DOI: 10.1002/jcb.10761. Mediating of caspase‐independent apoptosis by cadmium through the mitochondria‐ROS pathway in MRC‐5 fibroblasts

Mediating of caspase‐independent apoptosis by cadmium through the mitochondria‐ROS pathway in MRC‐5 fibroblasts

10.1002/jcb.10761

Crossref journal-article

Wiley

Journal of Cellular Biochemistry (311)

Abstract

AbstractCadmium (Cd) is an environmental pollutant of global concern with a 10–30‐year biological half‐life in humans. Accumulating evidence suggests that the lung is one of the major target organs of inhaled Cd compounds. Our previous report demonstrated that 100 μM Cd induces MRC‐5 cells, normal human lung fibroblasts, to undergo caspase‐independent apoptosis mediated by mitochondrial membrane depolarization and translocation of apoptosis‐inducing factor (AIF) from mitochondria into the nucleus. Here, using benzyloxycarbonyl‐Val‐Ala‐Asp‐(ome) fluoromethyl ketone (Z‐VAD.fmk) as a tool, we further demonstrated that Cd could induce caspase‐independent apoptosis at concentrations varied from 25 to 150 μM, which was modulated by reactive oxygen species (ROS) scavengers, such as N‐acetylcysteine (NAC), mannitol, and tiron, indicating that ROS play a crucial role in the apoptogenic activity of Cd. Consistent with this notion, the intracellular hydrogen peroxide (H2O2) was 2.9‐fold elevated after 3 h of Cd treatment and diminished rapidly within 1 h as detected by flow cytometry with 2′,7′‐dichlorodihydrofluorescein diacetate (DCFH‐DA) staining. Using inhibitors of the mitochondrial electron transport chain (ETC) (oligomycin A and rotenone for complex I and V, respectively) and mitochondrial permeability transition pore (MPTP) (cyclosporin A and aristolochic acid), we coincidently found the ROS production, mitochondrial membrane depolarization, and apoptotic content were almost completely or partially abolished. As revealed by confocal microscopy staining with chloromethyl‐X‐rosamine (CMXRos) and an anti‐AIF antibody, the collapse of mitochondrial membrane potential induced by Cd (3 h‐treatment) was a prelude to the translocation of caspase‐independent pro‐apoptotic factor, AIF, into the nucleus (after 4 h of Cd treatment). In summary, this study demonstrated that, in MRC‐5 fibroblasts, Cd induced caspase‐independent apoptosis through a mitochondria‐ROS pathway. More importantly, we provide several lines of evidence supporting a role of mitochondrial ETC and MPTP in the regulation of caspase‐independent cell death triggered by Cd. © 2003 Wiley‐Liss, Inc.

Authors 9

Chwen‐Ming Shih (first)
Wun‐Chang Ko (additional)
Jui‐Sheng Wu (additional)
Yau‐Huei Wei (additional)
Leng‐Fang Wang (additional)
E‐E. Chang (additional)
Tsui‐Yun Lo (additional)
Huey‐Hwa Cheng (additional)
Chien‐Tsu Chen (additional)

References 59 Referenced 144

10.1006/taap.1999.8907
10.1091/mbc.12.10.3016
10.1016/0891-5849(89)90066-X
10.1007/s002040100236
10.1038/sj.cdd.4400525
10.1086/324013
10.1074/jbc.273.36.22983
10.1016/S0300-9084(02)01374-3
10.1038/sj.cdd.4400646
10.1016/S0022-1759(02)00069-8
10.1006/bbrc.1993.2438
10.1006/excr.2000.4856
10.1016/S0140-6736(88)91474-2
10.1016/S0005-2728(98)00029-2
10.1182/blood.V96.3.1030 / Blood / Caspase‐independent commitment phase to apoptosis in activated blood T lymphocyte: Reversibility at low apoptotic insult by Dumont C (2000)
10.1006/bbrc.1999.1888
10.1007/978-3-642-79162-8
{'key': 'e_1_2_5_19_1', 'first-page': '6698', 'article-title': 'Evidence supporting a role for mitochondrial respiration in apoptosis induction by the synthetic retinoid CD437', 'volume': '61', 'author': 'Hail N', 'year': '2001', 'journal-title': 'Cancer Res'} / Cancer Res / Evidence supporting a role for mitochondrial respiration in apoptosis induction by the synthetic retinoid CD437 by Hail N (2001)
10.1006/taap.2001.9362
10.1016/S0300-483X(99)00013-X
10.1128/MCB.17.5.2468
{'key': 'e_1_2_5_23_1', 'first-page': '923', 'article-title': 'Zinc stimulates DNA synthesis during its antiapoptotic action independently with increments of an antiapoptotic protein, Bcl‐2, in porcine kidney LLC‐PK1 cells', 'volume': '290', 'author': 'Ishido M', 'year': '1999', 'journal-title': 'J Pharmacol Exp Ther'} / J Pharmacol Exp Ther / Zinc stimulates DNA synthesis during its antiapoptotic action independently with increments of an antiapoptotic protein, Bcl‐2, in porcine kidney LLC‐PK1 cells by Ishido M (1999)
10.1016/S0896-6273(00)80573-5
10.1038/227168a0
10.1074/jbc.275.1.705
10.1016/S0300-483X(99)00176-6
10.1016/S0022-1759(02)00073-X
10.1016/S0300-483X(01)00536-4
{'key': 'e_1_2_5_30_1', 'first-page': '391', 'article-title': 'A simple assay of the superoxide generation rate with tiron as an EPR‐visible radical scavenger', 'volume': '13', 'author': 'Ledenev AN', 'year': '1986', 'journal-title': 'Biochem Int'} / Biochem Int / A simple assay of the superoxide generation rate with tiron as an EPR‐visible radical scavenger by Ledenev AN (1986)
10.1074/jbc.M007369200
10.1038/35083620
10.1096/fj.00-0388com
{'key': 'e_1_2_5_34_1', 'first-page': 'I91', 'article-title': 'The mechanism of mannitol in reducing ischemic injury: Hyperosmolarity or hydroxyl scavenger?', 'volume': '70', 'author': 'Magovern GJ', 'year': '1984', 'journal-title': 'Circulation'} / Circulation / The mechanism of mannitol in reducing ischemic injury: Hyperosmolarity or hydroxyl scavenger? by Magovern GJ (1984)
10.1016/0300-483X(90)90170-L
10.1042/bj3590537 / Biochem J / Cladribine induces apoptosis in human leukaemia cells by caspase‐dependent and ‐independent pathways acting on mitochondria by Marzo I (2001)
10.1038/nsb793
10.1002/(SICI)1097-4652(199711)173:2<178::AID-JCP17>3.0.CO;2-C
{'key': 'e_1_2_5_39_1', 'first-page': '3', 'volume-title': 'Cadmium in the human environment: Toxicity and carcinogenecity', 'author': 'Nordberg GF', 'year': '1992'} / Cadmium in the human environment: Toxicity and carcinogenecity by Nordberg GF (1992)
10.1016/0022-1759(92)90305-D
{'key': 'e_1_2_5_41_1', 'first-page': '8218', 'article-title': 'Phases of apoptosis of melanoma cells, but not of normal melanocytes, differently affect maturation of myeloid dendritic cells', 'volume': '61', 'author': 'Pietra G', 'year': '2001', 'journal-title': 'Cancer Res'} / Cancer Res / Phases of apoptosis of melanoma cells, but not of normal melanocytes, differently affect maturation of myeloid dendritic cells by Pietra G (2001)
10.1038/ncb0901-839
10.1002/jcp.10111
10.1016/S0166-445X(00)00154-5
10.1080/10408440008951122
10.1016/S0002-9343(99)00259-4
10.1006/taap.2000.9092
10.1073/pnas.91.23.10771
10.1016/0891-5849(94)00159-H
10.1038/17135
10.1084/jem.192.4.571
10.1016/S1097-2765(01)00341-0
10.1006/excr.2001.5447
10.1002/(SICI)1097-0320(19960601)24:2<131::AID-CYTO5>3.0.CO;2-M
10.1016/0022-1759(95)00072-I
10.1038/35023643
10.1038/377248a0
10.1289/ehp.97105712
10.1006/taap.2000.8921
10.1038/43591

Dates

Type	When
Created	21 years, 7 months ago (Jan. 21, 2004, 4:01 a.m.)
Deposited	1 year, 9 months ago (Nov. 17, 2023, 4:13 p.m.)
Indexed	1 week, 3 days ago (Aug. 23, 2025, 9:47 p.m.)
Issued	21 years, 8 months ago (Dec. 15, 2003)
Published	21 years, 8 months ago (Dec. 15, 2003)
Published Online	21 years, 8 months ago (Dec. 15, 2003)
Published Print	21 years, 7 months ago (Feb. 1, 2004)

Funders 0

None

BibTeX

@article{Shih_2003, title={Mediating of caspase‐independent apoptosis by cadmium through the mitochondria‐ROS pathway in MRC‐5 fibroblasts}, volume={91}, ISSN={1097-4644}, url={http://dx.doi.org/10.1002/jcb.10761}, DOI={10.1002/jcb.10761}, number={2}, journal={Journal of Cellular Biochemistry}, publisher={Wiley}, author={Shih, Chwen‐Ming and Ko, Wun‐Chang and Wu, Jui‐Sheng and Wei, Yau‐Huei and Wang, Leng‐Fang and Chang, E‐E. and Lo, Tsui‐Yun and Cheng, Huey‐Hwa and Chen, Chien‐Tsu}, year={2003}, month=dec, pages={384–397} }

JSON

{
  "indexed": {
    "date-parts": [
      [
        2025,
        8,
        24
      ]
    ],
    "date-time": "2025-08-24T01:47:51Z",
    "timestamp": 1756000071922
  },
  "reference-count": 59,
  "publisher": "Wiley",
  "issue": "2",
  "license": [
    {
      "start": {
        "date-parts": [
          [
            2003,
            12,
            15
          ]
        ],
        "date-time": "2003-12-15T00:00:00Z",
        "timestamp": 1071446400000
      },
      "content-version": "vor",
      "delay-in-days": 0,
      "URL": "http://onlinelibrary.wiley.com/termsAndConditions#vor"
    }
  ],
  "content-domain": {
    "domain": [],
    "crossmark-restriction": false
  },
  "published-print": {
    "date-parts": [
      [
        2004,
        2
      ]
    ]
  },
  "abstract": "<jats:title>Abstract</jats:title><jats:p>Cadmium (Cd) is an environmental pollutant of global concern with a 10\u201330\u2010year biological half\u2010life in humans. Accumulating evidence suggests that the lung is one of the major target organs of inhaled Cd compounds. Our previous report demonstrated that 100 \u03bcM Cd induces MRC\u20105 cells, normal human lung fibroblasts, to undergo caspase\u2010independent apoptosis mediated by mitochondrial membrane depolarization and translocation of apoptosis\u2010inducing factor (AIF) from mitochondria into the nucleus. Here, using benzyloxycarbonyl\u2010Val\u2010Ala\u2010Asp\u2010(ome) fluoromethyl ketone (Z\u2010VAD.fmk) as a tool, we further demonstrated that Cd could induce caspase\u2010independent apoptosis at concentrations varied from 25 to 150 \u03bcM, which was modulated by reactive oxygen species (ROS) scavengers, such as <jats:italic>N</jats:italic>\u2010acetylcysteine (NAC), mannitol, and tiron, indicating that ROS play a crucial role in the apoptogenic activity of Cd. Consistent with this notion, the intracellular hydrogen peroxide (H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub>) was 2.9\u2010fold elevated after 3 h of Cd treatment and diminished rapidly within 1 h as detected by flow cytometry with 2\u2032,7\u2032\u2010dichlorodihydrofluorescein diacetate (DCFH\u2010DA) staining. Using inhibitors of the mitochondrial electron transport chain (ETC) (oligomycin A and rotenone for complex I and V, respectively) and mitochondrial permeability transition pore (MPTP) (cyclosporin A and aristolochic acid), we coincidently found the ROS production, mitochondrial membrane depolarization, and apoptotic content were almost completely or partially abolished. As revealed by confocal microscopy staining with chloromethyl\u2010X\u2010rosamine (CMXRos) and an anti\u2010AIF antibody, the collapse of mitochondrial membrane potential induced by Cd (3 h\u2010treatment) was a prelude to the translocation of caspase\u2010independent pro\u2010apoptotic factor, AIF, into the nucleus (after 4 h of Cd treatment). In summary, this study demonstrated that, in MRC\u20105 fibroblasts, Cd induced caspase\u2010independent apoptosis through a mitochondria\u2010ROS pathway. More importantly, we provide several lines of evidence supporting a role of mitochondrial ETC and MPTP in the regulation of caspase\u2010independent cell death triggered by Cd. \u00a9 2003 Wiley\u2010Liss, Inc.</jats:p>",
  "DOI": "10.1002/jcb.10761",
  "type": "journal-article",
  "created": {
    "date-parts": [
      [
        2004,
        1,
        21
      ]
    ],
    "date-time": "2004-01-21T09:01:37Z",
    "timestamp": 1074675697000
  },
  "page": "384-397",
  "source": "Crossref",
  "is-referenced-by-count": 144,
  "title": "Mediating of caspase\u2010independent apoptosis by cadmium through the mitochondria\u2010ROS pathway in MRC\u20105 fibroblasts",
  "prefix": "10.1002",
  "volume": "91",
  "author": [
    {
      "given": "Chwen\u2010Ming",
      "family": "Shih",
      "sequence": "first",
      "affiliation": []
    },
    {
      "given": "Wun\u2010Chang",
      "family": "Ko",
      "sequence": "additional",
      "affiliation": []
    },
    {
      "given": "Jui\u2010Sheng",
      "family": "Wu",
      "sequence": "additional",
      "affiliation": []
    },
    {
      "given": "Yau\u2010Huei",
      "family": "Wei",
      "sequence": "additional",
      "affiliation": []
    },
    {
      "given": "Leng\u2010Fang",
      "family": "Wang",
      "sequence": "additional",
      "affiliation": []
    },
    {
      "given": "E\u2010E.",
      "family": "Chang",
      "sequence": "additional",
      "affiliation": []
    },
    {
      "given": "Tsui\u2010Yun",
      "family": "Lo",
      "sequence": "additional",
      "affiliation": []
    },
    {
      "given": "Huey\u2010Hwa",
      "family": "Cheng",
      "sequence": "additional",
      "affiliation": []
    },
    {
      "given": "Chien\u2010Tsu",
      "family": "Chen",
      "sequence": "additional",
      "affiliation": []
    }
  ],
  "member": "311",
  "published-online": {
    "date-parts": [
      [
        2003,
        12,
        15
      ]
    ]
  },
  "reference": [
    {
      "key": "e_1_2_5_2_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1006/taap.1999.8907"
    },
    {
      "key": "e_1_2_5_3_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1091/mbc.12.10.3016"
    },
    {
      "key": "e_1_2_5_4_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0891-5849(89)90066-X"
    },
    {
      "key": "e_1_2_5_5_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1007/s002040100236"
    },
    {
      "key": "e_1_2_5_6_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/sj.cdd.4400525"
    },
    {
      "key": "e_1_2_5_7_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1086/324013"
    },
    {
      "key": "e_1_2_5_8_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.273.36.22983"
    },
    {
      "key": "e_1_2_5_9_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0300-9084(02)01374-3"
    },
    {
      "key": "e_1_2_5_10_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/sj.cdd.4400646"
    },
    {
      "key": "e_1_2_5_11_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0022-1759(02)00069-8"
    },
    {
      "key": "e_1_2_5_12_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1006/bbrc.1993.2438"
    },
    {
      "key": "e_1_2_5_13_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1006/excr.2000.4856"
    },
    {
      "key": "e_1_2_5_14_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0140-6736(88)91474-2"
    },
    {
      "key": "e_1_2_5_15_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0005-2728(98)00029-2"
    },
    {
      "key": "e_1_2_5_16_1",
      "doi-asserted-by": "crossref",
      "first-page": "1030",
      "DOI": "10.1182/blood.V96.3.1030",
      "article-title": "Caspase\u2010independent commitment phase to apoptosis in activated blood T lymphocyte: Reversibility at low apoptotic insult",
      "volume": "96",
      "author": "Dumont C",
      "year": "2000",
      "journal-title": "Blood"
    },
    {
      "key": "e_1_2_5_17_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1006/bbrc.1999.1888"
    },
    {
      "key": "e_1_2_5_18_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1007/978-3-642-79162-8"
    },
    {
      "key": "e_1_2_5_19_1",
      "first-page": "6698",
      "article-title": "Evidence supporting a role for mitochondrial respiration in apoptosis induction by the synthetic retinoid CD437",
      "volume": "61",
      "author": "Hail N",
      "year": "2001",
      "journal-title": "Cancer Res"
    },
    {
      "key": "e_1_2_5_20_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1006/taap.2001.9362"
    },
    {
      "key": "e_1_2_5_21_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0300-483X(99)00013-X"
    },
    {
      "key": "e_1_2_5_22_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1128/MCB.17.5.2468"
    },
    {
      "key": "e_1_2_5_23_1",
      "first-page": "923",
      "article-title": "Zinc stimulates DNA synthesis during its antiapoptotic action independently with increments of an antiapoptotic protein, Bcl\u20102, in porcine kidney LLC\u2010PK1 cells",
      "volume": "290",
      "author": "Ishido M",
      "year": "1999",
      "journal-title": "J Pharmacol Exp Ther"
    },
    {
      "key": "e_1_2_5_24_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0896-6273(00)80573-5"
    },
    {
      "key": "e_1_2_5_25_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/227168a0"
    },
    {
      "key": "e_1_2_5_26_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.275.1.705"
    },
    {
      "key": "e_1_2_5_27_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0300-483X(99)00176-6"
    },
    {
      "key": "e_1_2_5_28_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0022-1759(02)00073-X"
    },
    {
      "key": "e_1_2_5_29_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0300-483X(01)00536-4"
    },
    {
      "key": "e_1_2_5_30_1",
      "first-page": "391",
      "article-title": "A simple assay of the superoxide generation rate with tiron as an EPR\u2010visible radical scavenger",
      "volume": "13",
      "author": "Ledenev AN",
      "year": "1986",
      "journal-title": "Biochem Int"
    },
    {
      "key": "e_1_2_5_31_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.M007369200"
    },
    {
      "key": "e_1_2_5_32_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/35083620"
    },
    {
      "key": "e_1_2_5_33_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1096/fj.00-0388com"
    },
    {
      "key": "e_1_2_5_34_1",
      "first-page": "I91",
      "article-title": "The mechanism of mannitol in reducing ischemic injury: Hyperosmolarity or hydroxyl scavenger?",
      "volume": "70",
      "author": "Magovern GJ",
      "year": "1984",
      "journal-title": "Circulation"
    },
    {
      "key": "e_1_2_5_35_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0300-483X(90)90170-L"
    },
    {
      "key": "e_1_2_5_36_1",
      "doi-asserted-by": "crossref",
      "first-page": "537",
      "DOI": "10.1042/bj3590537",
      "article-title": "Cladribine induces apoptosis in human leukaemia cells by caspase\u2010dependent and \u2010independent pathways acting on mitochondria",
      "volume": "359",
      "author": "Marzo I",
      "year": "2001",
      "journal-title": "Biochem J"
    },
    {
      "key": "e_1_2_5_37_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/nsb793"
    },
    {
      "key": "e_1_2_5_38_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1002/(SICI)1097-4652(199711)173:2<178::AID-JCP17>3.0.CO;2-C"
    },
    {
      "key": "e_1_2_5_39_1",
      "first-page": "3",
      "volume-title": "Cadmium in the human environment: Toxicity and carcinogenecity",
      "author": "Nordberg GF",
      "year": "1992"
    },
    {
      "key": "e_1_2_5_40_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0022-1759(92)90305-D"
    },
    {
      "key": "e_1_2_5_41_1",
      "first-page": "8218",
      "article-title": "Phases of apoptosis of melanoma cells, but not of normal melanocytes, differently affect maturation of myeloid dendritic cells",
      "volume": "61",
      "author": "Pietra G",
      "year": "2001",
      "journal-title": "Cancer Res"
    },
    {
      "key": "e_1_2_5_42_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/ncb0901-839"
    },
    {
      "key": "e_1_2_5_43_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1002/jcp.10111"
    },
    {
      "key": "e_1_2_5_44_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0166-445X(00)00154-5"
    },
    {
      "key": "e_1_2_5_45_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1080/10408440008951122"
    },
    {
      "key": "e_1_2_5_46_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0002-9343(99)00259-4"
    },
    {
      "key": "e_1_2_5_47_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1006/taap.2000.9092"
    },
    {
      "key": "e_1_2_5_48_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.91.23.10771"
    },
    {
      "key": "e_1_2_5_49_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0891-5849(94)00159-H"
    },
    {
      "key": "e_1_2_5_50_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/17135"
    },
    {
      "key": "e_1_2_5_51_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1084/jem.192.4.571"
    },
    {
      "key": "e_1_2_5_52_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S1097-2765(01)00341-0"
    },
    {
      "key": "e_1_2_5_53_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1006/excr.2001.5447"
    },
    {
      "key": "e_1_2_5_54_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1002/(SICI)1097-0320(19960601)24:2<131::AID-CYTO5>3.0.CO;2-M"
    },
    {
      "key": "e_1_2_5_55_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0022-1759(95)00072-I"
    },
    {
      "key": "e_1_2_5_56_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/35023643"
    },
    {
      "key": "e_1_2_5_57_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/377248a0"
    },
    {
      "key": "e_1_2_5_58_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1289/ehp.97105712"
    },
    {
      "key": "e_1_2_5_59_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1006/taap.2000.8921"
    },
    {
      "key": "e_1_2_5_60_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/43591"
    }
  ],
  "container-title": "Journal of Cellular Biochemistry",
  "original-title": [],
  "language": "en",
  "link": [
    {
      "URL": "https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1002%2Fjcb.10761",
      "content-type": "unspecified",
      "content-version": "vor",
      "intended-application": "text-mining"
    },
    {
      "URL": "https://onlinelibrary.wiley.com/doi/pdf/10.1002/jcb.10761",
      "content-type": "unspecified",
      "content-version": "vor",
      "intended-application": "similarity-checking"
    }
  ],
  "deposited": {
    "date-parts": [
      [
        2023,
        11,
        17
      ]
    ],
    "date-time": "2023-11-17T21:13:18Z",
    "timestamp": 1700255598000
  },
  "score": 1,
  "resource": {
    "primary": {
      "URL": "https://onlinelibrary.wiley.com/doi/10.1002/jcb.10761"
    }
  },
  "subtitle": [],
  "short-title": [],
  "issued": {
    "date-parts": [
      [
        2003,
        12,
        15
      ]
    ]
  },
  "references-count": 59,
  "journal-issue": {
    "issue": "2",
    "published-print": {
      "date-parts": [
        [
          2004,
          2
        ]
      ]
    }
  },
  "alternative-id": [
    "10.1002/jcb.10761"
  ],
  "URL": "http://dx.doi.org/10.1002/jcb.10761",
  "relation": {},
  "ISSN": [
    "0730-2312",
    "1097-4644"
  ],
  "subject": [],
  "container-title-short": "J of Cellular Biochemistry",
  "published": {
    "date-parts": [
      [
        2003,
        12,
        15
      ]
    ]
  }
}