Clarifying the role of Fbxw7 in cancer
B6;129P2-Fbxw7<tm1Kei> (RBRC06393, floxed mouse)
B6;129P2-Fbxw7<tm1Kin> (RBRC06394, knockout mouse)
Courtesy of Keiichi Nakayama, M.D., Ph.D.
Gross appearance of the lungs of wild-type mice that had been reconstituted with bone marrow (BM) cells from CAG-EGFP/Fbxw7F/F (Control) or CAG–EGFP/Mx1-Cre/Fbxw7F/F (Fbxw7 cKO) mice and injected with pIpC and mouse B16F10 melanoma cells (2.0 × 105). After 2 weeks, the animals were killed and the lungs were removed and fixed in Bouin’s solution. Scale bar, 10 mm.
|F-box and WD-40 domain protein 7 (Fbxw7, also known as Fbw7) is an E3 ubiquitin ligase and the component of an F-box protein of the Skp, Cullin, F-box containing complex (SCF complex). Fbxw7 targets substrate proteins including c-Myc, cyclin E, and Notch for ubiquitination and degradation. Nakayama and colleagues generated mice with Fbxw7 conditionally deleted in the T cell lineage and showed that loss of Fbxw7 resulted in c-Myc accumulation, which led to hyperproliferation of immature T cells but apoptosis of mature T cells [1, 2].|
|Cancer-initiating cells (CICs) are quiescent cells that are required for cancer initiation and maintenance. As most anti-cancer drugs target dividing cells, CICs are resistant to such therapies, resulting in disease relapse. Using a mouse model of chronic myeloid leukemia, the group revealed that ablation of Fbxw7 in leukemia-initiating cells abrogated their quiescence via c-Myc accumulation and increased their sensitivity to anti-cancer drugs. Combination therapy with Fbxw7 ablation and anti-cancer drugs was effective for leukemia-initiating cell depletion in mice [3, 4]. A recent report focused on the host environment and revealed the suppressive role of Fbxw7 in cancer metastasis via C-C motif chemokine 2 , showing Fbxw7 to be a therapeutic target of many kinds of human cancer.|
|Depositor||:||Keiichi Nakayama, M.D., Ph.D.
Department of Molecular and Cellular Biology
Medical Institute of Bioregulation, Kyushu University
|References||:||||Tsunematsu R, Nakayama K, Oike Y, Nishiyama M, Ishida N, Hatakeyama S, Bessho Y, Kageyama R, Suda T, Nakayama KI. Mouse Fbw7/Sel-10/Cdc4 is required for notch degradation during vascular development.J Biol Chem.; 279(10):9417-23, 2004.|
|||Onoyama I, Tsunematsu R, Matsumoto A, Kimura T, de Alborán IM, Nakayama K, Nakayama KI. Conditional inactivation of Fbxw7 impairs cell-cycle exit during T cell differentiation and results in lymphomatogenesis. J Exp Med.; 204(12):2875-88, 2007.|
|||Takeishi S, Matsumoto A, Onoyama I, Naka K, Hirao A, Nakayama KI. Ablation of Fbxw7 eliminates leukemia-initiating cells by preventing quiescence. Cancer Cell; 23(3):347-61, 2013.|
|||Reavie L, Buckley SM, Loizou E, Takeishi S, Aranda-Orgilles B, Ndiaye-Lobry D, Abdel-Wahab O, Ibrahim S, Nakayama KI, Aifantis I. Regulation of c-Myc ubiquitination controls chronic myelogenous leukemia initiation and progression. Cancer Cell; 23(3):362-75, 2013.|
|||Yumimoto K, Akiyoshi S, Ueo H, Sagara Y, Onoyama I, Ueo H, Ohno S, Mori M, Mimori K, Nakayama KI. F-box protein FBXW7 inhibits cancer metastasis in a non-cell-autonomous manner. J Clin Invest.; in press, 2015.|
| January 2015
Contact: Shinya Ayabe, Ph.D.
Experimental Animal Division, RIKEN BioResource Center
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