Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules

Rock, Kenneth L.; Gramm, Colette F.; Rothstein, Lisa; Clark, Karen; Stein, Ross L.; Dick, Lawrence R.; Hwang, Daniel; Goldberg, Alfred L.

doi:10.1016/s0092-8674(94)90462-6

Cited by 2,363 publications

(1,863 citation statements)

References 40 publications

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“…A prominent mechanism involved in regulating p27 Kip1 levels is proteasomal degradation (Slingerland and Pagano, 2000). Treatment of WM793 cells with the proteasomal inhibitors, ALLN and MG132 (Rock et al, 1994;Brandeis and Hunt, 1996), increased p27 Kip1 protein expression (Figure 3c), demonstrating control of p27 Kip1 levels in melanoma cells occurs through the 26S proteasome.…”

Section: Resultsmentioning

confidence: 93%

Mutant B-RAF signaling and cyclin D1 regulate Cks1/S-phase kinase-associated protein 2-mediated degradation of p27Kip1 in human melanoma cells

Bhatt

Spofford

et al. 2006

Oncogene

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Section: Resultsmentioning

confidence: 93%

Mutant B-RAF signaling and cyclin D1 regulate Cks1/S-phase kinase-associated protein 2-mediated degradation of p27Kip1 in human melanoma cells

Bhatt

Spofford

et al. 2006

Oncogene

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“…HeLa cells were treated with the speci®c proteasome inhibitor lactacystin (Fenteany et al, 1995), and with the peptide aldehyde N-acetyl-Leu-Leu-norleucinal or calpain inhibitor I (ALLN), which is known to inhibit proteasome-mediated proteolysis, but also non-proteosomal thiol proteases such as calpains and cathepsins (Coux et al, 1996). As controls, we also treated cells with N-acetyl-Leu-Leu-methional or calpain inhibitor II (ALLM), a structurally related peptide aldehyde and a potent inhibitor of calpains and cathepsins that does not inhibit the proteolytic activity of the proteasome (Rock et al, 1994). As shown in Figure 6, none of these inhibitors resulted in a modi®cation of the expression of BLM, whereas probing the same membrane with an antibody speci®c for b-catenin clearly showed the expected accumulation of high molecular weight species, as previously described (Orford et al, 1997;Aberle et al, 1997).…”

Section: Blm Protein Is Not Degraded Through the 26s Proteasome Pathwaymentioning

confidence: 99%

Cell cycle regulation of the endogenous wild type Bloom's syndrome DNA helicase

et al. 2000

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Bloom's syndrome (BS) is a rare human autosomal recessive disorder characterized by an increased risk to develop cancer of all types. BS cells are characterized by a generalized genetic instability including a high level of sister chromatid exchanges. BS arises through mutations in both alleles of the BLM gene which encodes a 3' ± 5' DNA helicase identi®ed as a member of the RecQ family. We developed polyclonal antibodies speci®c for the NH 2 -and COOH-terminal region of BLM. Using these antibodies, we analysed BLM expression during the cell cycle and showed that the BLM protein accumulates to high levels in S phase, persists in G2/ M and sharply declines in G1, strongly suggestive of degradation during mitosis. The BLM protein is subject to post-translational modi®cations in mitosis, as revealed by slow migrating forms of BLM found in both demecolcine-treated cells and in mitotic cells isolated from non-treated asynchronous populations. Phosphatase treatment indicated that phosphorylation events were solely responsible for the appearance of the retarded moieties, a possible signal for subsequent degradation. Together, these results are consistent with a role of BLM in a replicative (S phase) and/or post-replicative (G2 phase) process.

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“…We found that both p21 and p21D were stabilized when proteasome activity was inhibited. In AG1523 cells, the level of full length p21 was increased dramatically by the proteasome inhibitor (Rock et al, 1994;Vinitsky et al, 1992) (Figure 2a). In transformed cells, like 293 cells, the level of p21D was increased by LLnL.…”

Section: Both P21 and P21d Are Stabilized By A Proteasome Inhibitormentioning

confidence: 99%

Expression of a novel form of p21Cip1/Waf1 in UV-irradiated and transformed cells

Poon

Hunter

1998

Oncogene

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The tumor suppressor p53 and its target the CDK inhibitor p21 (Cip1/Waf1) are key components of the cellular response to DNA damage. Insight into how p21 is regulated in normal cells, and how it may be deregulated in tumor cells is important for the understanding of tumorigenesis. p21 was induced in normal human diploid ®broblasts after UV irradiationinduced DNA damage, but, at a high dose of UV irradiation, a faster mobility form of p21 on SDS ± PAGE (designated p21D) was expressed. Surprisingly, in a variety of growing transformed cell lines, the level of p21 was low but p21D was prominent. We found that p21D appeared to be derived through a loss of around 10 amino acids from the C-terminus of p21, which theoretically would remove the PCNA binding domain, a second cyclin binding domain and the nuclear localization signal sequence. Several characteristics distinguish p21 from p21D. Both the full length p21 and p21D could be stabilized by a proteasome inhibitor, but only the full length p21 was associated with Cdk2 and PCNA. Consistent with this, gel ®ltration chromatography revealed that all the full length p21 in the cell was complexed to other proteins, whereas a signi®cant portion of p21D was in monomeric form. Moreover, p21 was mainly localized to the nucleus, but p21D was mainly localized to the cytoplasm. We propose that the decrease in p21 and increase in p21D could contribute to the deregulation of the cell cycle, and could be a mechanism involved in cellular transformation.

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Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules

Cited by 2,363 publications

References 40 publications

Mutant B-RAF signaling and cyclin D1 regulate Cks1/S-phase kinase-associated protein 2-mediated degradation of p27Kip1 in human melanoma cells

Mutant B-RAF signaling and cyclin D1 regulate Cks1/S-phase kinase-associated protein 2-mediated degradation of p27Kip1 in human melanoma cells

Cell cycle regulation of the endogenous wild type Bloom's syndrome DNA helicase

Expression of a novel form of p21Cip1/Waf1 in UV-irradiated and transformed cells

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