Department of Veterinary Biochemistry, Yamaguchi University, Yamaguchi 753-8511, Japan.
Department of Veterinary Pathology, Yamaguchi University, Yamaguchi 753-8511, Japan.
Proc Natl Acad Sci U S A. 2024 Oct 8;121(41):e2414618121. doi: 10.1073/pnas.2414618121. Epub 2024 Oct 3.
The transcription factor E2F1 serves as a regulator of the cell cycle and promotes cell proliferation. It is highly expressed in cancer tissues and contributes to their malignant transformation. Degradation by the ubiquitin-proteasome system may help to prevent such overexpression of E2F1 and thereby to suppress carcinogenesis. A detailed understanding of the mechanisms underlying E2F1 degradation may therefore inform the development of new cancer treatments. We here identified SCF as a ubiquitin ligase for E2F1 by comprehensive analysis. We found that phosphorylation of E2F1 at serine-403 promotes its binding to FBXW7 (F-box/WD repeat-containing protein 7) followed by its ubiquitination and degradation. Furthermore, calcineurin, a Ca/calmodulin-dependent serine-threonine phosphatase, was shown to stabilize E2F1 by mediating its dephosphorylation at serine-403 and thereby preventing FBXW7 binding. Treatment of cells with Ca channel blockers resulted in downregulation of both E2F1 protein and the expression of E2F1 target genes, whereas treatment with the Ca ionophore ionomycin induced upregulation of E2F1. Finally, the calcineurin inhibitor FK506 attenuated xenograft tumor growth in mice in association with downregulation of E2F1 in the tumor tissue. Impairment of the balance between the opposing actions of FBXW7 and calcineurin in the regulation of E2F1 abundance may therefore play an important role in carcinogenesis.
转录因子 E2F1 作为细胞周期的调节剂，促进细胞增殖。它在癌症组织中高度表达，有助于它们的恶性转化。通过泛素蛋白酶体系统的降解可能有助于防止 E2F1 的这种过度表达，并从而抑制致癌作用。因此，对 E2F1 降解的机制的深入了解可能为新的癌症治疗方法的开发提供信息。我们通过全面分析鉴定了 SCF 是 E2F1 的泛素连接酶。我们发现 E2F1 在丝氨酸 403 处的磷酸化促进其与 FBXW7（F-box/WD 重复蛋白 7）结合，随后进行泛素化和降解。此外，钙调神经磷酸酶，一种 Ca2+/钙调蛋白依赖性丝氨酸/苏氨酸磷酸酶，通过介导 E2F1 在丝氨酸 403 处去磷酸化来稳定 E2F1，从而防止 FBXW7 结合。用钙通道阻滞剂处理细胞会导致 E2F1 蛋白和 E2F1 靶基因的表达下调，而用钙离子载体离子霉素处理会导致 E2F1 的上调。最后，钙调神经磷酸酶抑制剂 FK506 与肿瘤组织中 E2F1 的下调相关，减弱了小鼠异种移植肿瘤的生长。因此，在调节 E2F1 丰度方面，FBXW7 和钙调神经磷酸酶的相反作用之间的平衡的破坏可能在致癌作用中起重要作用。
