Fbxw7作为防止造血干细胞过早丢失和T细胞急性淋巴细胞白血病发生的关键安全保障机制。
Fbxw7 acts as a critical fail-safe against premature loss of hematopoietic stem cells and development of T-ALL.
作者信息
Matsuoka Sahoko, Oike Yuichi, Onoyama Ichiro, Iwama Atsushi, Arai Fumio, Takubo Keiyo, Mashimo Yoichi, Oguro Hideyuki, Nitta Eriko, Ito Keisuke, Miyamoto Kana, Yoshiwara Hiroki, Hosokawa Kentaro, Nakamura Yuka, Gomei Yumiko, Iwasaki Hiroko, Hayashi Yasuhide, Matsuzaki Yumi, Nakayama Keiko, Ikeda Yasuo, Hata Akira, Chiba Shigeru, Nakayama Keiichi I, Suda Toshio
机构信息
Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo 160-8582, Japan.
出版信息
Genes Dev. 2008 Apr 15;22(8):986-91. doi: 10.1101/gad.1621808. Epub 2008 Mar 26.
Abstract
Common molecular machineries between hematopoietic stem cell (HSC) maintenance and leukemia prevention have been highlighted. The tumor suppressor Fbxw7 (F-box and WD-40 domain protein 7), a subunit of an SCF-type ubiquitin ligase complex, induces the degradation of positive regulators of the cell cycle. We demonstrate that inactivation of Fbxw7 in hematopoietic cells causes premature depletion of HSCs due to active cell cycling and p53-dependent apoptosis. Interestingly, Fbxw7 deletion also confers a selective advantage to cells with suppressed p53 function, eventually leading to development of T-cell acute lymphoblastic leukemia (T-ALL). Thus, Fbxw7 functions as a fail-safe mechanism against both premature HSC loss and leukemogenesis.
摘要
造血干细胞（HSC）维持与白血病预防之间常见的分子机制已得到凸显。肿瘤抑制因子Fbxw7（F-box和WD-40结构域蛋白7）是SCF型泛素连接酶复合物的一个亚基，可诱导细胞周期正调控因子的降解。我们证明，造血细胞中Fbxw7的失活会由于活跃的细胞周期和p53依赖的凋亡导致HSCs过早耗竭。有趣的是，Fbxw7缺失也赋予p53功能受抑制的细胞选择性优势，最终导致T细胞急性淋巴细胞白血病（T-ALL）的发生。因此，Fbxw7作为一种针对过早的HSC损失和白血病发生的故障安全机制发挥作用。
相似文献
1
Fbxw7 acts as a critical fail-safe against premature loss of hematopoietic stem cells and development of T-ALL.Fbxw7作为防止造血干细胞过早丢失和T细胞急性淋巴细胞白血病发生的关键安全保障机制。
Genes Dev. 2008 Apr 15;22(8):986-91. doi: 10.1101/gad.1621808. Epub 2008 Mar 26.
2
Conditional inactivation of Fbxw7 impairs cell-cycle exit during T cell differentiation and results in lymphomatogenesis.Fbxw7 的条件性失活会损害 T 细胞分化过程中的细胞周期退出，并导致淋巴瘤发生。
J Exp Med. 2007 Nov 26;204(12):2875-88. doi: 10.1084/jem.20062299. Epub 2007 Nov 12.
3
Self-renewal versus transformation: Fbxw7 deletion leads to stem cell activation and leukemogenesis.自我更新与转化：Fbxw7缺失导致干细胞激活和白血病发生。
Genes Dev. 2008 May 1;22(9):1107-9. doi: 10.1101/gad.1670708.
4
The ubiquitin ligase FBXW7 modulates leukemia-initiating cell activity by regulating MYC stability.泛素连接酶 FBXW7 通过调节 MYC 稳定性来调节白血病起始细胞的活性。
Cell. 2013 Jun 20;153(7):1552-66. doi: 10.1016/j.cell.2013.05.041.
5
Fbxw7 in cell cycle exit and stem cell maintenance: insight from gene-targeted mice.Fbxw7在细胞周期退出和干细胞维持中的作用：来自基因敲除小鼠的见解
Cell Cycle. 2008 Nov 1;7(21):3307-13. doi: 10.4161/cc.7.21.6931. Epub 2008 Nov 5.
6
Ex vivo maintenance of hematopoietic stem cells by quiescence induction through Fbxw7α overexpression.通过过表达 Fbxw7α诱导静止状态来维持造血干细胞的体外活力。
Blood. 2011 Feb 24;117(8):2373-7. doi: 10.1182/blood-2010-07-294801. Epub 2010 Dec 29.
7
Fbxw7 regulates lipid metabolism and cell fate decisions in the mouse liver.Fbxw7 调节小鼠肝脏中的脂质代谢和细胞命运决定。
J Clin Invest. 2011 Jan;121(1):342-54. doi: 10.1172/JCI40725. Epub 2010 Dec 1.
8
Control of hematopoietic stem cell quiescence by the E3 ubiquitin ligase Fbw7.E3泛素连接酶Fbw7对造血干细胞静止状态的调控
J Exp Med. 2008 Jun 9;205(6):1395-408. doi: 10.1084/jem.20080277. Epub 2008 May 12.
9
Chromosome instability underlies hematopoietic stem cell dysfunction and lymphoid neoplasia associated with impaired Fbw7-mediated cyclin E regulation.染色体不稳定是造血干细胞功能障碍和与Fbw7介导的细胞周期蛋白E调控受损相关的淋巴样肿瘤的基础。
Mol Cell Biol. 2014 Sep;34(17):3244-58. doi: 10.1128/MCB.01528-13. Epub 2014 Jun 23.
10
Skp1-Cullin-F-box (SCF)-type ubiquitin ligase FBXW7 negatively regulates spermatogonial stem cell self-renewal.Skp1-Cullin-F-box (SCF)- 型泛素连接酶 FBXW7 负调控精原干细胞自我更新。
Proc Natl Acad Sci U S A. 2014 Jun 17;111(24):8826-31. doi: 10.1073/pnas.1401837111. Epub 2014 May 30.
引用本文的文献
1
Haematopoietic stem cell number is not solely defined by niche availability.造血干细胞数量并非仅由龛位可用性决定。
Nature. 2025 Aug 27. doi: 10.1038/s41586-025-09462-5.
2
PSMG2 role in tumorigenesis and stemness mediated by protein accumulation, reticulum stress and autophagy.PSMG2在由蛋白质积累、内质网应激和自噬介导的肿瘤发生和干性中的作用。
Int J Biol Sci. 2025 Mar 21;21(6):2531-2549. doi: 10.7150/ijbs.105263. eCollection 2025.
3
Impact of G1 phase kinetics on the acquisition of stemness in cancer cells: the critical role of cyclin D.G1期动力学对癌细胞干性获得的影响：细胞周期蛋白D的关键作用。
Mol Biol Rep. 2025 Feb 14;52(1):230. doi: 10.1007/s11033-025-10351-3.
4
Clinical significance of NOTCH1 and FBXW7 alterations in adult T-cell leukemia/lymphoma.NOTCH1和FBXW7改变在成人T细胞白血病/淋巴瘤中的临床意义
Int J Hematol. 2025 Feb;121(2):206-221. doi: 10.1007/s12185-024-03880-3. Epub 2024 Nov 25.
5
Exploiting the potential of the ubiquitin-proteasome system in overcoming tyrosine kinase inhibitor resistance in chronic myeloid leukemia.利用泛素-蛋白酶体系统在克服慢性髓性白血病中酪氨酸激酶抑制剂耐药性方面的潜力。
Genes Dis. 2023 Oct 26;11(5):101150. doi: 10.1016/j.gendis.2023.101150. eCollection 2024 Sep.
6
Molecular insights and clinical implications for the tumor suppressor role of SCF E3 ubiquitin ligase.SCF E3 泛素连接酶的肿瘤抑制作用的分子见解和临床意义。
Biochim Biophys Acta Rev Cancer. 2024 Sep;1879(5):189140. doi: 10.1016/j.bbcan.2024.189140. Epub 2024 Jun 21.
7
CRL2 and CRL1 cooperatively mediate c-Myc degradation.CRL2 和 CRL1 协同介导 c-Myc 降解。
Oncogene. 2024 Jun;43(25):1917-1929. doi: 10.1038/s41388-024-03048-7. Epub 2024 May 2.
8
Selective deletion of E3 ubiquitin ligase FBW7 in VE-cadherin-positive cells instigates diffuse large B-cell lymphoma in mice in vivo.在体内，E3 泛素连接酶 FBW7 在血管内皮钙黏蛋白阳性细胞中的选择性缺失引发了小鼠弥漫性大 B 细胞淋巴瘤。
Cell Death Dis. 2024 Mar 14;15(3):212. doi: 10.1038/s41419-024-06597-7.
9
The Highs and Lows of FBXW7: New Insights into Substrate Affinity in Disease and Development.FBXW7 的优缺点：疾病和发育中底物亲和力的新见解。
Cells. 2023 Aug 24;12(17):2141. doi: 10.3390/cells12172141.
10
The Role of FBXW7 in Gynecologic Malignancies.FBXW7 在妇科恶性肿瘤中的作用。
Cells. 2023 May 17;12(10):1415. doi: 10.3390/cells12101415.
本文引用的文献
1
Conditional inactivation of Fbxw7 impairs cell-cycle exit during T cell differentiation and results in lymphomatogenesis.Fbxw7 的条件性失活会损害 T 细胞分化过程中的细胞周期退出，并导致淋巴瘤发生。
J Exp Med. 2007 Nov 26;204(12):2875-88. doi: 10.1084/jem.20062299. Epub 2007 Nov 12.
2
The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia.SCFFBW7泛素连接酶复合体作为T细胞白血病中的一种肿瘤抑制因子。
J Exp Med. 2007 Aug 6;204(8):1825-35. doi: 10.1084/jem.20070872. Epub 2007 Jul 23.
3
Chromosomally unstable mouse tumours have genomic alterations similar to diverse human cancers.染色体不稳定的小鼠肿瘤具有与多种人类癌症相似的基因组改变。
Nature. 2007 Jun 21;447(7147):966-71. doi: 10.1038/nature05886. Epub 2007 May 21.
4
CARF binds to three members (ARF, p53, and HDM2) of the p53 tumor-suppressor pathway.CARF与p53肿瘤抑制途径的三个成员（ARF、p53和HDM2）结合。
Ann N Y Acad Sci. 2007 Apr;1100:312-5. doi: 10.1196/annals.1395.033.
5
FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress.FoxO蛋白是造血干细胞抵抗生理性氧化应激的关键介质。
Cell. 2007 Jan 26;128(2):325-39. doi: 10.1016/j.cell.2007.01.003.
6
c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma.c-Myc是T细胞急性淋巴细胞白血病/淋巴瘤中Notch1的重要直接靶点。
Genes Dev. 2006 Aug 1;20(15):2096-109. doi: 10.1101/gad.1450406. Epub 2006 Jul 17.
7
Ubiquitin ligases: cell-cycle control and cancer.泛素连接酶：细胞周期调控与癌症
Nat Rev Cancer. 2006 May;6(5):369-81. doi: 10.1038/nrc1881.
8
PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention.PTEN维持造血干细胞，并在谱系选择和白血病预防中发挥作用。
Nature. 2006 May 25;441(7092):518-22. doi: 10.1038/nature04747. Epub 2006 Apr 23.
9
Notch 1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia.Notch 1激活在T细胞急性淋巴细胞白血病分子发病机制中的作用
Nat Rev Cancer. 2006 May;6(5):347-59. doi: 10.1038/nrc1880.
10
Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells.PTEN依赖性将造血干细胞与白血病起始细胞区分开来。
Nature. 2006 May 25;441(7092):475-82. doi: 10.1038/nature04703. Epub 2006 Apr 5.
Zotero 插件