Conditional inactivation of Fbxw7 impairs cell-cycle exit during T cell differentiation and results in lymphomatogenesis

Abstract

Cell proliferation is strictly controlled during differentiation. In T cell development, the cell cycle is normally arrested at the CD4+CD8+ stage, but the mechanism underlying such differentiation-specific exit from the cell cycle has been unclear. Fbxw7 (also known as Fbw7, Sel-10, hCdc4, or hAgo), an F-box protein subunit of an SCF-type ubiquitin ligase complex, induces the degradation of positive regulators of the cell cycle, such as c-Myc, c-Jun, cyclin E, and Notch. FBXW7 is often mutated in a subset of human cancers. We have now achieved conditional inactivation of Fbxw7 in the T cell lineage of mice and found that the cell cycle is not arrested at the CD4+CD8+ stage in the homozygous mutant animals. The mutant mice manifested thymic hyperplasia as a result of c-Myc accumulation and eventually developed thymic lymphoma. In contrast, mature T cells of the mutant mice failed to proliferate in response to mitogenic stimulation and underwent apoptosis in association with accumulation of c-Myc and p53. These latter abnormalities were corrected by deletion of p53. Our results suggest that Fbxw7 regulates the cell cycle in a differentiation-dependent manner, with its loss resulting in c-Myc accumulation that leads to hyperproliferation in immature T cells but to p53-dependent cell-cycle arrest and apoptosis in mature T cells.

Notch-dependent cell cycle arrest and apoptosis in mouse embryonic fibroblasts lacking Fbxw7

“…The deregulation of cyclin E expression caused by mutation of FBXW7 thus likely contributes directly to the development of at least a subset of human tumors. However, the observations that the abundance of cyclin E was not increased either in the thymic lymphomas that develop in mice with conditional ablation of Fbxw7 (Fbxw7 D/D mice) (Onoyama et al, 2007) or in the radiation-induced lymphomas that are frequently observed in Fbxw7 þ /À mice (Mao et al, 2004) suggest that Fbxw7 contributes to cyclin E proteolysis in a contextdependent manner.…”

“…We have previously shown that abnormal accumulation of NICD1 and c-Myc and the associated overproliferation of thymocytes resulted in thymic lymphoma in mice with conditional inactivation of Fbxw7 in the T-cell lineage (Onoyama et al, 2007). Additional ablation of the c-Myc gene in Fbxw7 D/D T cells reversed the overproliferation phenotype.…”

“…To study the physiological role of Fbxw7, we prepared Fbxw7-null primary fibroblasts (Fbxw7 D/D MEFs) from mice homozygous for a 'floxed' Fbxw7 allele (Fbxw7 F/F mice) (Onoyama et al, 2007). Conditional inactivation of Fbxw7 was induced by infection of the primary Fbxw7 F/F MEFs with a retrovirus encoding Cre recombinase.…”

Triggering Fbw7-Mediated Proteasomal Degradation of c-Myc by Oridonin Induces Cell Growth Inhibition and Apoptosis

“…As a component of the UPS, Fbw7 ubiquitin ligase plays a vital role in cell fate decisions (35,42). It was recently shown that Fbw7 controlled the fate of hematopoietic stem cells (43) and affected the proliferation and lymphomagenesis of mouse T cells (44), both through the regulation of c-Myc expression. In addition, as a tumor suppressor, Fbw7 is inactivated in numerous human malignancies.…”

Regulation of APCCdh1 E3 ligase activity by the Fbw7/cyclin E signaling axis contributes to the tumor suppressor function of Fbw7

“…However, how Fbw7 suppresses tumor formation is currently not well understood. Although negative regulation of c-Myc and NOTCH-1 by Fbw7 has been implicated in tumorigenesis, their contributions to the tumor suppressor function of Fbw7 still require substantial characterization [16,[18][19][20]. On the other hand, cyclin E has garnered much attention as a possible key mediator for the ability of Fbw7 to inhibit tumorigenesis.…”