts of mutant GST--Fbxw7R465C. Lysates were subjected to Western blot analysis. Note the increase in cyclin E1 level in cells expressing wild-type -Fbxw7 + -Fbxw7R465C compared with wild-type -Fbxw7 alone. An equal amount of total plasmid DNA was transfected in each lane. *, background band. B, coexpression of wild-type -Fbxw7 + -Fbxw7R465C leads to an increase in cyclin E1 half-life. HCT116Fbxw7–/– cells were cotransfected with plasmids that express wild-type -Fbxw7 (wt), -Fbxw7R465C, or wild-type -Fbxw7 + -Fbxw7R465C, and cyclin E1 half-life was determined by cycloheximide-chase experiments. Western blot for actin is shown as a loading control. C, graphical representation of results for cycloheximide-chase experiments.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

FBXW7 mutations were found localized throughout the coding region of the gene including the isoform-specific 5'-exons, nuclear localization signal, F-box motif, and WD40 repeats. These mutations are predicted to adversely affect isoform-specific functions, subunit dimerization, Pin-1 association, localization, SCF assembly, and substrate recognition, highlighting the plethora of ways Fbxw7 can be functionally inactivated in tumors. Interestingly, 6% of FBXW7 mutations are isoform specific, suggesting that inactivation of an individual isoform could play a causative role in human tumorigenesis. This finding could reflect the potential of a mutant Fbxw7 isoform to act dominant negatively (see below) or that individual Fbxw7 isoforms may target a unique set of substrates for ubiquitination. In support of the latter hypothesis, Fbxw7 isoforms are differentially localized in mammalian cells (-nuclear, ß-cytoplasmic, and -nucleolar; ref. 20). Furthermore, ubiquitination of c-Myc has been shown to be mediated by -Fbxw7, which selectively binds substrate in the nucleolus (2). Additionally, ubiquitination of cyclin E1 is mediated through a cooperative effort of - and -Fbxw7, in which -Fbxw7 binds cyclin E1 and stimulates prolyl-isomerization by Pin-1, which then promotes efficient ubiquitylation by SCF^-Fbxw7 (20). Indeed, one of the -isoform–specific mutations detected in tumors (D124Y) was shown to be defective in supporting Pin-1–mediated isomerization of cyclin E1 but was not defective in ubiquitylation function (20). It is currently not understood whether other SCF^Fbxw7 substrates are ubiquitinated via an analogous cooperative mechanism of Fbxw7 isoforms.

Our analysis identified seven mutational hotspots in FBXW7, representing >60% of the total mutations. Two major hotspots located at nucleotides 1,393–1,394 (Arg⁴⁶⁵) and 1,435–1,436 (Arg⁴⁷⁹) account for 43% of all mutations. The amino acid residues corresponding to six of seven mutational hotspots in primary human tumors are evolutionarily conserved in flies, worms, and yeast (2), showing their potential importance in Fbxw7 function. Interestingly, all seven FBXW7 mutational hotspots involve CG dinucleotides, where the resultant mutation is primarily a CT or GA transition. Consistent with 5'-methylcytosine deamination as a mechanism for FBXW7 mutation, the cytosine nucleotide at hotspot position 1,435–1,436 (Arg⁴⁷⁹) was found to be methylated in all primary tumors analyzed. These data stress the potential importance of endogenous methylation in mutational inactivation of Fbxw7 in tumors, as has previously been postulated for the tumor suppressor p53 (18).

It is currently not understood what role, if any, other genetic and epigenetic mechanisms play in FBXW7 inactivation in human tumors. In many primary tumors and derived cell lines, FBXW7 mutations frequently occur without a concomitant loss or mutation of the remaining allele, suggesting that FBXW7 may not follow the classic "two-hit" model of tumor suppressor gene inactivation. It is possible that reduced expression of the wild-type allele might be sufficient to abrogate tumor suppressor activity or that FBXW7 mutations could act dominant negatively. The former possibility is supported by a study that showed that loss of a single FBXW7 allele can accelerate tumor development in p53^+/– mice (4), suggesting FBXW7 is a p53-dependent haploinsufficient tumor suppressor. However, we analyzed FBXW7 and p53 mutations in gastric cancers and failed to detect cooperation between these proteins (Supplementary Table S1). It remains to be determined whether FBXW7 expression is reduced or silenced in tumors through epigenetic mechanisms such as promoter methylation.

Our data show that Fbxw7 mutants corresponding to the major mutational hotspots in primary tumors (Arg⁴⁶⁵ and Arg⁴⁷⁹) can act dominant negatively to abrogate wild-type Fbxw7 function. Coexpression of wild-type -Fbxw7 and -Fbxw7^R465C was found to increase the steady-state level of cyclin E1 as well as its half-life, compared with expression of wild-type -Fbxw7 alone. The different isoforms of Fbxw7 interact in vivo through association of their D-box motifs located in the NH₂-terminal region of the protein, and this interaction enhances SCF^Fbxw7-associated ubiquitylation activity (19). If Fbxw7 predominantly functions as a homodimer or heterodimer in vivo, then expression of a single mutant allele may be sufficient to functionally inactivate its tumor suppressor function. This could explain why most primary tumors contain only a single mutant FBXW7 and retain a wild-type allele. Further study is needed to determine whether other Fbxw7 mutations also act dominant negatively and whether expression at physiologic levels is sufficient to exert the dominant negative effects on wild-type Fbxw7.

	Acknowledgments

 
Grant support: University of California Tobacco-Related Disease Research Program, Swedish Cancer Society, the Swedish Research Council, the Swedish Institute, the Children Cancer Foundation, the Cancer Society of Stockholm, and Karolinska Institute Foundations.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

We thank Dr. Katayoun Aghajani, Mohsen Chiani, and Dr. Ali Mansouri for technical support in tumor specimen preparation. We also thank Bert Vogelstein for providing HCT116^FBXW7–/– cells for this study.

	Footnotes

 
Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

Received 4/10/07. Revised 6/19/07. Accepted 7/12/07.

	References

Top Abstract Introduction Materials and Methods Results Discussion References

 

1. Reed SI. The ubiquitin-proteasome pathway in cell cycle control. Results Probl Cell Differ 2006;42:147–81.[Medline]
2. Minella AC, Clurman BE. Mechanisms of tumor suppression by the SCF(Fbw7). Cell Cycle 2005;4:1356–9.[Medline]
3. Nash P, Tang X, Orlicky S, et al. Multisite phosphorylation of a CDK inhibitor sets a threshold for the onset of DNA replication. Nature 2001;414:514–21.[CrossRef][Medline]
4. Mao JH, Perez-Losada J, Wu D, et al. Fbxw7/Cdc4 is a p53-dependent, haploinsufficient tumour suppressor gene. Nature 2004;432:775–9.[CrossRef][Medline]
5. Rajagopalan H, Jallepalli PV, Rago C, et al. Inactivation of hCDC4 can cause chromosomal instability. Nature 2004;428:77–81.[CrossRef][Medline]
6. Spruck CH, Strohmaier H, Sangfelt O, et al. hCDC4 gene mutations in endometrial cancer. Cancer Res 2002;62:4535–9.[Abstract/Free Full Text]
7. Widschwendter M, Berger J, Hermann M, et al. Methylation and silencing of the retinoic acid receptor-ß2 gene in breast cancer. J Natl Cancer Inst 2000;92:826–32.[Abstract/Free Full Text]
8. Lundgren C, Auer G, Frankendal B, et al. Nuclear DNA content, proliferative activity, and p53 expression related to clinical and histopathologic features in endometrial carcinoma. Int J Gynecol Cancer 2002;12:110–8.[CrossRef][Medline]
9. Kemp Z, Rowan A, Chambers W, et al. CDC4 mutations occur in a subset of colorectal cancers but are not predicted to cause loss of function and are not associated with chromosomal instability. Cancer Res 2005;65:11361–6.[Abstract/Free Full Text]
10. Cassia R, Moreno-Bueno G, Rodriguez-Perales S, et al. Cyclin E gene (CCNE) amplification and hCDC4 mutations in endometrial carcinoma. J Pathol 2003;201:589–95.[CrossRef][Medline]
11. Sterian A, Kan T, Berki AT, et al. Mutational and LOH analyses of the chromosome 4q region in esophageal adenocarcinoma. Oncology 2006;70:168–72.[CrossRef][Medline]
12. Nowak D, Mossner M, Baldus CD, et al. Mutation analysis of hCDC4 in AML cells identifies a new intronic polymorphism. Int J Med Sci 2006;3:148–51.[Medline]
13. Woo LJ, Hwa SY, Young KS, et al. Somatic mutation of hCDC4 gene is rare in lung adenocarcinomas. Acta Oncol 2006;45:487–8.[CrossRef][Medline]
14. Yan T, Wunder JS, Gokgoz N, et al. hCDC4 variation in osteosarcoma. Cancer Genet Cytogenet 2006;169:138–42.[CrossRef][Medline]
15. 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.[CrossRef][Medline]
16. Calhoun ES, Jones JB, Ashfaq R, et al. BRAF and FBXW7 (CDC4, FBW7, AGO, SEL10) mutations in distinct subsets of pancreatic cancer: potential therapeutic targets. Am J Pathol 2003;163:1255–60.[Abstract/Free Full Text]
17. Lee JW, Soung HY, Kim HJ, et al. Mutational analysis of the hCDC4 gene in gastric carcinomas. Eur J Cancer 2006;42:2369–73.[CrossRef][Medline]
18. Jones PA. DNA methylation and cancer. Oncogene 2002;21:5358–60.[CrossRef][Medline]
19. Zhang W, Koepp DM. Fbw7 isoform interaction contributes to cyclin E proteolysis. Mol Cancer Res 2006;4:935–43.[Abstract/Free Full Text]
20. Van Drogen F, Sangfelt O, Malyukova A, et al. Ubiquitylation of cyclin E requires the sequential function of SCF complexes containing distinct hCdc4 isoforms. Mol Cell 2006;23:37–48.[CrossRef][Medline]

This article has been cited by other articles:

				J.-H. Mao, I.-J. Kim, D. Wu, J. Climent, H. C. Kang, R. DelRosario, and A. Balmain FBXW7 Targets mTOR for Degradation and Cooperates with PTEN in Tumor Suppression Science, September 12, 2008; 321(5895): 1499 - 1502. [Abstract] [Full Text] [PDF]

				T. Palomero and A. Ferrando Oncogenic NOTCH1 Control of MYC and PI3K: Challenges and Opportunities for Anti-NOTCH1 Therapy in T-Cell Acute Lymphoblastic Leukemias and Lymphomas Clin. Cancer Res., September 1, 2008; 14(17): 5314 - 5317. [Abstract] [Full Text] [PDF]

				J. E. Grim, M. P. Gustafson, R. K. Hirata, A. C. Hagar, J. Swanger, M. Welcker, H. C. Hwang, J. Ericsson, D. W. Russell, and B. E. Clurman Isoform- and cell cycle-dependent substrate degradation by the Fbw7 ubiquitin ligase J. Cell Biol., June 16, 2008; 181(6): 913 - 920. [Abstract] [Full Text] [PDF]

				B. J. Thompson, V. Jankovic, J. Gao, S. Buonamici, A. Vest, J. M. Lee, J. Zavadil, S. D. Nimer, and I. Aifantis Control of hematopoietic stem cell quiescence by the E3 ubiquitin ligase Fbw7 J. Exp. Med., June 9, 2008; 205(6): 1395 - 1408. [Abstract] [Full Text] [PDF]

				J. M. Perry and L. Li Self-renewal versus transformation: Fbxw7 deletion leads to stem cell activation and leukemogenesis Genes & Dev., May 1, 2008; 22(9): 1107 - 1109. [Abstract] [Full Text] [PDF]

				Correction: The FBXW7 Gene Is Mutated in a Variety of Human Tumors Cancer Res., February 15, 2008; 68(4): 1245 - 1245. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Supplementary Data Correction (v68,p1245) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Akhoondi, S. Articles by Spruck, C. Search for Related Content PubMed PubMed Citation Articles by Akhoondi, S. Articles by Spruck, C.