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首页> 外文期刊>Nature >SCF~(FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction
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SCF~(FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction

机译：SCF〜（FBW7）通过靶向MCL1进行泛素化和破坏来调节细胞凋亡

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摘要

肿瘤抑制因子Fbw7的失去在各种不同类型的rn人类癌症中经常被发现，但其作为一个肿瘤抑rn制因子的作用机制仍不清楚。两个小组发现，rn在包括卵巢癌和T-细胞白血病在内的几种癌症rn类型中，凋亡调控因子Mcl-1被Fbw7作为降解rn目标。Inuzuka等人发现，这个机制能够决定rn对以BCI-2家族的凋亡因子为目标的药物的反rn应；Wertz等人发现，该机制是在有丝分裂停rn止期间被激活的，它决定对“抗微管蛋白”化rn疗的反应。因此，癌症患者Fbw7的删除或突rn变能使肿瘤对这些疗法产生抵抗力。%The effective use of targeted therapy is highly dependent on the identification of responder patient populations. Loss of FBW7, which encodes a tumour-suppressor protein, is frequently found in various types of human cancer, including breast cancer, colon cancer and T-cell acute lymphoblastic leukaemia (T-ALL). In line with these genomic data, engineered deletion of Fbw7 in mouse T cells results in T-ALL, validating FBW7 as a T-ALL tumour suppressor. Determining the precise molecular mechanisms by which FBW7 exerts antitumour activity is an area of intensive investigation. These mechanisms are thought to relate in part to FBW7-mediated destruction of key proteins relevant to cancer, including Jun, Myc, cyclin E and notch 1 (ref. 9), all of which have oncoprotein activity and are overexpressed in various human cancers, including leukaemia. In addition to accelerating cell growth, overexpression of Jun, Myc or notch 1 can also induce programmed cell death. Thus, considerable uncertainty surrounds how FBW7-deficient cells evade cell death in the setting of upregulated Jun, Myc and/or notch 1. Here we show that the E3 ubiquitin ligase SC~(FB W7) (a SKP1-cullin-1-F-box complex that contains FBW7 as the F-box protein) governs cellular apoptosis by targeting MCL1, a pro-survival BCL2 family member, for ubiquitylation and destruction in a manner that depends on phos-phorylation by glycogen synthase kinase 3. Human T-ALL cell lines showed a close relationship between FBW7 loss and MCL1 over-expression. Correspondingly, T-ALL cell lines with defective FBW7 are particularly sensitive to the multi-kinase inhibitor sorafenib but resistant to the BCL2 antagonist ABT-737. On the genetic level, FBW7 reconstitution or MCL1 depletion restores sensitivity to ABT-737, establishing MCL1 as a therapeutically relevant bypass survival mechanism that enables FBW7-deficient cells to evade apoptosis. Therefore, our work provides insight into the molecular mechanism of direct tumour suppression by FB W7 and has implications for the targeted treatment of patients with FBW7-deficient TALL.
机译：肿瘤抑制因子Fbw7的失去在各种不同类型的rn人类癌症中经常被发现，但其作为一个肿瘤抑rn制因子的作用机制仍不清楚。两个小组发现，rn在包括卵巢癌和T-细胞白血病在内的几种癌症rn类型中，凋亡调控因子Mcl-1被Fbw7作为降解rn目标。Inuzuka等人发现，这个机制能够决定rn对以BCI-2家族的凋亡因子为目标的药物的反rn应；Wertz等人发现，该机制是在有丝分裂停rn止期间被激活的，它决定对“抗微管蛋白”化rn疗的反应。因此，癌症患者Fbw7的删除或突rn变能使肿瘤对这些疗法产生抵抗力。%The effective use of targeted therapy is highly dependent on the identification of responder patient populations. Loss of FBW7, which encodes a tumour-suppressor protein, is frequently found in various types of human cancer, including breast cancer, colon cancer and T-cell acute lymphoblastic leukaemia (T-ALL). In line with these genomic data, engineered deletion of Fbw7 in mouse T cells results in T-ALL, validating FBW7 as a T-ALL tumour suppressor. Determining the precise molecular mechanisms by which FBW7 exerts antitumour activity is an area of intensive investigation. These mechanisms are thought to relate in part to FBW7-mediated destruction of key proteins relevant to cancer, including Jun, Myc, cyclin E and notch 1 (ref. 9), all of which have oncoprotein activity and are overexpressed in various human cancers, including leukaemia. In addition to accelerating cell growth, overexpression of Jun, Myc or notch 1 can also induce programmed cell death. Thus, considerable uncertainty surrounds how FBW7-deficient cells evade cell death in the setting of upregulated Jun, Myc and/or notch 1. Here we show that the E3 ubiquitin ligase SC~(FB W7) (a SKP1-cullin-1-F-box complex that contains FBW7 as the F-box protein) governs cellular apoptosis by targeting MCL1, a pro-survival BCL2 family member, for ubiquitylation and destruction in a manner that depends on phos-phorylation by glycogen synthase kinase 3. Human T-ALL cell lines showed a close relationship between FBW7 loss and MCL1 over-expression. Correspondingly, T-ALL cell lines with defective FBW7 are particularly sensitive to the multi-kinase inhibitor sorafenib but resistant to the BCL2 antagonist ABT-737. On the genetic level, FBW7 reconstitution or MCL1 depletion restores sensitivity to ABT-737, establishing MCL1 as a therapeutically relevant bypass survival mechanism that enables FBW7-deficient cells to evade apoptosis. Therefore, our work provides insight into the molecular mechanism of direct tumour suppression by FB W7 and has implications for the targeted treatment of patients with FBW7-deficient TALL.

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  • 来源
    《Nature》 |2011年第7336期|p.104-109|共6页
  • 作者

    Hiroyuki Inuzuka; Shavali Shaik; Ichiro Onoyama; Darning Gao; Alan Tseng; Richard S. Maser; Bo Zhai; Lixin Wan; Alejandro Gutierrez; Alan W. Lau; Yonghong Xiao; Amanda L. Christie; Jon Aster; Jeffrey Settleman; Steven P. Gygi; Andrew L. Kung; Thomas Look; Keiichi I. Nakayama; Ronald A. DePinho; Wenyi Wei;

  • 作者单位

    Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA;

    Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA;

    Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan;

    Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA;

    Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA;

    Belfer Institute for Applied Cancer Science, Department of Medical Oncology, Dana-Farber Cancer Institute,Harvard Medical School, Boston, Massachusetts 02115, USA,The Jackson Laboratory, Bar Harbor, Maine 04609, USA;

    Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115,USA;

    Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA;

    Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA;

    Belfer Institute for Applied Cancer Science, Department of Medical Oncology, Dana-Farber Cancer Institute,Harvard Medical School, Boston, Massachusetts 02115, USA;

    Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA,Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston,Massachusetts 02115, USA;

    Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA;

    Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115,USA;

    Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA,Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston,Massachusetts 02115, USA;

    Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan;

    Belfer Institute for Applied Cancer Science, Department of Medical Oncology, Dana-Farber Cancer Institute,Harvard Medical School, Boston, Massachusetts 02115, USA;

    Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA;

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