The role of the ubiquitin-proteasome pathway in apoptosis

Orłowski, Robert Z.

doi:10.1038/sj.cdd.4400505

Cited by 346 publications

(253 citation statements)

References 74 publications

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“…We and others have provided evidence that PSI kills cells by an apoptotic mechanism involving the activation of caspases, 9,6,44 which emphasizes the link between ubiquitinproteasome pathways and apoptosis. We have shown that caspase-2, 3, 7 and 8 are activated during PSI-induced apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Sensitivity of human multiple myelomas and myeloid leukemias to the proteasome inhibitor I

et al. 2005

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The proteasome inhibitor PSI is potently cytotoxic in vitro against human chronic myeloid leukemia (CML) and acute myeloid leukemias (AML). Here, we have tested proteasome inhibitor I (PSI) in a panel of 11 human multiple myeloma (MM) cell lines and found that it has antiproliferative activity, with an IC 50 between 4.5 and 557 nM at 48 h. PSI potentiated the toxicity of a number of chemotherapeutic agents in myeloid leukemia but not in MM cell lines, while in combination with therapeutic proteasome inhibitor PS-341 (Bortezomib) it had a synergistic effect. PSI suppressed the growth of AML cell lines more effectively than PS-341. CFU-GM colony assays revealed that CD34 þ bone marrow progenitors from CML and AML patients were more sensitive to PSI than those from normal subjects (IC 50 : 5, 15 and 50 nM for AML, CML and normal, respectively). Moreover, the growth of normal primitive progenitors (LTC-IC) was unaffected by 15 nM PSI (P ¼ 0.576). PSI-induced cell death required RNA transcription and protein synthesis, but not DNA replication, was accompanied by the upregulation of Bcl-2 and modest reduction of Bax and Bcl-X L proteins, and involved the activation of caspases 2, 3, 7 and 8. These findings lend additional support to preclinical investigations with PSI.

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Section: Discussionmentioning

confidence: 99%

Sensitivity of human multiple myelomas and myeloid leukemias to the proteasome inhibitor I

et al. 2005

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“…Protein degradation also plays an important role in T cell apoptosis [35]. This is exemplified by the finding that proteasome inhibitors can effectively block thymocyte apoptosis induced by various apoptotic stimuli [36].…”

Section: Iaps and Protein Ubiquitinationmentioning

confidence: 99%

The IAP family: endogenous caspase inhibitors with multiple biological activities

2000

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IAPs (inhibitors of apoptosis) are a family of proteins containing one or more characteristic BIR domains. These proteins have multiple biological activities that include binding and inhibiting caspases, regulating cell cycle progression, and modulating receptor-mediated signal transduction. Our recent studies found the IAP family members XIAP and c-IAP1 are ubiquitinated and degraded in proteasomes in response to apoptotic stimuli in T cells, and their degradation appears to be important for T cells to commit to death. In addition to three BIR domains, each of these IAPs also contains a RING finger domain. We found this region confers ubiquitin protease ligase (E3) activity to IAPs, and is responsible for the auto-ubiquitination and degradation of IAPs after an apoptotic stimulus. Given the fact that IAPs can bind a variety of proteins, such as caspases and TRAFs, it will be of interest to characterize potential substrates of the E3 activity of IAPs and the effects of ubiquitination by IAPs on signal transduction, cell cycle, and apoptosis.

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“…[9][10][11] Disruption of this process in proliferating cells leads to cell cycle arrest at G 1 /S, G 2 /M, or both, depending on the cell type. 12 The proteasome controls gene expression by degrading transcription factors such as NF-B, p53, c-Jun, c-Myc, c-Fos, HIFl␣, sterol-regulated elementbinding proteins and MAT␣2. 1,8,13 Perhaps the best charac-…”

Section: Functions Of the Ubiquitin-proteasome Systemmentioning

confidence: 99%

“…The ubiquitin-proteasome system is an important regulator of cellular sensitivity to apoptosis as it regulates the levels of many proteins involved in the control of apoptosis including some members of the Bcl-2 family, inhibitor of apoptosis proteins (IAPs) and some caspases. 12,[21][22][23][24][25] Many currently used anticancer agents exert their anticancer effects by inducing apoptosis, and resistance to apoptosis contributes to drug resistance and tumour progression. Therefore, clinical manipulation of the proteasome could potentially be useful in the treatment of cancer.…”

Section: Apoptosis and Cancermentioning

confidence: 99%

The proteasome: a novel target for cancer chemotherapy

2002

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The ubiquitin-proteasome system is an important regulator of cell growth and apoptosis. The potential of specific proteasome inhibitors to act as novel anti-cancer agents is currently under intensive investigation. Several proteasome inhibitors exert anti-tumour activity in vivo and potently induce apoptosis in tumour cells in vitro, including those resistant to conventional chemotherapeutic agents. By inhibiting NF-B transcriptional activity, proteasome inhibitors may also prevent angiogenesis and metastasis in vivo and further increase the sensitivity of cancer cells to apoptosis. Proteasome inhibitors also exhibit some level of selective cytotoxicity to cancer cells by preferentially inducing apoptosis in proliferating or transformed cells or by overcoming deficiencies in growth-inhibitory or proapoptotic molecules. High expression of oncogene products like c-Myc also makes cancer cells more susceptible to proteasome inhibitor-induced apoptosis. The induction of apoptosis by proteasome inhibitors varies between cell types but often occurs following an initial accumulation of short-lived proteins such as p53, p27, pro-apoptotic Bcl-2 family members or activation of the stress kinase JNK. These initial events often result in a perturbation of mitochondria with concomitant release of cytochrome c and activation of the Apaf-1 containing apoptosome complex. This results in activation of the apical caspase-9 followed by activation of effector caspases-3 and -7, which are responsible for the biochemical and morphological changes associated with apoptosis.

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The role of the ubiquitin-proteasome pathway in apoptosis

Cited by 346 publications

References 74 publications

Sensitivity of human multiple myelomas and myeloid leukemias to the proteasome inhibitor I

Sensitivity of human multiple myelomas and myeloid leukemias to the proteasome inhibitor I

The IAP family: endogenous caspase inhibitors with multiple biological activities

The proteasome: a novel target for cancer chemotherapy

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