Hepatocytes Lacking Thioredoxin Reductase 1 Have Normal Replicative Potential During Development And Regeneration

Title:
Hepatocytes Lacking Thioredoxin Reductase 1 Have Normal Replicative Potential During Development And Regeneration
Authors:
Rollins, MaryClare F.; van der Heide, Dana M.; Weisend, Carla M.; Kundert, Jean A.; Comstock, Kristin M.; Suvorova, Elena S.; Capecchi, Mario R.; Merrill, Gary F.; Schmidt, Edward E.
Abstract:
Cells require ribonucleotide reductase (RNR) activity for DNA replication. In bacteria, electrons can flow from NADPH to RNR by either a thioredoxin-reductase- or a glutathione-reductase-dependent route. Yeast and plants artificially lacking thioredoxin reductases exhibit a slow-growth phenotype, suggesting glutathione-reductase-dependent routes are poor at supporting DNA replication in these organisms. We have studied proliferation of thioredoxin-reductase-1 (Txnrd1)-deficient hepatocytes in mice. During development and regeneration, normal mice and mice having Txnrd1-deficient hepatocytes exhibited similar liver growth rates. Proportions of hepatocytes that immunostained for PCNA, phosphohistone H3 or incorporated BrdU were also similar, indicating livers of either genotype had similar levels of proliferative, S and M phase hepatocytes, respectively. Replication was blocked by hydroxyurea, confirming that RNR activity was required by Txnrd1-deficient hepatocytes. Regenerative thymidine incorporation was similar in normal and Txnrd1-deficient livers, further indicating that DNA synthesis was unaffected. Using genetic chimeras in which a fluorescently marked subset of hepatocytes was Txnrd1-deficient while others were not, we found that the multigenerational contributions of both hepatocyte types to development and to liver regeneration were indistinguishable. We conclude that, in mouse hepatocytes, a Txnrd1-independent route for the supply of electrons to RNR can fully support DNA replication and normal proliferative growth.
Citation:
Rollins, MaryClare F., Dana M. van der Heide, Carla M. Weisend, Jean A. Kundert, et al. 2010. "Hepatocytes Lacking Thioredoxin Reductase 1 Have Normal Replicative Potential During Development And Regeneration." Journal Of Cell Science 123(14): 2402-2412.
Publisher:
Company of Biologists
DATE ISSUED:
2010-07
Department:
Biology
Type:
article
PUBLISHED VERSION:
10.1242/jcs.068106
PERMANENT LINK:
http://hdl.handle.net/11282/309911

Full metadata record

DC FieldValue Language
dc.contributor.authorRollins, MaryClare F.en_US
dc.contributor.authorvan der Heide, Dana M.en_US
dc.contributor.authorWeisend, Carla M.en_US
dc.contributor.authorKundert, Jean A.en_US
dc.contributor.authorComstock, Kristin M.en_US
dc.contributor.authorSuvorova, Elena S.en_US
dc.contributor.authorCapecchi, Mario R.en_US
dc.contributor.authorMerrill, Gary F.en_US
dc.contributor.authorSchmidt, Edward E.en_US
dc.date.accessioned2013-12-23T16:20:54Z-
dc.date.available2013-12-23T16:20:54Z-
dc.date.issued2010-07en
dc.identifier.citationRollins, MaryClare F., Dana M. van der Heide, Carla M. Weisend, Jean A. Kundert, et al. 2010. "Hepatocytes Lacking Thioredoxin Reductase 1 Have Normal Replicative Potential During Development And Regeneration." Journal Of Cell Science 123(14): 2402-2412.en_US
dc.identifier.issn0021-9533en_US
dc.identifier.urihttp://hdl.handle.net/11282/309911-
dc.description.abstractCells require ribonucleotide reductase (RNR) activity for DNA replication. In bacteria, electrons can flow from NADPH to RNR by either a thioredoxin-reductase- or a glutathione-reductase-dependent route. Yeast and plants artificially lacking thioredoxin reductases exhibit a slow-growth phenotype, suggesting glutathione-reductase-dependent routes are poor at supporting DNA replication in these organisms. We have studied proliferation of thioredoxin-reductase-1 (Txnrd1)-deficient hepatocytes in mice. During development and regeneration, normal mice and mice having Txnrd1-deficient hepatocytes exhibited similar liver growth rates. Proportions of hepatocytes that immunostained for PCNA, phosphohistone H3 or incorporated BrdU were also similar, indicating livers of either genotype had similar levels of proliferative, S and M phase hepatocytes, respectively. Replication was blocked by hydroxyurea, confirming that RNR activity was required by Txnrd1-deficient hepatocytes. Regenerative thymidine incorporation was similar in normal and Txnrd1-deficient livers, further indicating that DNA synthesis was unaffected. Using genetic chimeras in which a fluorescently marked subset of hepatocytes was Txnrd1-deficient while others were not, we found that the multigenerational contributions of both hepatocyte types to development and to liver regeneration were indistinguishable. We conclude that, in mouse hepatocytes, a Txnrd1-independent route for the supply of electrons to RNR can fully support DNA replication and normal proliferative growth.en_US
dc.language.isoen_USen_US
dc.publisherCompany of Biologistsen_US
dc.identifier.doi10.1242/jcs.068106-
dc.subject.departmentBiologyen_US
dc.titleHepatocytes Lacking Thioredoxin Reductase 1 Have Normal Replicative Potential During Development And Regenerationen_US
dc.typearticleen_US
dc.identifier.journalJournal Of Cell Scienceen_US
dc.subject.keywordRibonucleotide reductaseen_US
dc.subject.keywordLiver regenerationen_US
dc.subject.keywordPartial hepatectomyen_US
dc.subject.keywordDNA precursorsen_US
dc.subject.keywordCell cycleen_US
dc.subject.keywordReplicationen_US
dc.subject.keywordProliferationen_US
dc.identifier.volume123en_US
dc.identifier.issue14en_US
dc.identifier.startpage2402en_US
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