| Loss of transforming growth factor β adaptor protein β-2 spectrin leads to delayed liver regeneration in mice. | |
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MedLine Citation:
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PMID: 21520177 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Liver regeneration, following partial hepatectomy (PHx), occurs through precisely controlled and synchronized cell proliferation, in which quiescent hepatocytes undergo one to two rounds of replication, with restoration of liver mass and function. We previously demonstrated that loss of the Smad3/4 adaptor protein β-2 spectrin (β2SP) is associated with faster entry into S phase, and hepatocellular cancer formation. These observations led us to further pursue the role of β2SP in cell cycle progression in vivo. Liver regeneration studies with PHx in β2SP(+/-) mice reveal a surprising and significant decrease in liver/body weight ratio at 48 hours after PHx in β2SP(+/-) mice in comparison to wildtype mice. At 48 hours after PHx we also observe decreased levels of cyclin E (2.4-fold, P < 0.05), Cdk1 (7.2-fold, P < 0.05), cyclin A, pRb (Ser249/Thr252), proliferative cell nuclear antigen (PCNA), cyclin D1 with elevated levels of pCdk1 (Thr14) (3.6-fold, P < 0.05). Strikingly, at 24 hours elevated levels of p53 (4-fold, P < 0.05), phospho-p53 (ser15 and ser20), and p21 (200-fold, P < 0.05) persisting to 48 hours after PHx further correlated with raised expression of the DNA damage markers pChk2 (Thr68) and γH2AX (S139). However, compromised cell cycle progression with loss of β2SP is not rescued by inhibiting p53 function, and that G(2) /M phase arrest observed is independent and upstream of p53. CONCLUSION: β2SP deficiency results in dysfunctional hepatocyte cell cycle progression and delayed liver regeneration at 48 hours after PHx, which is p53-independent. β2SP loss may increase susceptibility to DNA damage, impair cell cycle progression, and ultimately lead to hepatocellular cancer. |
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Authors:
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Arun Thenappan; Vivek Shukla; Feras J Abdul Khalek; Ying Li; Kirti Shetty; Pu Liu; Lu Li; Randy L Johnson; Lynt Johnson; Lopa Mishra |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S. |
Journal Detail:
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Title: Hepatology (Baltimore, Md.) Volume: 53 ISSN: 1527-3350 ISO Abbreviation: Hepatology Publication Date: 2011 May |
Date Detail:
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Created Date: 2011-04-26 Completed Date: 2011-07-19 Revised Date: 2012-05-02 |
Medline Journal Info:
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Nlm Unique ID: 8302946 Medline TA: Hepatology Country: United States |
Other Details:
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Languages: eng Pagination: 1641-50 Citation Subset: IM |
Copyright Information:
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Copyright © 2011 American Association for the Study of Liver Diseases. |
Affiliation:
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Department of Surgery, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Carrier Proteins / physiology* Cell Cycle / physiology Cyclin-Dependent Kinase Inhibitor p21 / physiology Liver Regeneration / physiology* Mice Microfilament Proteins / physiology* Receptors, Transforming Growth Factor beta / physiology* Time Factors Tumor Suppressor Protein p53 / physiology |
| Grant Support | |
ID/Acronym/Agency:
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P01 CA130821-01A1/CA/NCI NIH HHS; P01CA130821/CA/NCI NIH HHS; R01 CA042857-21/CA/NCI NIH HHS; R01 CA106614-04/CA/NCI NIH HHS; R01CA042857/CA/NCI NIH HHS; R01CA106614/CA/NCI NIH HHS; RC2-AA019392/AA/NIAAA NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Carrier Proteins; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Microfilament Proteins; 0/Receptors, Transforming Growth Factor beta; 0/Tumor Suppressor Protein p53; 0/fodrin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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