{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T23:54:28Z","timestamp":1791158068826,"version":"4.1.0"},"reference-count":34,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":1735,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2010,12]]},"abstract":"<jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      The cellular basis of liver regeneration has been intensely investigated for many years. However, the mechanisms initiating hepatocyte \u2018\u2018plasticity\u2019\u2019 and priming for proliferation are not yet fully clear. We investigated alterations in gene expression patterns during the \ufb01rst 72 hours of C57BL\/6N mouse hepatocyte culture on collagen monolayers (CM), which display a high basal frequency of proliferation in the absence of cytokines. Although many metabolic genes were down-regulated, genes related to mitogen-activated protein kinase (MAPK) signaling and cell cycle were up-regulated. The latter genes showed an overrepresen-tation of transcription factor binding sites (TFBS) for ETF (TEA domain family member 2), E2F1 (E2F transcription factor 1), and SP-1 (Sp1 transcription factor) (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt; 0.001), all depending on MAPK signaling. Time-dependent increase of ERK1\/2 phosphorylation occurred during the \ufb01rst 48 hours (and beyond) in the absence of cytokines, accompanied by an enhanced bromodeoxyuridine labeling index of 20%. The MEK inhibitor PD98059 blunted these effects indicating MAPK signaling as major trigger for this cytokine-independ-ent proliferative response. In line with these\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      \ufb01ndings, liver tissue of mice challenged with CCl\n                      <jats:sub>4<\/jats:sub>\n                      displayed hepatocytes with intense p-ERK1\/2 staining and nuclear SP-1 and E2F1 expression. Furthermore, differentially expressed genes in mice after partial hepatectomy con-tained overrepresented TFBS for ETF, E2F1, and SP-1 and displayed increased expression of E2F1.\n                      <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic>\n                      Cultivation of murine hepatocytes on CM primes cells for proliferation through cytokine-independent activation of MAPK signaling. The transcription factors ETF, E2F1, and SP-1 seem to play a pronounced role in mediating proliferation-dependent differ-ential gene expression. Similar events, but on a shorter time-scale, occur very early after liver damage\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      . (HEPATOLOGY 2010;52:2127-2136)\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.23930","type":"journal-article","created":{"date-parts":[[2010,8,22]],"date-time":"2010-08-22T08:06:42Z","timestamp":1282464402000},"page":"2127-2136","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":80,"title":["Transcription Factors ETF, E2F, and SP-1 Are Involved in Cytokine-Independent Proliferation of Murine Hepatocytes"],"prefix":"10.1097","volume":"52","author":[{"given":"Sebastian","family":"Zellmer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Schmidt-Heck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricio","family":"Godoy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Honglei","family":"Weng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Meyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Lehmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Titus","family":"Sparna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wiebke","family":"Schormann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seddik","family":"Hammad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clemens","family":"Kreutz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens","family":"Timmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fritz 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