DOI: 10.1182/blood.v96.1.269. Deregulation of the ubiquitin system and p53 proteolysis modify the apoptotic response in B-CLL lymphocytes

Deregulation of the ubiquitin system and p53 proteolysis modify the apoptotic response in B-CLL lymphocytes

10.1182/blood.v96.1.269

Crossref journal-article

American Society of Hematology

Blood (234)

Abstract

AbstractWe recently reported increased sensitivity of B-cell chronic lymphocytic leukemia (B-CLL) lymphocytes to apoptotic death activation by the proteasome-specific inhibitor lactacystin. Here, we show that only specific—not nonspecific—proteasomal inhibitors can discriminate between malignant and normal lymphocytes in inducing the apoptotic death response. Indeed, lactacystin and its active metaboliteclasto-lactacystin β-lactone induced apoptotic death in CLL but not in normal lymphocytes. This difference was completely abolished when tripeptide aldehydes such as MG132 or LLnL (which can also inhibit calpains) were used as less specific proteasomal inhibitors. Moreover, B-CLL cells exhibited a constitutive altered ubiquitin-proteasome system, including a threefold higher chymotrypsin-like proteasomal activity and high levels of nuclear ubiquitin-conjugated proteins compared with normal lymphocytes. Interestingly, B-CLL cells also displayed altered proteolytic regulation of wild-type p53, an apoptotic factor reported to be a substrate for the ubiquitin-proteasome system. Nuclear wild-type p53 accumulated after lactacystin treatment used at the discriminating concentration in malignant, but not in normal, lymphocytes. In contrast, p53 was stabilized by MG132 or LLnL in malignant and normal cells undergoing apoptosis, indicating that in normal lymphocytes p53 is regulated mainly by calpains and not by the ubiquitin-proteasome system. This work raises the possibility that two different proteolytic pathways controlling p53 stability may be pathologically imbalanced. This could result in modification of apoptosis control, since in CLL-lymphocytes a highly upregulated ubiquitin-proteasome system, which controls p53 stability among other apoptotic factors, was correlated with an increased propensity of these cells to apoptosis triggered by lactacystin.

Bibliography

Masdehors, P., Merle-BeÌral, H., Maloum, K., OÌmura, S., MagdeleÌnat, H., & Delic, J. (2000). Deregulation of the ubiquitin system and p53 proteolysis modify the apoptotic response in B-CLL lymphocytes. Blood, 96(1), 269â274.

Authors 6

Peggy Masdehors (first)
Hélène Merle-Béral (additional)
Karim Maloum (additional)
Satoshi Ömura (additional)
Henri Magdelénat (additional)
Jozo Delic (additional)

References 50 Referenced 66

{'key': '2020021222514390400_B1', 'first-page': '11', 'article-title': 'Molecular biology of chronic lymphocytic leukemia.', 'volume': '25', 'author': 'Reed', 'year': '1998', 'journal-title': 'Semin Oncol.'} / Semin Oncol. / Molecular biology of chronic lymphocytic leukemia. by Reed (1998)
10.1016/0968-0004(91)90101-Z / Trends Biochem Sci. / The ubiquitin pathway for protein degradation. by Hershko (1991)
10.1016/0092-8674(94)90396-4 / Cell. / The ubiquitin-proteasome proteolytic pathway. by Ciechanover (1994)
10.1093/emboj/17.24.7151 / EMBO J. / The ubiquitin-proteasome pathway: on death and cell life. by Ciechanover (1998)
10.1146/annurev.biochem.67.1.425 / Ann Rev Biochem. / The ubiquitin system. by Hershko (1998)
10.1038/bjc.1998.71 / Br J Cancer. / The ubiquitin-proteasome pathway in cancer. by Spataro (1998)
10.1006/bbrc.1998.8604 / Biochem Biophys Res Commun. / The proteasome is involved in angiogenesis. by Oikawa (1998)
10.1128/MCB.13.8.4875 / Mol Cell Biol. / Ubiquitin pathway involvement in γ-ray-irradiation-induced apoptosis. by Delic (1993)
10.4049/jimmunol.161.1.35 / J Immunol. / Proteasome activation occurs at an early, premitochondrial step of thymocyte apoptosis. by Hirsch (1998)
10.1038/sj.cdd.4400505 / Cell Death Differ. / The role of the ubiquitin-proteasome pathway in apoptosis. by Orlowski (1999)
10.1006/bbrc.1995.2878 / Biochem Biophys Res Commun. / Lactacystin, a specific inhibitor of the proteasome, induces apoptosis in human monoblast U937 cells. by Imajoh-Ohmi (1995)
10.1073/pnas.94.3.855 / Proc Natl Acad Sci U S A. / Activation of the cell death program by inhibition of proteasome function. by Drexler (1997)
10.1038/bjc.1998.183 / Br J Cancer. / The proteasome inhibitor lactacystin induces apoptosis and sensitizes chemo- and radioresistant human chronic lymphocytic leukaemia lymphocytes to TNF-α-initiated apoptosis. by Delic (1998)
10.1182/blood.V92.11.4220 / Blood. / Proteasome inhibitors induce apoptosis in glucocorticoid-resistant chronic lymphocytic leukemic lymphocytes. by Chandra (1998)
10.1182/blood.V91.12.4624 / Blood. / Inhibition of nuclear factor κB activation attenuates apoptosis resistance in lymphoid cells. by Jeremias (1998)
10.1046/j.1365-2141.1999.01388.x / Br J Haematol. / Ömura S, Merle-Béral H, et al. Increased sensitivity of CLL-derived lymphocytes to apoptotic death activation by the proteasome specific inhibitor lactacystin. by Masdehors (1999)
10.1038/362847a0 / Nature. / p53 is required for radiation-induced apoptosis in mouse thymocytes. by Lowe (1993)
10.1016/S0092-8674(00)81871-1 / Cell. / p53, the cellular gatekeeper for growth and division. by Levine (1997)
10.1016/0092-8674(93)90384-3 / Cell. / The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. by Scheffner (1993)
10.1016/S0021-9258(17)36921-1 / J Biol Chem. / Degradation of the tumor suppressor protein p53 by the ubiquitin-mediated proteolytic system requires a novel species of ubiquitin-carrier protein, E2. by Ciechanover (1994)
10.1128/MCB.14.3.1997 / Mol Cell Biol. / Accumulation of p53 in a mutant cell line defective in the ubiquitin pathway. by Chowdary (1994)
{'key': '2020021222514390400_B22', 'first-page': '2649', 'article-title': 'In vivo ubiquitination and proteasome-mediated degradation of p53.', 'volume': '56', 'author': 'Maki', 'year': '1996', 'journal-title': 'Cancer Res.'} / Cancer Res. / In vivo ubiquitination and proteasome-mediated degradation of p53. by Maki (1996)
10.1038/387299a0 / Nature. / Regulation of p53 stability by Mdm-2. by Kubbutat (1997)
10.1038/387296a0 / Nature. / Mdm-2 promotes the rapid degradation of p53. by Haupt (1997)
10.1016/S0014-5793(97)00225-1 / FEBS Lett. / On the involvement of calpains in the degradation of the tumor suppressor protein p53. by Gonen (1997)
10.1128/MCB.17.1.460 / Mol Cell Biol. / Proteolytic cleavage of human p53 by calpain: a potential regulator of protein stability. by Kubbutat (1997)
10.1128/MCB.17.5.2806 / Mol Cell Biol. / Proteolysis by calpains: a possible contribution to degradation of p53. by Pariat (1997)
10.7164/antibiotics.44.113 / J Antibiot (Tokyo). / Lactacystin, a novel microbial metabolite, induces neuritogenesis of neuroblastoma cells. by Ömura (1991)
10.1126/science.7732382 / Science. / Inhibition of proteasome activities and specific amino-terminal threonine modification by lactacystin. by Fenteany (1995)
10.1074/jbc.273.15.8545 / J Biol Chem. / Lactacystin, proteasome function and cell fate. by Fenteany (1998)
10.1016/S0092-8674(94)90462-6 / Cell. / Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules. by Rock (1994)
10.1074/jbc.273.12.6916 / J Biol Chem. / Granzyme release and caspase activation in activated human T-lymphocytes. by Zapata (1998)
{'key': '2020021222514390400_B33'}
10.1074/jbc.272.47.29899 / J Biol Chem. / Specificities of cell permeant peptidyl inhibitors for the proteinase activities of μ-calpain and the 20 S proteasome. by Mellgren (1997)
10.1074/jbc.273.12.6656 / J Biol Chem. / Proteolytic regulation of the zinc finger transcription factor YY1, a repressor of muscle-restricted gene expression. by Walowitz (1998)
10.4049/jimmunol.158.8.3690 / J Immunol. / Calpain, an upstream regulator of thymocyte apoptosis. by Squier (1997)
{'key': '2020021222514390400_B37', 'first-page': '2752', 'article-title': 'Human colorectal carcinomas specifically accumulate Mr 42,000 ubiquitin-conjugated cytokeratin 8 fragments.', 'volume': '56', 'author': 'Nishibori', 'year': '1996', 'journal-title': 'Cancer Res.'} / Cancer Res. / Human colorectal carcinomas specifically accumulate Mr 42,000 ubiquitin-conjugated cytokeratin 8 fragments. by Nishibori (1996)
10.1038/bjc.1991.75 / Br J Cancer. / Ubiquitin immunoreactivity in human malignant tumors. by Ishibashi (1991)
{'key': '2020021222514390400_B39', 'first-page': '6677', 'article-title': 'Changes in expressions of proteasome and ubiquitin genes in human renal cancer cells.', 'volume': '51', 'author': 'Kanayama', 'year': '1991', 'journal-title': 'Cancer Res.'} / Cancer Res. / Changes in expressions of proteasome and ubiquitin genes in human renal cancer cells. by Kanayama (1991)
10.1073/pnas.87.18.7071 / Proc Natl Acad Sci U S A. / Abnormally high expression of proteasomes in human leukemic cells. by Kumatori (1990)
{'key': '2020021222514390400_B41', 'first-page': '669', 'article-title': 'Novel cellular markers in breast cancer: differential presence of p23K and p30.33K prosomal antigens in tumors of Parsi and non-Parsi women.', 'volume': '9', 'author': 'Bhui', 'year': '1996', 'journal-title': 'Int J Oncol.'} / Int J Oncol. / Novel cellular markers in breast cancer: differential presence of p23K and p30.33K prosomal antigens in tumors of Parsi and non-Parsi women. by Bhui (1996)
{'key': '2020021222514390400_B42', 'first-page': '3881', 'article-title': "Apoptosis of Ewing's sarcoma cell is accompanied by accumulation of ubiquitinated proteins.", 'volume': '57', 'author': 'Soldatenkov', 'year': '1997', 'journal-title': 'Cancer Res.'} / Cancer Res. / Apoptosis of Ewing's sarcoma cell is accompanied by accumulation of ubiquitinated proteins. by Soldatenkov (1997)
{'key': '2020021222514390400_B43', 'first-page': '4342', 'article-title': "Tumor growth inhibition induced in a murine model of Burkitt's lymphoma by a proteasome inhibitor.", 'volume': '58', 'author': 'Orlowski', 'year': '1998', 'journal-title': 'Cancer Res.'} / Cancer Res. / Tumor growth inhibition induced in a murine model of Burkitt's lymphoma by a proteasome inhibitor. by Orlowski (1998)
10.1038/sj.onc.1200841 / Oncogene. / Inhibition of the growth of WI-38 fibroblasts by benzyloxycarbonyl-Leu-Leu-Tyr diazomethyl ketone: evidence that cleavage of p53 by a calpain-like protease is necessary for G1 to S-phase transition. by Zhang (1997)
10.1074/jbc.272.40.24735 / J Biol Chem. / Serine phosphorylation-regulated ubiquitination and degradation of β-catenin. by Orford (1997)
10.1038/370220a0 / Nature. / p53-dependent apoptosis in the absence of transcriptional activation of p53-target genes. by Caelles (1994)
10.1101/gad.8.23.2817 / Genes Dev. / Myc-mediated apoptosis requires wild-type p53 in a manner independent of cell cycle arrest and the ability of p53 to induce p21waf1/cip1. by Wagner (1994)
10.1101/gad.9.17.2170 / Genes Dev. / Induction of apoptosis in HeLa cells by transactivation-deficient p53. by Haupt (1995)
10.1002/j.1460-2075.1996.tb00418.x / EMBO J. / Specific loss of apoptotic but not cell-cycle arrest function in a human tumor-derived p53 mutant. by Rowan (1996)
10.1021/bi970998j / Biochemistry. / Rapid deubiquitination of nucleosomal histones in human tumor cells caused by proteasome inhibitors and stress response inducers: effect on replication, transcription, translation, and the cellular stress response. by Mimnaugh (1997)

Dates

Type	When
Created	5 years, 10 months ago (Oct. 14, 2019, 7:49 a.m.)
Deposited	1 year, 11 months ago (Sept. 21, 2023, 12:54 p.m.)
Indexed	4 months, 4 weeks ago (March 29, 2025, 12:39 p.m.)
Issued	25 years, 1 month ago (July 1, 2000)
Published	25 years, 1 month ago (July 1, 2000)
Published Print	25 years, 1 month ago (July 1, 2000)

Funders 0

None

BibTeX

@article{Masdehors_2000, title={Deregulation of the ubiquitin system and p53 proteolysis modify the apoptotic response in B-CLL lymphocytes}, volume={96}, ISSN={0006-4971}, url={http://dx.doi.org/10.1182/blood.v96.1.269}, DOI={10.1182/blood.v96.1.269}, number={1}, journal={Blood}, publisher={American Society of Hematology}, author={Masdehors, Peggy and Merle-Béral, Hélène and Maloum, Karim and Ömura, Satoshi and Magdelénat, Henri and Delic, Jozo}, year={2000}, month=jul, pages={269–274} }

JSON

{
  "indexed": {
    "date-parts": [
      [
        2025,
        3,
        29
      ]
    ],
    "date-time": "2025-03-29T16:39:52Z",
    "timestamp": 1743266392891
  },
  "reference-count": 50,
  "publisher": "American Society of Hematology",
  "issue": "1",
  "content-domain": {
    "domain": [
      "ashpublications.org"
    ],
    "crossmark-restriction": true
  },
  "published-print": {
    "date-parts": [
      [
        2000,
        7,
        1
      ]
    ]
  },
  "abstract": "<jats:title>Abstract</jats:title><jats:p>We recently reported increased sensitivity of B-cell chronic lymphocytic leukemia (B-CLL) lymphocytes to apoptotic death activation by the proteasome-specific inhibitor lactacystin. Here, we show that only specific\u2014not nonspecific\u2014proteasomal inhibitors can discriminate between malignant and normal lymphocytes in inducing the apoptotic death response. Indeed, lactacystin and its active metaboliteclasto-lactacystin \u03b2-lactone induced apoptotic death in CLL but not in normal lymphocytes. This difference was completely abolished when tripeptide aldehydes such as MG132 or LLnL (which can also inhibit calpains) were used as less specific proteasomal inhibitors. Moreover, B-CLL cells exhibited a constitutive altered ubiquitin-proteasome system, including a threefold higher chymotrypsin-like proteasomal activity and high levels of nuclear ubiquitin-conjugated proteins compared with normal lymphocytes. Interestingly, B-CLL cells also displayed altered proteolytic regulation of wild-type p53, an apoptotic factor reported to be a substrate for the ubiquitin-proteasome system. Nuclear wild-type p53 accumulated after lactacystin treatment used at the discriminating concentration in malignant, but not in normal, lymphocytes. In contrast, p53 was stabilized by MG132 or LLnL in malignant and normal cells undergoing apoptosis, indicating that in normal lymphocytes p53 is regulated mainly by calpains and not by the ubiquitin-proteasome system. This work raises the possibility that two different proteolytic pathways controlling p53 stability may be pathologically imbalanced. This could result in modification of apoptosis control, since in CLL-lymphocytes a highly upregulated ubiquitin-proteasome system, which controls p53 stability among other apoptotic factors, was correlated with an increased propensity of these cells to apoptosis triggered by lactacystin.</jats:p>",
  "DOI": "10.1182/blood.v96.1.269",
  "type": "journal-article",
  "created": {
    "date-parts": [
      [
        2019,
        10,
        14
      ]
    ],
    "date-time": "2019-10-14T11:49:17Z",
    "timestamp": 1571053757000
  },
  "page": "269-274",
  "update-policy": "http://dx.doi.org/10.1182/blood.2019cm0000",
  "source": "Crossref",
  "is-referenced-by-count": 66,
  "title": "Deregulation of the ubiquitin system and p53 proteolysis modify the apoptotic response in B-CLL lymphocytes",
  "prefix": "10.1182",
  "volume": "96",
  "author": [
    {
      "given": "Peggy",
      "family": "Masdehors",
      "sequence": "first",
      "affiliation": [
        {
          "name": "From Laboratoire de Recherche Correspondant and Laboratoire de Radiopathologie, Institut Curie, Paris; Service d'He\u0301matologie Biologique, Ho\u0302pital Pitie\u0301-Salpe\u0302trie\u0300re, Paris, France; and Kitasato Institute, Tokyo, Japan."
        }
      ]
    },
    {
      "given": "He\u0301le\u0300ne",
      "family": "Merle-Be\u0301ral",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "From Laboratoire de Recherche Correspondant and Laboratoire de Radiopathologie, Institut Curie, Paris; Service d'He\u0301matologie Biologique, Ho\u0302pital Pitie\u0301-Salpe\u0302trie\u0300re, Paris, France; and Kitasato Institute, Tokyo, Japan."
        }
      ]
    },
    {
      "given": "Karim",
      "family": "Maloum",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "From Laboratoire de Recherche Correspondant and Laboratoire de Radiopathologie, Institut Curie, Paris; Service d'He\u0301matologie Biologique, Ho\u0302pital Pitie\u0301-Salpe\u0302trie\u0300re, Paris, France; and Kitasato Institute, Tokyo, Japan."
        }
      ]
    },
    {
      "given": "Satoshi",
      "family": "O\u0308mura",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "From Laboratoire de Recherche Correspondant and Laboratoire de Radiopathologie, Institut Curie, Paris; Service d'He\u0301matologie Biologique, Ho\u0302pital Pitie\u0301-Salpe\u0302trie\u0300re, Paris, France; and Kitasato Institute, Tokyo, Japan."
        }
      ]
    },
    {
      "given": "Henri",
      "family": "Magdele\u0301nat",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "From Laboratoire de Recherche Correspondant and Laboratoire de Radiopathologie, Institut Curie, Paris; Service d'He\u0301matologie Biologique, Ho\u0302pital Pitie\u0301-Salpe\u0302trie\u0300re, Paris, France; and Kitasato Institute, Tokyo, Japan."
        }
      ]
    },
    {
      "given": "Jozo",
      "family": "Delic",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "From Laboratoire de Recherche Correspondant and Laboratoire de Radiopathologie, Institut Curie, Paris; Service d'He\u0301matologie Biologique, Ho\u0302pital Pitie\u0301-Salpe\u0302trie\u0300re, Paris, France; and Kitasato Institute, Tokyo, Japan."
        }
      ]
    }
  ],
  "member": "234",
  "reference": [
    {
      "key": "2020021222514390400_B1",
      "first-page": "11",
      "article-title": "Molecular biology of chronic lymphocytic leukemia.",
      "volume": "25",
      "author": "Reed",
      "year": "1998",
      "journal-title": "Semin Oncol."
    },
    {
      "key": "2020021222514390400_B2",
      "doi-asserted-by": "crossref",
      "first-page": "265",
      "DOI": "10.1016/0968-0004(91)90101-Z",
      "article-title": "The ubiquitin pathway for protein degradation.",
      "volume": "16",
      "author": "Hershko",
      "year": "1991",
      "journal-title": "Trends Biochem Sci."
    },
    {
      "key": "2020021222514390400_B3",
      "doi-asserted-by": "crossref",
      "first-page": "13",
      "DOI": "10.1016/0092-8674(94)90396-4",
      "article-title": "The ubiquitin-proteasome proteolytic pathway.",
      "volume": "79",
      "author": "Ciechanover",
      "year": "1994",
      "journal-title": "Cell."
    },
    {
      "key": "2020021222514390400_B4",
      "doi-asserted-by": "crossref",
      "first-page": "7151",
      "DOI": "10.1093/emboj/17.24.7151",
      "article-title": "The ubiquitin-proteasome pathway: on death and cell life.",
      "volume": "17",
      "author": "Ciechanover",
      "year": "1998",
      "journal-title": "EMBO J."
    },
    {
      "key": "2020021222514390400_B5",
      "doi-asserted-by": "crossref",
      "first-page": "425",
      "DOI": "10.1146/annurev.biochem.67.1.425",
      "article-title": "The ubiquitin system.",
      "volume": "67",
      "author": "Hershko",
      "year": "1998",
      "journal-title": "Ann Rev Biochem."
    },
    {
      "key": "2020021222514390400_B6",
      "doi-asserted-by": "crossref",
      "first-page": "448",
      "DOI": "10.1038/bjc.1998.71",
      "article-title": "The ubiquitin-proteasome pathway in cancer.",
      "volume": "77",
      "author": "Spataro",
      "year": "1998",
      "journal-title": "Br J Cancer."
    },
    {
      "key": "2020021222514390400_B7",
      "doi-asserted-by": "crossref",
      "first-page": "243",
      "DOI": "10.1006/bbrc.1998.8604",
      "article-title": "The proteasome is involved in angiogenesis.",
      "volume": "246",
      "author": "Oikawa",
      "year": "1998",
      "journal-title": "Biochem Biophys Res Commun."
    },
    {
      "key": "2020021222514390400_B8",
      "doi-asserted-by": "crossref",
      "first-page": "4875",
      "DOI": "10.1128/MCB.13.8.4875",
      "article-title": "Ubiquitin pathway involvement in \u03b3-ray-irradiation-induced apoptosis.",
      "volume": "13",
      "author": "Delic",
      "year": "1993",
      "journal-title": "Mol Cell Biol."
    },
    {
      "key": "2020021222514390400_B9",
      "doi-asserted-by": "crossref",
      "first-page": "35",
      "DOI": "10.4049/jimmunol.161.1.35",
      "article-title": "Proteasome activation occurs at an early, premitochondrial step of thymocyte apoptosis.",
      "volume": "161",
      "author": "Hirsch",
      "year": "1998",
      "journal-title": "J Immunol."
    },
    {
      "key": "2020021222514390400_B10",
      "doi-asserted-by": "crossref",
      "first-page": "303",
      "DOI": "10.1038/sj.cdd.4400505",
      "article-title": "The role of the ubiquitin-proteasome pathway in apoptosis.",
      "volume": "6",
      "author": "Orlowski",
      "year": "1999",
      "journal-title": "Cell Death Differ."
    },
    {
      "key": "2020021222514390400_B11",
      "doi-asserted-by": "crossref",
      "first-page": "1070",
      "DOI": "10.1006/bbrc.1995.2878",
      "article-title": "Lactacystin, a specific inhibitor of the proteasome, induces apoptosis in human monoblast U937 cells.",
      "volume": "217",
      "author": "Imajoh-Ohmi",
      "year": "1995",
      "journal-title": "Biochem Biophys Res Commun."
    },
    {
      "key": "2020021222514390400_B12",
      "doi-asserted-by": "crossref",
      "first-page": "855",
      "DOI": "10.1073/pnas.94.3.855",
      "article-title": "Activation of the cell death program by inhibition of proteasome function.",
      "volume": "94",
      "author": "Drexler",
      "year": "1997",
      "journal-title": "Proc Natl Acad Sci U S A."
    },
    {
      "key": "2020021222514390400_B13",
      "doi-asserted-by": "crossref",
      "first-page": "1103",
      "DOI": "10.1038/bjc.1998.183",
      "article-title": "The proteasome inhibitor lactacystin induces apoptosis and sensitizes chemo- and radioresistant human chronic lymphocytic leukaemia lymphocytes to TNF-\u03b1-initiated apoptosis.",
      "volume": "77",
      "author": "Delic",
      "year": "1998",
      "journal-title": "Br J Cancer."
    },
    {
      "key": "2020021222514390400_B14",
      "doi-asserted-by": "crossref",
      "first-page": "4220",
      "DOI": "10.1182/blood.V92.11.4220",
      "article-title": "Proteasome inhibitors induce apoptosis in glucocorticoid-resistant chronic lymphocytic leukemic lymphocytes.",
      "volume": "92",
      "author": "Chandra",
      "year": "1998",
      "journal-title": "Blood."
    },
    {
      "key": "2020021222514390400_B15",
      "doi-asserted-by": "crossref",
      "first-page": "4624",
      "DOI": "10.1182/blood.V91.12.4624",
      "article-title": "Inhibition of nuclear factor \u03baB activation attenuates apoptosis resistance in lymphoid cells.",
      "volume": "91",
      "author": "Jeremias",
      "year": "1998",
      "journal-title": "Blood."
    },
    {
      "key": "2020021222514390400_B16",
      "doi-asserted-by": "crossref",
      "first-page": "752",
      "DOI": "10.1046/j.1365-2141.1999.01388.x",
      "article-title": "O\u0308mura S, Merle-Be\u0301ral H, et al. Increased sensitivity of CLL-derived lymphocytes to apoptotic death activation by the proteasome specific inhibitor lactacystin.",
      "volume": "105",
      "author": "Masdehors",
      "year": "1999",
      "journal-title": "Br J Haematol."
    },
    {
      "key": "2020021222514390400_B17",
      "doi-asserted-by": "crossref",
      "first-page": "847",
      "DOI": "10.1038/362847a0",
      "article-title": "p53 is required for radiation-induced apoptosis in mouse thymocytes.",
      "volume": "362",
      "author": "Lowe",
      "year": "1993",
      "journal-title": "Nature."
    },
    {
      "key": "2020021222514390400_B18",
      "doi-asserted-by": "crossref",
      "first-page": "323",
      "DOI": "10.1016/S0092-8674(00)81871-1",
      "article-title": "p53, the cellular gatekeeper for growth and division.",
      "volume": "88",
      "author": "Levine",
      "year": "1997",
      "journal-title": "Cell."
    },
    {
      "key": "2020021222514390400_B19",
      "doi-asserted-by": "crossref",
      "first-page": "495",
      "DOI": "10.1016/0092-8674(93)90384-3",
      "article-title": "The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53.",
      "volume": "75",
      "author": "Scheffner",
      "year": "1993",
      "journal-title": "Cell."
    },
    {
      "key": "2020021222514390400_B20",
      "doi-asserted-by": "crossref",
      "first-page": "9582",
      "DOI": "10.1016/S0021-9258(17)36921-1",
      "article-title": "Degradation of the tumor suppressor protein p53 by the ubiquitin-mediated proteolytic system requires a novel species of ubiquitin-carrier protein, E2.",
      "volume": "269",
      "author": "Ciechanover",
      "year": "1994",
      "journal-title": "J Biol Chem."
    },
    {
      "key": "2020021222514390400_B21",
      "doi-asserted-by": "crossref",
      "first-page": "1997",
      "DOI": "10.1128/MCB.14.3.1997",
      "article-title": "Accumulation of p53 in a mutant cell line defective in the ubiquitin pathway.",
      "volume": "14",
      "author": "Chowdary",
      "year": "1994",
      "journal-title": "Mol Cell Biol."
    },
    {
      "key": "2020021222514390400_B22",
      "first-page": "2649",
      "article-title": "In vivo ubiquitination and proteasome-mediated degradation of p53.",
      "volume": "56",
      "author": "Maki",
      "year": "1996",
      "journal-title": "Cancer Res."
    },
    {
      "key": "2020021222514390400_B23",
      "doi-asserted-by": "crossref",
      "first-page": "299",
      "DOI": "10.1038/387299a0",
      "article-title": "Regulation of p53 stability by Mdm-2.",
      "volume": "387",
      "author": "Kubbutat",
      "year": "1997",
      "journal-title": "Nature."
    },
    {
      "key": "2020021222514390400_B24",
      "doi-asserted-by": "crossref",
      "first-page": "296",
      "DOI": "10.1038/387296a0",
      "article-title": "Mdm-2 promotes the rapid degradation of p53.",
      "volume": "387",
      "author": "Haupt",
      "year": "1997",
      "journal-title": "Nature."
    },
    {
      "key": "2020021222514390400_B25",
      "doi-asserted-by": "crossref",
      "first-page": "17",
      "DOI": "10.1016/S0014-5793(97)00225-1",
      "article-title": "On the involvement of calpains in the degradation of the tumor suppressor protein p53.",
      "volume": "406",
      "author": "Gonen",
      "year": "1997",
      "journal-title": "FEBS Lett."
    },
    {
      "key": "2020021222514390400_B26",
      "doi-asserted-by": "crossref",
      "first-page": "460",
      "DOI": "10.1128/MCB.17.1.460",
      "article-title": "Proteolytic cleavage of human p53 by calpain: a potential regulator of protein stability.",
      "volume": "17",
      "author": "Kubbutat",
      "year": "1997",
      "journal-title": "Mol Cell Biol."
    },
    {
      "key": "2020021222514390400_B27",
      "doi-asserted-by": "crossref",
      "first-page": "2806",
      "DOI": "10.1128/MCB.17.5.2806",
      "article-title": "Proteolysis by calpains: a possible contribution to degradation of p53.",
      "volume": "17",
      "author": "Pariat",
      "year": "1997",
      "journal-title": "Mol Cell Biol."
    },
    {
      "key": "2020021222514390400_B28",
      "doi-asserted-by": "crossref",
      "first-page": "113",
      "DOI": "10.7164/antibiotics.44.113",
      "article-title": "Lactacystin, a novel microbial metabolite, induces neuritogenesis of neuroblastoma cells.",
      "volume": "44",
      "author": "O\u0308mura",
      "year": "1991",
      "journal-title": "J Antibiot (Tokyo)."
    },
    {
      "key": "2020021222514390400_B29",
      "doi-asserted-by": "crossref",
      "first-page": "726",
      "DOI": "10.1126/science.7732382",
      "article-title": "Inhibition of proteasome activities and specific amino-terminal threonine modification by lactacystin.",
      "volume": "268",
      "author": "Fenteany",
      "year": "1995",
      "journal-title": "Science."
    },
    {
      "key": "2020021222514390400_B30",
      "doi-asserted-by": "crossref",
      "first-page": "8545",
      "DOI": "10.1074/jbc.273.15.8545",
      "article-title": "Lactacystin, proteasome function and cell fate.",
      "volume": "273",
      "author": "Fenteany",
      "year": "1998",
      "journal-title": "J Biol Chem."
    },
    {
      "key": "2020021222514390400_B31",
      "doi-asserted-by": "crossref",
      "first-page": "761",
      "DOI": "10.1016/S0092-8674(94)90462-6",
      "article-title": "Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules.",
      "volume": "78",
      "author": "Rock",
      "year": "1994",
      "journal-title": "Cell."
    },
    {
      "key": "2020021222514390400_B32",
      "doi-asserted-by": "crossref",
      "first-page": "6916",
      "DOI": "10.1074/jbc.273.12.6916",
      "article-title": "Granzyme release and caspase activation in activated human T-lymphocytes.",
      "volume": "273",
      "author": "Zapata",
      "year": "1998",
      "journal-title": "J Biol Chem."
    },
    {
      "key": "2020021222514390400_B33"
    },
    {
      "key": "2020021222514390400_B34",
      "doi-asserted-by": "crossref",
      "first-page": "29899",
      "DOI": "10.1074/jbc.272.47.29899",
      "article-title": "Specificities of cell permeant peptidyl inhibitors for the proteinase activities of \u03bc-calpain and the 20 S proteasome.",
      "volume": "272",
      "author": "Mellgren",
      "year": "1997",
      "journal-title": "J Biol Chem."
    },
    {
      "key": "2020021222514390400_B35",
      "doi-asserted-by": "crossref",
      "first-page": "6656",
      "DOI": "10.1074/jbc.273.12.6656",
      "article-title": "Proteolytic regulation of the zinc finger transcription factor YY1, a repressor of muscle-restricted gene expression.",
      "volume": "273",
      "author": "Walowitz",
      "year": "1998",
      "journal-title": "J Biol Chem."
    },
    {
      "key": "2020021222514390400_B36",
      "doi-asserted-by": "crossref",
      "first-page": "3690",
      "DOI": "10.4049/jimmunol.158.8.3690",
      "article-title": "Calpain, an upstream regulator of thymocyte apoptosis.",
      "volume": "158",
      "author": "Squier",
      "year": "1997",
      "journal-title": "J Immunol."
    },
    {
      "key": "2020021222514390400_B37",
      "first-page": "2752",
      "article-title": "Human colorectal carcinomas specifically accumulate Mr 42,000 ubiquitin-conjugated cytokeratin 8 fragments.",
      "volume": "56",
      "author": "Nishibori",
      "year": "1996",
      "journal-title": "Cancer Res."
    },
    {
      "key": "2020021222514390400_B38",
      "doi-asserted-by": "crossref",
      "first-page": "320",
      "DOI": "10.1038/bjc.1991.75",
      "article-title": "Ubiquitin immunoreactivity in human malignant tumors.",
      "volume": "63",
      "author": "Ishibashi",
      "year": "1991",
      "journal-title": "Br J Cancer."
    },
    {
      "key": "2020021222514390400_B39",
      "first-page": "6677",
      "article-title": "Changes in expressions of proteasome and ubiquitin genes in human renal cancer cells.",
      "volume": "51",
      "author": "Kanayama",
      "year": "1991",
      "journal-title": "Cancer Res."
    },
    {
      "key": "2020021222514390400_B40",
      "doi-asserted-by": "crossref",
      "first-page": "7071",
      "DOI": "10.1073/pnas.87.18.7071",
      "article-title": "Abnormally high expression of proteasomes in human leukemic cells.",
      "volume": "87",
      "author": "Kumatori",
      "year": "1990",
      "journal-title": "Proc Natl Acad Sci U S A."
    },
    {
      "key": "2020021222514390400_B41",
      "first-page": "669",
      "article-title": "Novel cellular markers in breast cancer: differential presence of p23K and p30.33K prosomal antigens in tumors of Parsi and non-Parsi women.",
      "volume": "9",
      "author": "Bhui",
      "year": "1996",
      "journal-title": "Int J Oncol."
    },
    {
      "key": "2020021222514390400_B42",
      "first-page": "3881",
      "article-title": "Apoptosis of Ewing's sarcoma cell is accompanied by accumulation of ubiquitinated proteins.",
      "volume": "57",
      "author": "Soldatenkov",
      "year": "1997",
      "journal-title": "Cancer Res."
    },
    {
      "key": "2020021222514390400_B43",
      "first-page": "4342",
      "article-title": "Tumor growth inhibition induced in a murine model of Burkitt's lymphoma by a proteasome inhibitor.",
      "volume": "58",
      "author": "Orlowski",
      "year": "1998",
      "journal-title": "Cancer Res."
    },
    {
      "key": "2020021222514390400_B44",
      "doi-asserted-by": "crossref",
      "first-page": "255",
      "DOI": "10.1038/sj.onc.1200841",
      "article-title": "Inhibition of the growth of WI-38 fibroblasts by benzyloxycarbonyl-Leu-Leu-Tyr diazomethyl ketone: evidence that cleavage of p53 by a calpain-like protease is necessary for G1 to S-phase transition.",
      "volume": "14",
      "author": "Zhang",
      "year": "1997",
      "journal-title": "Oncogene."
    },
    {
      "key": "2020021222514390400_B45",
      "doi-asserted-by": "crossref",
      "first-page": "24735",
      "DOI": "10.1074/jbc.272.40.24735",
      "article-title": "Serine phosphorylation-regulated ubiquitination and degradation of \u03b2-catenin.",
      "volume": "272",
      "author": "Orford",
      "year": "1997",
      "journal-title": "J Biol Chem."
    },
    {
      "key": "2020021222514390400_B46",
      "doi-asserted-by": "crossref",
      "first-page": "220",
      "DOI": "10.1038/370220a0",
      "article-title": "p53-dependent apoptosis in the absence of transcriptional activation of p53-target genes.",
      "volume": "370",
      "author": "Caelles",
      "year": "1994",
      "journal-title": "Nature."
    },
    {
      "key": "2020021222514390400_B47",
      "doi-asserted-by": "crossref",
      "first-page": "2817",
      "DOI": "10.1101/gad.8.23.2817",
      "article-title": "Myc-mediated apoptosis requires wild-type p53 in a manner independent of cell cycle arrest and the ability of p53 to induce p21waf1/cip1.",
      "volume": "8",
      "author": "Wagner",
      "year": "1994",
      "journal-title": "Genes Dev."
    },
    {
      "key": "2020021222514390400_B48",
      "doi-asserted-by": "crossref",
      "first-page": "2170",
      "DOI": "10.1101/gad.9.17.2170",
      "article-title": "Induction of apoptosis in HeLa cells by transactivation-deficient p53.",
      "volume": "9",
      "author": "Haupt",
      "year": "1995",
      "journal-title": "Genes Dev."
    },
    {
      "key": "2020021222514390400_B49",
      "doi-asserted-by": "crossref",
      "first-page": "827",
      "DOI": "10.1002/j.1460-2075.1996.tb00418.x",
      "article-title": "Specific loss of apoptotic but not cell-cycle arrest function in a human tumor-derived p53 mutant.",
      "volume": "15",
      "author": "Rowan",
      "year": "1996",
      "journal-title": "EMBO J."
    },
    {
      "key": "2020021222514390400_B50",
      "doi-asserted-by": "crossref",
      "first-page": "14418",
      "DOI": "10.1021/bi970998j",
      "article-title": "Rapid deubiquitination of nucleosomal histones in human tumor cells caused by proteasome inhibitors and stress response inducers: effect on replication, transcription, translation, and the cellular stress response.",
      "volume": "36",
      "author": "Mimnaugh",
      "year": "1997",
      "journal-title": "Biochemistry."
    }
  ],
  "container-title": "Blood",
  "original-title": [],
  "language": "en",
  "link": [
    {
      "URL": "http://ashpublications.org/blood/article-pdf/96/1/269/1665209/269.pdf",
      "content-type": "application/pdf",
      "content-version": "vor",
      "intended-application": "syndication"
    },
    {
      "URL": "http://ashpublications.org/blood/article-pdf/96/1/269/1665209/269.pdf",
      "content-type": "unspecified",
      "content-version": "vor",
      "intended-application": "similarity-checking"
    }
  ],
  "deposited": {
    "date-parts": [
      [
        2023,
        9,
        21
      ]
    ],
    "date-time": "2023-09-21T16:54:25Z",
    "timestamp": 1695315265000
  },
  "score": 1,
  "resource": {
    "primary": {
      "URL": "https://ashpublications.org/blood/article/96/1/269/257807/Deregulation-of-the-ubiquitin-system-and-p53"
    }
  },
  "subtitle": [],
  "short-title": [],
  "issued": {
    "date-parts": [
      [
        2000,
        7,
        1
      ]
    ]
  },
  "references-count": 50,
  "journal-issue": {
    "issue": "1",
    "published-print": {
      "date-parts": [
        [
          2000,
          7,
          1
        ]
      ]
    }
  },
  "URL": "http://dx.doi.org/10.1182/blood.V96.1.269",
  "relation": {},
  "ISSN": [
    "1528-0020",
    "0006-4971"
  ],
  "subject": [],
  "published": {
    "date-parts": [
      [
        2000,
        7,
        1
      ]
    ]
  }
}