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FBXW7  -  F-box and WD repeat domain containing 7,...

Homo sapiens

Synonyms: AGO, Archipelago homolog, CDC4, F-box and WD-40 domain-containing protein 7, F-box protein FBX30, ...
 
 
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Disease relevance of FBXW7

  • Both BRAF and FBXW7 mutations functionally activate kinase effectors important in pancreatic cancer and extend the potential options for therapeutic targeting of kinases in the treatment of phenotypically distinct pancreatic adenocarcinoma subsets [1].
  • Human F-box protein hCdc4 targets cyclin E for proteolysis and is mutated in a breast cancer cell line [2].
  • hCDC4 gene mutations in endometrial cancer [3].
  • Infrequent mutations of Archipelago (hAGO, hCDC4, Fbw7) in primary ovarian cancer [4].
  • T58 is the most frequent site of c-myc mutations in lymphoma cells, and our findings suggest that c-Myc activation is one of the key oncogenic consequences of Fbw7 loss in cancer [5].
  • Although the mutant forms of FBW7 were still able to bind to MYC, they do not target it for degradation, suggesting that stabilization of both NICD and its principle downstream target, MYC, may contribute to transformation in leukemias with FBW7 mutations [6].
 

High impact information on FBXW7

  • These features account for the observed phosphorylation threshold in Sic1 recognition and suggest an equilibrium binding mode between a single receptor site in Cdc4 and multiple low-affinity CPD sites in Sic1 [7].
  • Furthermore, depletion of Fbw7 by RNA interference increased both the abundance and transactivation activity of c-Myc [8].
  • These results identify GSK3beta and FBW7 as potential cancer therapeutic targets and MYC as a critical substrate in the GSK3beta survival-signaling pathway [9].
  • The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation [5].
  • When expressed in mammalian cells, SEL-10 protein coimmunoprecipitates with FEM-1, FEM-2, and FEM-3, which are required for masculinization, and FEM-1 and FEM-3 are targeted by SEL-10 for proteasomal degradation [10].
 

Chemical compound and disease context of FBXW7

 

Biological context of FBXW7

  • FBXW7 is an inhibitor of inflammatory signaling through targeting CEBPD for degradation [13]
  • nThe FBXW7/hCDC4 gene encodes a ubiquitin ligase implicated in the control of chromosome stability [14].
  • Mutations were found either in the substrate-binding domain of the protein or at the amino terminus, suggesting a critical role for the region of hCdc4 upstream of the F-box. hCDC4 gene mutations were accompanied by loss of heterozygosity and correlated with aggressive disease [3].
  • We then demonstrated that SEL-10 specifically interacts with nuclear forms of Notch1 and that this interaction requires a phosphorylation event [15].
  • Here we show that hCDC4 gene mutation and hyperphosphorylation of cyclin E, a parameter that usually correlates with hCDC4 mutation, have a strong statistically significant association with polypoidy and aneuploidy in endometrial cancer [16].
  • Mutation of hCDC4 leads to cell cycle deregulation of cyclin E in cancer [17].
 

Anatomical context of FBXW7

 

Associations of FBXW7 with chemical compounds

  • Mutation of Ser(384) to alanine also rendered cyclin E resistant to degradation by Fbw7, with the largest effects being observed with Fbw7beta [21].
  • Ser-243 is mutated to phenylalanine in v-Jun and allows it to escape recognition by Fbw7 [22].
 

Physical interactions of FBXW7

  • SEL-10 bound Notch4 via the WD40 repeats and bound preferentially to a phosphorylated form of Notch4 in cells [23].
  • We mapped the region of Notch4 essential for SEL-10 binding to the C-terminal region downstream of the ankyrin repeats [23].
  • FBXW7 targets CEBPD for degradation and thereby attenuates inflammatory signaling [13]
 

Regulatory relationships of FBXW7

  • Thus, SEL-10 functions to promote the ubiquitination of Notch proteins; however, the fates of these proteins may differ [23].
  • Thus, our results suggest that Fbw7 may be a major regulator of lipid metabolism through control of the phosphorylation-dependent degradation of the SREBP family of transcription factors [24].
  • We used a phosphorylation-specific antibody raised against the c-Myc T58 region to attempt to identify other proteins regulated by the Fbw7 pathway [25].
  • This phenotype can be traced to a defect in the execution of metaphase and subsequent transmission of chromosomes, and is dependent on cyclin E--a protein that is regulated by hCDC4 (refs 2-4) [26].
  • FBXW7 gene transcription is inhibited by CEBPD [27], while FBXW7 targets CEBPD for degradation [13]
 

Other interactions of FBXW7

  • Expression of dominant-negative SEL-10 leads to stabilization of the intracellular domain of Notch1 [23].
  • When this C-terminal fragment of Notch4 was expressed in cells, it was highly labile but could be stabilized by the expression of dominant-negative SEL-10 [23].
  • Fbxw7 is identified herein as an E2F-responsive and TRIP-Br coregulated gene [28].
  • One EEC harboured an hCDC4 mutation: a CGA to CAA (Arg/Gln) change at codon 479 [29].
  • Evidence for functional and physical association between Caenorhabditis elegans SEL-10, a Cdc4p-related protein, and SEL-12 presenilin [30].
  • Because MYCN is itself a target of FBXW7-mediated ubiquitination and degradation, these results suggest that a common pathway is dysregulated by different mechanisms in various WT subtypes [31].
 

Analytical, diagnostic and therapeutic context of FBXW7

  • Sequence analysis shows that SEL-10 is a member of the CDC4 family of proteins and has a potential human ortholog [32].
  • Using a monoclonal antibody (CDC4) that recognizes both the cardiac and slow skeletal isoforms of troponin T in an immunoblotting procedure, the composition of troponin T isoforms in adult and developing skeletal muscles of the rat and human were studied [33].
  • We used a selfmade ELISA obtained from an established panel of HIV-1 V3 loop peptides (ANRS, France) and derived from seven isolates: MN, HXB2, SC, Z6, Z2, ELI and CDC4 [34].

References

  1. BRAF and FBXW7 (CDC4, FBW7, AGO, SEL10) mutations in distinct subsets of pancreatic cancer: potential therapeutic targets. Calhoun, E.S., Jones, J.B., Ashfaq, R., Adsay, V., Baker, S.J., Valentine, V., Hempen, P.M., Hilgers, W., Yeo, C.J., Hruban, R.H., Kern, S.E. Am. J. Pathol. (2003) [Pubmed]
  2. Human F-box protein hCdc4 targets cyclin E for proteolysis and is mutated in a breast cancer cell line. Strohmaier, H., Spruck, C.H., Kaiser, P., Won, K.A., Sangfelt, O., Reed, S.I. Nature (2001) [Pubmed]
  3. hCDC4 gene mutations in endometrial cancer. Spruck, C.H., Strohmaier, H., Sangfelt, O., Müller, H.M., Hubalek, M., Müller-Holzner, E., Marth, C., Widschwendter, M., Reed, S.I. Cancer Res. (2002) [Pubmed]
  4. Infrequent mutations of Archipelago (hAGO, hCDC4, Fbw7) in primary ovarian cancer. Kwak, E.L., Moberg, K.H., Wahrer, D.C., Quinn, J.E., Gilmore, P.M., Graham, C.A., Hariharan, I.K., Harkin, D.P., Haber, D.A., Bell, D.W. Gynecol. Oncol. (2005) [Pubmed]
  5. The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation. Welcker, M., Orian, A., Jin, J., Grim, J.E., Grim, J.A., Harper, J.W., Eisenman, R.N., Clurman, B.E. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  6. FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors. O'Neil, J., Grim, J., Strack, P., Rao, S., Tibbitts, D., Winter, C., Hardwick, J., Welcker, M., Meijerink, J.P., Pieters, R., Draetta, G., Sears, R., Clurman, B.E., Look, A.T. J. Exp. Med. (2007) [Pubmed]
  7. Structural basis for phosphodependent substrate selection and orientation by the SCFCdc4 ubiquitin ligase. Orlicky, S., Tang, X., Willems, A., Tyers, M., Sicheri, F. Cell (2003) [Pubmed]
  8. Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7. Yada, M., Hatakeyama, S., Kamura, T., Nishiyama, M., Tsunematsu, R., Imaki, H., Ishida, N., Okumura, F., Nakayama, K., Nakayama, K.I. EMBO J. (2004) [Pubmed]
  9. A TRAIL receptor-dependent synthetic lethal relationship between MYC activation and GSK3beta/FBW7 loss of function. Rottmann, S., Wang, Y., Nasoff, M., Deveraux, Q.L., Quon, K.C. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  10. The Caenorhabditis elegans F-box protein SEL-10 promotes female development and may target FEM-1 and FEM-3 for degradation by the proteasome. Jäger, S., Schwartz, H.T., Horvitz, H.R., Conradt, B. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  11. 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. Kemp, Z., Rowan, A., Chambers, W., Wortham, N., Halford, S., Sieber, O., Mortensen, N., von Herbay, A., Gunther, T., Ilyas, M., Tomlinson, I. Cancer Res. (2005) [Pubmed]
  12. Changes in natural immunity during the course of HIV-1 infection. Brenner, B.G., Gryllis, C., Gornitsky, M., Wainberg, M.A. Clin. Exp. Immunol. (1993) [Pubmed]
  13. FBXW7α attenuates inflammatory signalling by downregulating C/EBPδ and its target gene Tlr4. Balamurugan, K., Sharan, S., Klarmann, K.D., Zhang, Y., Coppola, V., Summers, G.H., Roger, T., Morrison, D.K., Keller, J.R., Sterneck, E. Nat. Commun. (2013) [Pubmed]
  14. Fbxw7/Cdc4 is a p53-dependent, haploinsufficient tumour suppressor gene. Mao, J.H., Perez-Losada, J., Wu, D., Delrosario, R., Tsunematsu, R., Nakayama, K.I., Brown, K., Bryson, S., Balmain, A. Nature (2004) [Pubmed]
  15. Functional interaction between SEL-10, an F-box protein, and the nuclear form of activated Notch1 receptor. Gupta-Rossi, N., Le Bail, O., Gonen, H., Brou, C., Logeat, F., Six, E., Ciechanover, A., Israël, A. J. Biol. Chem. (2001) [Pubmed]
  16. Cyclin E dysregulation and chromosomal instability in endometrial cancer. Hubalek, M.M., Widschwendter, A., Erdel, M., Gschwendtner, A., Fiegl, H.M., Müller, H.M., Goebel, G., Mueller-Holzner, E., Marth, C., Spruck, C.H., Reed, S.I., Widschwendter, M. Oncogene (2004) [Pubmed]
  17. Mutation of hCDC4 leads to cell cycle deregulation of cyclin E in cancer. Ekholm-Reed, S., Spruck, C.H., Sangfelt, O., van Drogen, F., Mueller-Holzner, E., Widschwendter, M., Zetterberg, A., Reed, S.I., Reed, S.E. Cancer Res. (2004) [Pubmed]
  18. Mutation Analysis of hCDC4 in AML Cells Identifies a New Intronic Polymorphism. Nowak, D., Mossner, M., Baldus, C.D., Hopfer, O., Thiel, E., Hofmann, W.K. International journal of medical sciences (2006) [Pubmed]
  19. CDC4 gene expression as potential biomarker for targeted therapy in prostate cancer. Koh, M.S., Ittmann, M., Kadmon, D., Thompson, T.C., Leach, F.S. Cancer Biol. Ther. (2006) [Pubmed]
  20. Defective cardiovascular development and elevated cyclin E and Notch proteins in mice lacking the Fbw7 F-box protein. Tetzlaff, M.T., Yu, W., Li, M., Zhang, P., Finegold, M., Mahon, K., Harper, J.W., Schwartz, R.J., Elledge, S.J. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  21. Recognition of phosphodegron motifs in human cyclin E by the SCF(Fbw7) ubiquitin ligase. Ye, X., Nalepa, G., Welcker, M., Kessler, B.M., Spooner, E., Qin, J., Elledge, S.J., Clurman, B.E., Harper, J.W. J. Biol. Chem. (2004) [Pubmed]
  22. The v-Jun point mutation allows c-Jun to escape GSK3-dependent recognition and destruction by the Fbw7 ubiquitin ligase. Wei, W., Jin, J., Schlisio, S., Harper, J.W., Kaelin, W.G. Cancer Cell (2005) [Pubmed]
  23. SEL-10 is an inhibitor of notch signaling that targets notch for ubiquitin-mediated protein degradation. Wu, G., Lyapina, S., Das, I., Li, J., Gurney, M., Pauley, A., Chui, I., Deshaies, R.J., Kitajewski, J. Mol. Cell. Biol. (2001) [Pubmed]
  24. Control of lipid metabolism by phosphorylation-dependent degradation of the SREBP family of transcription factors by SCF(Fbw7). Sundqvist, A., Bengoechea-Alonso, M.T., Ye, X., Lukiyanchuk, V., Jin, J., Harper, J.W., Ericsson, J. Cell metabolism. (2005) [Pubmed]
  25. Zcchc8 is a glycogen synthase kinase-3 substrate that interacts with RNA-binding proteins. Gustafson, M.P., Welcker, M., Hwang, H.C., Clurman, B.E. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  26. Inactivation of hCDC4 can cause chromosomal instability. Rajagopalan, H., Jallepalli, P.V., Rago, C., Velculescu, V.E., Kinzler, K.W., Vogelstein, B., Lengauer, C. Nature (2004) [Pubmed]
  27. The tumour suppressor C/EBPδ inhibits FBXW7 expression and promotes mammary tumour metastasis. Balamurugan, K., Wang, J.M., Tsai, H.H., Sharan, S., Anver, M., Leighty, R., Sterneck, E. EMBO. J. (2010) [Pubmed]
  28. TRIP-Br links E2F to novel functions in the regulation of cyclin E expression during cell cycle progression and in the maintenance of genomic stability. Sim, K.G., Zang, Z., Yang, C.M., Bonventre, J.V., Hsu, S.I. Cell Cycle (2004) [Pubmed]
  29. Cyclin E gene (CCNE) amplification and hCDC4 mutations in endometrial carcinoma. Cassia, R., Moreno-Bueno, G., Rodríguez-Perales, S., Hardisson, D., Cigudosa, J.C., Palacios, J. J. Pathol. (2003) [Pubmed]
  30. Evidence for functional and physical association between Caenorhabditis elegans SEL-10, a Cdc4p-related protein, and SEL-12 presenilin. Wu, G., Hubbard, E.J., Kitajewski, J.K., Greenwald, I. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  31. Subtype-specific FBXW7 mutation and MYCN copy number gain in Wilms' tumor. Williams, R.D., Al-Saadi, R., Chagtai, T., Popov, S., Messahel, B., Sebire, N., Gessler, M., Wegert, J., Graf, N., Leuschner, I., Hubank, M., Jones, C., Vujanic, G., Pritchard-Jones, K. Clin. Cancer Res. (2010) [Pubmed]
  32. sel-10, a negative regulator of lin-12 activity in Caenorhabditis elegans, encodes a member of the CDC4 family of proteins. Hubbard, E.J., Wu, G., Kitajewski, J., Greenwald, I. Genes Dev. (1997) [Pubmed]
  33. Identification of and pattern of transitions of cardiac, adult slow and slow skeletal muscle-like embryonic isoforms of troponin T in developing rat and human skeletal muscles. Sabry, M.A., Dhoot, G.K. J. Muscle Res. Cell. Motil. (1991) [Pubmed]
  34. Serological investigation of HIV-1 variant subtype strains in transmission in Nairobi. Songok, E.M., Tukei, P.M., Mulaa, F.J. East African medical journal. (1996) [Pubmed]
 
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