DOI: 10.1101/gad.12.23.3639. Transcription factor CREM coordinates the timing of hepatocyte proliferation in the regenerating liver

Transcription factor CREM coordinates the timing of hepatocyte proliferation in the regenerating liver

10.1101/gad.12.23.3639

Crossref journal-article

Cold Spring Harbor Laboratory

Genes & Development (246)

Abstract

The liver regenerates upon partial hepatectomy (PH) as terminally differentiated hepatocytes undergo a tremendous proliferative process. CREM gene expression is powerfully induced during liver regeneration. We show that cell proliferation is significantly reduced upon PH in CREM−/− mice. There is a reduction in DNA synthesis, in the number of mitosis and of phosphorylated histone H3-positive cells. The post-PH proliferation peak is delayed by 10 hr, indicating an altered hepatocyte cell cycle. Expression of cyclins A, B, D1, E, and cdc2, of c-fos and tyrosine aminotransferase is deregulated. CREM mutation results in delayed S-phase entry, impairing the synchronization of proliferation.

Bibliography

Servillo, G., Della Fazia, M. A., & Sassone-Corsi, P. (1998). Transcription factor CREM coordinates the timing of hepatocyte proliferation in the regenerating liver. Genes & Development, 12(23), 3639â3643.

Authors 3

Giuseppe Servillo (first)
Maria Agnese Della Fazia (additional)
Paolo Sassone-Corsi (additional)

References 41 Referenced 58

{'key': '2021111418584030000_12.23.3639.1', 'first-page': 'G857', 'article-title': 'Cyclin and cyclin-dependent kinase 1 mRNA expression in models of regenerating liver and human liver diseases.', 'volume': '265', 'author': 'Albrecht', 'year': '1993', 'journal-title': 'Am. J. Physiol.'} / Am. J. Physiol. / Cyclin and cyclin-dependent kinase 1 mRNA expression in models of regenerating liver and human liver diseases. by Albrecht (1993)
10.1006/bbrc.1995.1548
10.1016/S0074-7696(08)61119-5 / Int. Rev. Cytol. / Regeneration of mammalian liver. by Bucher (1963)
10.1128/MCB.16.3.1157 / Mol. Cell. Biol. / Analysis of ATF3, a transcription factor induced by physiological stresses and modulated by gadd153/Chop10. by Chen (1996)
10.1126/science.274.5291.1379
10.1002/j.1460-2075.1993.tb06068.x / EMBO J. / Multiple and cooperative phosphorylation events regulate the CREM activator function. by De Groot (1993)
10.1016/0006-291X(92)91796-S
10.1016/S0014-5793(97)00445-6
10.1128/MCB.15.6.3301 / Mol. Cell. Biol. / Cell cycle regulation of cyclin A gene expression by the cyclic AMP-responsive transcription factors CREB and CREM. by Desdouets (1995)
10.1096/fasebj.10.2.8641555 / FASEB J. / Regulation of signal transduction during liver regeneration. by Diehl (1996)
10.1172/JCI115771 / J. Clin. Invest. / Differential expression of guanine nucleotide-binding proteins enhances cAMP synthesis in regenerating rat liver. by Diehl (1992)
Fausto N. (1994) Liver regeneration. in The liver: Biology and pathobiology, eds Arias I.M. Boyer J.L. Jakoby W.B. Fausto N. Schachter D. Shafritz D.A. (Raven Press, New York, NY), pp 1059–1084.
10.1096/fasebj.9.15.8529831 / FASEB J. / Role of growth factors and cytokines in hepatic regeneration. by Fausto (1995)
10.1016/0092-8674(91)90503-Q
10.1073/pnas.88.12.5448
10.1073/pnas.93.24.14140
10.1016/0092-8674(89)90013-5
10.1007/s004120050256
{'key': '2021111418584030000_12.23.3639.19', 'first-page': '186', 'article-title': 'Experimental pathology of liver: Restoration of liver in white rat following partial surgical removal.', 'volume': '12', 'author': 'Higgins', 'year': '1931', 'journal-title': 'Arch. Pathology'} / Arch. Pathology / Experimental pathology of liver: Restoration of liver in white rat following partial surgical removal. by Higgins (1931)
10.1073/pnas.92.21.9633
10.1210/me.11.10.1425
10.1016/S0021-9258(17)41972-7 / J. Biol. Chem. / Expression and activation of cdks (1 and 2) and cyclins in the cell cycle progression during liver regeneration. by Loyer (1994)
10.1016/S0021-9258(19)50657-3 / J. Biol. Chem. / Induction of cyclin mRNA and cyclin-associated histone H1 kinase during liver regeneration. by Lu (1992)
10.1096/fasebj.4.2.2404819 / FASEB J. / Liver regeneration: Molecular mechanisms of growth control. by Michalopoulos (1990)
10.1126/science.276.5309.60
10.1016/S0021-9258(18)45825-5 / J. Biol. Chem. / Immediate-early gene expression differs between regenerating liver, insulin-stimulated H-35 cells, and mitogen-stimulated Balb/c 3T3 cells. Liver-specific induction patterns of gene 33, phosphoenolpyruvate carboxykinase, and the jun, fos, and egr families. by Mohn (1990)
10.1016/0092-8674(93)90532-U
10.1073/pnas.92.23.10673
10.1146/annurev.biochem.66.1.807
10.1038/380159a0
10.1002/j.1460-2075.1992.tb05412.x / EMBO J. / Phosphorylation of CREB affects its binding to high and low affinity sites: implications for cAMP induced gene transcription. by Nichols (1992)
{'key': '2021111418584030000_12.23.3639.32', 'first-page': '305', 'article-title': 'The cell cycle kinases.', 'volume': '5', 'author': 'Pines', 'year': '1994', 'journal-title': 'Semin. Cancer Biol.'} / Semin. Cancer Biol. / The cell cycle kinases. by Pines (1994)
10.1016/0168-9525(91)90279-Y / Trends Genet. / G1-specific cyclins: In search of an S-phase promoting factor. by Reed (1991)
10.1146/annurev.cb.11.110195.002035
10.1038/sj.onc.1200996
10.1016/0092-8674(94)90540-1
10.1038/365314a0
10.1096/fasebj.10.4.8647340 / FASEB J. / Transcriptional control of liver regeneration. by Taub (1996)
{'key': '2021111418584030000_12.23.3639.39', 'first-page': '99', 'article-title': 'Posttranscriptional regulation of cyclin B messenger RNA expression in the regenerating rat liver.', 'volume': '5', 'author': 'Trembley', 'year': '1994', 'journal-title': 'Cell. Growth Differ.'} / Cell. Growth Differ. / Posttranscriptional regulation of cyclin B messenger RNA expression in the regenerating rat liver. by Trembley (1994)
10.1006/bbrc.1996.5851
10.1073/pnas.94.4.1441

Dates

Type	When
Created	17 years, 6 months ago (Feb. 20, 2008, 5:15 p.m.)
Deposited	3 years, 9 months ago (Nov. 14, 2021, 10:25 p.m.)
Indexed	49 minutes ago (Sept. 2, 2025, 8:17 p.m.)
Issued	26 years, 9 months ago (Dec. 1, 1998)
Published	26 years, 9 months ago (Dec. 1, 1998)
Published Online	26 years, 9 months ago (Dec. 1, 1998)
Published Print	26 years, 9 months ago (Dec. 1, 1998)

Funders 0

None

BibTeX

@article{Servillo_1998, title={Transcription factor CREM coordinates the timing of hepatocyte proliferation in the regenerating liver}, volume={12}, ISSN={1549-5477}, url={http://dx.doi.org/10.1101/gad.12.23.3639}, DOI={10.1101/gad.12.23.3639}, number={23}, journal={Genes & Development}, publisher={Cold Spring Harbor Laboratory}, author={Servillo, Giuseppe and Della Fazia, Maria Agnese and Sassone-Corsi, Paolo}, year={1998}, month=dec, pages={3639–3643} }

JSON

{
  "indexed": {
    "date-parts": [
      [
        2025,
        9,
        3
      ]
    ],
    "date-time": "2025-09-03T00:17:35Z",
    "timestamp": 1756858655514
  },
  "reference-count": 41,
  "publisher": "Cold Spring Harbor Laboratory",
  "issue": "23",
  "content-domain": {
    "domain": [],
    "crossmark-restriction": false
  },
  "published-print": {
    "date-parts": [
      [
        1998,
        12,
        1
      ]
    ]
  },
  "abstract": "<jats:p>The liver regenerates upon partial hepatectomy (PH) as terminally differentiated hepatocytes undergo a tremendous proliferative process. CREM gene expression is powerfully induced during liver regeneration. We show that cell proliferation is significantly reduced upon PH in CREM<jats:sup>\u2212/\u2212</jats:sup> mice. There is a reduction in DNA synthesis, in the number of mitosis and of phosphorylated histone H3-positive cells. The post-PH proliferation peak is delayed by 10 hr, indicating an altered hepatocyte cell cycle. Expression of cyclins A, B, D1, E, and cdc2, of c-<jats:italic>fos</jats:italic> and tyrosine aminotransferase is deregulated. CREM mutation results in delayed S-phase entry, impairing the synchronization of proliferation.</jats:p>",
  "DOI": "10.1101/gad.12.23.3639",
  "type": "journal-article",
  "created": {
    "date-parts": [
      [
        2008,
        2,
        20
      ]
    ],
    "date-time": "2008-02-20T22:15:26Z",
    "timestamp": 1203545726000
  },
  "page": "3639-3643",
  "source": "Crossref",
  "is-referenced-by-count": 58,
  "title": "Transcription factor CREM coordinates the timing of hepatocyte proliferation in the regenerating liver",
  "prefix": "10.1101",
  "volume": "12",
  "author": [
    {
      "given": "Giuseppe",
      "family": "Servillo",
      "sequence": "first",
      "affiliation": []
    },
    {
      "given": "Maria Agnese",
      "family": "Della Fazia",
      "sequence": "additional",
      "affiliation": []
    },
    {
      "given": "Paolo",
      "family": "Sassone-Corsi",
      "sequence": "additional",
      "affiliation": []
    }
  ],
  "member": "246",
  "published-online": {
    "date-parts": [
      [
        1998,
        12,
        1
      ]
    ]
  },
  "reference": [
    {
      "key": "2021111418584030000_12.23.3639.1",
      "first-page": "G857",
      "article-title": "Cyclin and cyclin-dependent kinase 1 mRNA expression in models of regenerating liver and human liver diseases.",
      "volume": "265",
      "author": "Albrecht",
      "year": "1993",
      "journal-title": "Am. J. Physiol."
    },
    {
      "key": "2021111418584030000_12.23.3639.2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1006/bbrc.1995.1548"
    },
    {
      "key": "2021111418584030000_12.23.3639.3",
      "doi-asserted-by": "crossref",
      "first-page": "245",
      "DOI": "10.1016/S0074-7696(08)61119-5",
      "article-title": "Regeneration of mammalian liver.",
      "volume": "15",
      "author": "Bucher",
      "year": "1963",
      "journal-title": "Int. Rev. Cytol."
    },
    {
      "key": "2021111418584030000_12.23.3639.4",
      "doi-asserted-by": "crossref",
      "first-page": "1157",
      "DOI": "10.1128/MCB.16.3.1157",
      "article-title": "Analysis of ATF3, a transcription factor induced by physiological stresses and modulated by gadd153/Chop10.",
      "volume": "16",
      "author": "Chen",
      "year": "1996",
      "journal-title": "Mol. Cell. Biol."
    },
    {
      "key": "2021111418584030000_12.23.3639.5",
      "doi-asserted-by": "publisher",
      "DOI": "10.1126/science.274.5291.1379"
    },
    {
      "key": "2021111418584030000_12.23.3639.6",
      "doi-asserted-by": "crossref",
      "first-page": "3903",
      "DOI": "10.1002/j.1460-2075.1993.tb06068.x",
      "article-title": "Multiple and cooperative phosphorylation events regulate the CREM activator function.",
      "volume": "12",
      "author": "De Groot",
      "year": "1993",
      "journal-title": "EMBO J."
    },
    {
      "key": "2021111418584030000_12.23.3639.7",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0006-291X(92)91796-S"
    },
    {
      "key": "2021111418584030000_12.23.3639.8",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0014-5793(97)00445-6"
    },
    {
      "key": "2021111418584030000_12.23.3639.9",
      "doi-asserted-by": "crossref",
      "first-page": "3301",
      "DOI": "10.1128/MCB.15.6.3301",
      "article-title": "Cell cycle regulation of cyclin A gene expression by the cyclic AMP-responsive transcription factors CREB and CREM.",
      "volume": "15",
      "author": "Desdouets",
      "year": "1995",
      "journal-title": "Mol. Cell. Biol."
    },
    {
      "key": "2021111418584030000_12.23.3639.10",
      "doi-asserted-by": "crossref",
      "first-page": "215",
      "DOI": "10.1096/fasebj.10.2.8641555",
      "article-title": "Regulation of signal transduction during liver regeneration.",
      "volume": "10",
      "author": "Diehl",
      "year": "1996",
      "journal-title": "FASEB J."
    },
    {
      "key": "2021111418584030000_12.23.3639.11",
      "doi-asserted-by": "crossref",
      "first-page": "1706",
      "DOI": "10.1172/JCI115771",
      "article-title": "Differential expression of guanine nucleotide-binding proteins enhances cAMP synthesis in regenerating rat liver.",
      "volume": "89",
      "author": "Diehl",
      "year": "1992",
      "journal-title": "J. Clin. Invest."
    },
    {
      "key": "2021111418584030000_12.23.3639.12",
      "unstructured": "Fausto N. (1994) Liver regeneration. in The liver: Biology and pathobiology, eds Arias I.M. Boyer J.L. Jakoby W.B. Fausto N. Schachter D. Shafritz D.A. (Raven Press, New York, NY), pp 1059\u20131084."
    },
    {
      "key": "2021111418584030000_12.23.3639.13",
      "doi-asserted-by": "crossref",
      "first-page": "1527",
      "DOI": "10.1096/fasebj.9.15.8529831",
      "article-title": "Role of growth factors and cytokines in hepatic regeneration.",
      "volume": "9",
      "author": "Fausto",
      "year": "1995",
      "journal-title": "FASEB J."
    },
    {
      "key": "2021111418584030000_12.23.3639.14",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0092-8674(91)90503-Q"
    },
    {
      "key": "2021111418584030000_12.23.3639.15",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.88.12.5448"
    },
    {
      "key": "2021111418584030000_12.23.3639.16",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.93.24.14140"
    },
    {
      "key": "2021111418584030000_12.23.3639.17",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0092-8674(89)90013-5"
    },
    {
      "key": "2021111418584030000_12.23.3639.18",
      "doi-asserted-by": "publisher",
      "DOI": "10.1007/s004120050256"
    },
    {
      "key": "2021111418584030000_12.23.3639.19",
      "first-page": "186",
      "article-title": "Experimental pathology of liver: Restoration of liver in white rat following partial surgical removal.",
      "volume": "12",
      "author": "Higgins",
      "year": "1931",
      "journal-title": "Arch. Pathology"
    },
    {
      "key": "2021111418584030000_12.23.3639.20",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.92.21.9633"
    },
    {
      "key": "2021111418584030000_12.23.3639.21",
      "doi-asserted-by": "publisher",
      "DOI": "10.1210/me.11.10.1425"
    },
    {
      "key": "2021111418584030000_12.23.3639.22",
      "doi-asserted-by": "crossref",
      "first-page": "2491",
      "DOI": "10.1016/S0021-9258(17)41972-7",
      "article-title": "Expression and activation of cdks (1 and 2) and cyclins in the cell cycle progression during liver regeneration.",
      "volume": "269",
      "author": "Loyer",
      "year": "1994",
      "journal-title": "J. Biol. Chem."
    },
    {
      "key": "2021111418584030000_12.23.3639.23",
      "doi-asserted-by": "crossref",
      "first-page": "2841",
      "DOI": "10.1016/S0021-9258(19)50657-3",
      "article-title": "Induction of cyclin mRNA and cyclin-associated histone H1 kinase during liver regeneration.",
      "volume": "267",
      "author": "Lu",
      "year": "1992",
      "journal-title": "J. Biol. Chem."
    },
    {
      "key": "2021111418584030000_12.23.3639.24",
      "doi-asserted-by": "crossref",
      "first-page": "176",
      "DOI": "10.1096/fasebj.4.2.2404819",
      "article-title": "Liver regeneration: Molecular mechanisms of growth control.",
      "volume": "4",
      "author": "Michalopoulos",
      "year": "1990",
      "journal-title": "FASEB J."
    },
    {
      "key": "2021111418584030000_12.23.3639.25",
      "doi-asserted-by": "publisher",
      "DOI": "10.1126/science.276.5309.60"
    },
    {
      "key": "2021111418584030000_12.23.3639.26",
      "doi-asserted-by": "crossref",
      "first-page": "21914",
      "DOI": "10.1016/S0021-9258(18)45825-5",
      "article-title": "Immediate-early gene expression differs between regenerating liver, insulin-stimulated H-35 cells, and mitogen-stimulated Balb/c 3T3 cells. Liver-specific induction patterns of gene 33, phosphoenolpyruvate carboxykinase, and the jun, fos, and egr families.",
      "volume": "265",
      "author": "Mohn",
      "year": "1990",
      "journal-title": "J. Biol. Chem."
    },
    {
      "key": "2021111418584030000_12.23.3639.27",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0092-8674(93)90532-U"
    },
    {
      "key": "2021111418584030000_12.23.3639.28",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.92.23.10673"
    },
    {
      "key": "2021111418584030000_12.23.3639.29",
      "doi-asserted-by": "publisher",
      "DOI": "10.1146/annurev.biochem.66.1.807"
    },
    {
      "key": "2021111418584030000_12.23.3639.30",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/380159a0"
    },
    {
      "key": "2021111418584030000_12.23.3639.31",
      "doi-asserted-by": "crossref",
      "first-page": "3337",
      "DOI": "10.1002/j.1460-2075.1992.tb05412.x",
      "article-title": "Phosphorylation of CREB affects its binding to high and low affinity sites: implications for cAMP induced gene transcription.",
      "volume": "11",
      "author": "Nichols",
      "year": "1992",
      "journal-title": "EMBO J."
    },
    {
      "key": "2021111418584030000_12.23.3639.32",
      "first-page": "305",
      "article-title": "The cell cycle kinases.",
      "volume": "5",
      "author": "Pines",
      "year": "1994",
      "journal-title": "Semin. Cancer Biol."
    },
    {
      "key": "2021111418584030000_12.23.3639.33",
      "doi-asserted-by": "crossref",
      "first-page": "95",
      "DOI": "10.1016/0168-9525(91)90279-Y",
      "article-title": "G1-specific cyclins: In search of an S-phase promoting factor.",
      "volume": "7",
      "author": "Reed",
      "year": "1991",
      "journal-title": "Trends Genet."
    },
    {
      "key": "2021111418584030000_12.23.3639.34",
      "doi-asserted-by": "publisher",
      "DOI": "10.1146/annurev.cb.11.110195.002035"
    },
    {
      "key": "2021111418584030000_12.23.3639.35",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/sj.onc.1200996"
    },
    {
      "key": "2021111418584030000_12.23.3639.36",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0092-8674(94)90540-1"
    },
    {
      "key": "2021111418584030000_12.23.3639.37",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/365314a0"
    },
    {
      "key": "2021111418584030000_12.23.3639.38",
      "doi-asserted-by": "crossref",
      "first-page": "413",
      "DOI": "10.1096/fasebj.10.4.8647340",
      "article-title": "Transcriptional control of liver regeneration.",
      "volume": "10",
      "author": "Taub",
      "year": "1996",
      "journal-title": "FASEB J."
    },
    {
      "key": "2021111418584030000_12.23.3639.39",
      "first-page": "99",
      "article-title": "Posttranscriptional regulation of cyclin B messenger RNA expression in the regenerating rat liver.",
      "volume": "5",
      "author": "Trembley",
      "year": "1994",
      "journal-title": "Cell. Growth Differ."
    },
    {
      "key": "2021111418584030000_12.23.3639.40",
      "doi-asserted-by": "publisher",
      "DOI": "10.1006/bbrc.1996.5851"
    },
    {
      "key": "2021111418584030000_12.23.3639.41",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.94.4.1441"
    }
  ],
  "container-title": "Genes &amp; Development",
  "original-title": [],
  "language": "en",
  "link": [
    {
      "URL": "https://syndication.highwire.org/content/doi/10.1101/gad.12.23.3639",
      "content-type": "unspecified",
      "content-version": "vor",
      "intended-application": "similarity-checking"
    }
  ],
  "deposited": {
    "date-parts": [
      [
        2021,
        11,
        15
      ]
    ],
    "date-time": "2021-11-15T03:25:39Z",
    "timestamp": 1636946739000
  },
  "score": 1,
  "resource": {
    "primary": {
      "URL": "http://genesdev.cshlp.org/lookup/doi/10.1101/gad.12.23.3639"
    }
  },
  "subtitle": [],
  "short-title": [],
  "issued": {
    "date-parts": [
      [
        1998,
        12,
        1
      ]
    ]
  },
  "references-count": 41,
  "journal-issue": {
    "issue": "23",
    "published-print": {
      "date-parts": [
        [
          1998,
          12,
          1
        ]
      ]
    }
  },
  "alternative-id": [
    "10.1101/gad.12.23.3639"
  ],
  "URL": "http://dx.doi.org/10.1101/gad.12.23.3639",
  "relation": {},
  "ISSN": [
    "0890-9369",
    "1549-5477"
  ],
  "subject": [],
  "container-title-short": "Genes Dev.",
  "published": {
    "date-parts": [
      [
        1998,
        12,
        1
      ]
    ]
  }
}