Bik/NBK accumulation correlates with apoptosis-induction by bortezomib (PS-341, Velcade) and other proteasome inhibitors

Zhu, Hongbo; Zhang, Youmin; Dong, Fengqin; Guo, Wei; Wu, Shuhong; Teraishi, Fuminori; Davis, Joseph R.; Chiao, Paul J.; Fang, Bingliang

doi:10.1038/sj.onc.1208683

Cited by 112 publications

(100 citation statements)

References 19 publications

(20 reference statements)

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“…26 In our study, they also stabilized the SSRP1 N-terminal apoptotic fragment in U2OS and H1299. Further analyses revealed that this fragment is ubiquitylated in cells, demonstrating that the apoptotic N-terminal product of SSRP1 is degraded through the ubiquitin-proteasome pathway.…”

Section: Coupling Caspase Cleavage and Ubiquitinmediated Degradationsupporting

confidence: 67%

“…Proteasome inhibitors have emerged recently as potent apoptosis inducers even in resistant cell lines. 26 Accordingly, MG132 and ALLN were the only stimuli able to induce apoptosis in the three cell lines (Figure 2b, lanes 4-5, 11-12, 18-19). Finally, TNF-a treatment was efficient in Tera-2 and U2OS cells (lanes 7 and 21) but not in HEK293 (lane 14) cells.…”

Section: Ssrp1 Is Cleaved Into Two Fragments During Apoptosismentioning

confidence: 88%

“…The H1299 cell line is interesting in this regard because it is resistant to apoptosis (Supplementary Figure 3). 26 First, H1299 cells were transfected with FLAG-SSRP1 and his-ubiquitin or his-ubiquitin K48R (a mutant unable to form poly-ubiquitin chains) before MG132 treatment. Immunoblots demonstrated the equal expression of FLAG-SSRP1 and the presence of the N-terminal SSRP1 fragment (Figure 7a, bottom panel, lanes 4-6).…”

Section: Ssrp1 and Its Apoptotic N-terminal Fragment Are Ubiquitylatementioning

confidence: 99%

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Coupling caspase cleavage and ubiquitin–proteasome-dependent degradation of SSRP1 during apoptosis

Landais

Lee

2006

Cell Death Differ

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Structure-specific recognition protein (SSRP1) is an 87 kDa protein that heterodimerizes with Spt16 to form FACT, a complex initially shown to facilitate chromatin transcription. Despite its crucial roles in transcription and replication, little is known about the dynamics of FACT turnover in vivo. Here, we show that SSRP1 is cleaved during apoptosis by caspase 3 and/or 7 at the DQHD 450 site. Analysis of the resulting fragments suggests that cleavage of SSRP1 generates a truncated, chromatin-associated form of FACT. Furthermore, the N-terminal product is stabilized by proteasome inhibitors and ubiquitylated in cells, suggesting degradation through the ubiquitin-proteasome pathway. These results demonstrate that SSRP1 degradation during apoptosis is a two-step process coupling caspase cleavage and ubiquitin-dependent proteolysis.

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Section: Coupling Caspase Cleavage and Ubiquitinmediated Degradationsupporting

confidence: 67%

Section: Ssrp1 Is Cleaved Into Two Fragments During Apoptosismentioning

confidence: 88%

Section: Ssrp1 and Its Apoptotic N-terminal Fragment Are Ubiquitylatementioning

confidence: 99%

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Coupling caspase cleavage and ubiquitin–proteasome-dependent degradation of SSRP1 during apoptosis

Landais

Lee

2006

Cell Death Differ

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“…We first tested two clinically available agents, 17-AAG and PS-341, both of which are able to increase the levels of Bim, Bad, Bmf and/or Bik in cancer cells. 15,17,18 Indeed, 17-AAG potently increased Bim, Bmf and Bik expression and caused Bad dephosphorylation in Bcr-Abl þ cells, but its combination with INNO-406 did not further increase the expression of the BH3-only proteins or enhance cell killing. A possible explanation for this could be that there is a limit to how much expression levels of BH3-only proteins can be increased.…”

Section: Discussionmentioning

confidence: 99%

“…The drugs tested included 17-allylaminogeldanamycin (17-AAG), a heat shock protein (HSP)-90 inhibitor and PS-341, a proteasome inhibitor; both have previously been shown to elevate Bim, Bad, Bmf or Bik expression. [15][16][17][18] We also examined whether the killing of INNO-406 could be enhanced by co-treatment with ABT-737, a drug that decreases the antiapoptotic barrier imposed by the antiapoptotic Bcl-2 family members Bcl-2, Bcl-X L and Bcl-w. 19,20 Our study shows that simultaneously targeting both pro-and antiapoptotic molecules augments the killing achieved with INNO-406, even in Bcr-Abl þ leukemias bearing imatinib-resistant Bcr-Abl point mutations. Notably, like Ph þ leukemias, most cancers maintain and propagate themselves by resisting apoptosis and enhancing cell proliferation.…”

mentioning

confidence: 99%

Apoptosis-based dual molecular targeting by INNO-406, a second-generation Bcr-Abl inhibitor, and ABT-737, an inhibitor of antiapoptotic Bcl-2 proteins, against Bcr-Abl-positive leukemia

et al. 2007

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Bcr-Abl is the cause of Philadelphia-positive (Ph þ ) leukemias and also constitutes their principal therapeutic target, as exemplified by dramatic effects of imatinib mesylate. However, mono-targeting of Bcr-Abl does not always achieve complete leukemia eradication, and additional strategies those enable complete elimination of leukemic cells are desired to develop. Here we demonstrate that INNO-406, a much more active Bcr-Abl tyrosine kinase inhibitor than imatinib, augments the activities of several proapoptotic Bcl-2 homology (BH)3-only proteins (Bim, Bad, Bmf and Bik) and induces apoptosis in Ph þ leukemia cells via Bcl-2 family-regulated intrinsic apoptosis pathway. ABT-737, an inhibitor of antiapoptotic Bcl-2 and Bcl-X L , greatly enhanced the apoptosis by INNO-406, even in INNO-406-less sensitive cells with Bcr-Abl point mutations except T315I mutation. In contrast, co-treatment with INNO-406 and other pharmacologic inducers of those BH3-only proteins, such as 17-allylaminogeldanamycin, an heat shock protein-90 inhibitor, or PS-341, a proteasome inhibitor, did not further increase the BH3-only protein levels or sensitize leukemic cells to INNO-406-induced apoptosis, suggesting a limit to how much expression levels of BH3-only proteins can be increased by anticancer agents. Thus, double-barrelled molecular targeting for Bcr-Abl-driven oncogenic signaling and the cell protection by antiapoptotic Bcl-2 family proteins may be the rational therapeutic approach for eradicating Ph þ leukemic cells.

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Clinical Experience on Proteasome Inhibitors in Cancer

Biran¹,

Phull²,

Goy³

2023

Precision Cancer Therapies, Volume 1 ‐ Targeting Oncogenic Drivers and Signaling Pathways in Lymphoid Malignancies

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Bik/NBK accumulation correlates with apoptosis-induction by bortezomib (PS-341, Velcade) and other proteasome inhibitors

Cited by 112 publications

References 19 publications

Coupling caspase cleavage and ubiquitin–proteasome-dependent degradation of SSRP1 during apoptosis

Coupling caspase cleavage and ubiquitin–proteasome-dependent degradation of SSRP1 during apoptosis

Apoptosis-based dual molecular targeting by INNO-406, a second-generation Bcr-Abl inhibitor, and ABT-737, an inhibitor of antiapoptotic Bcl-2 proteins, against Bcr-Abl-positive leukemia

Clinical Experience on Proteasome Inhibitors in Cancer

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