Loss of transforming growth factor β adaptor protein β-2 spectrin leads to delayed liver regeneration in mice

Authors

  • Arun Thenappan,

    1. Cancer Genetics, Digestive Diseases, and Developmental Molecular Biology, Department of Surgery, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC
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    • These authors contributed equally to this work.

  • Vivek Shukla,

    1. Department of Gastroenterology, Hepatology, and Nutrition, University of Texas MD Anderson Cancer Center, Houston, TX
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    • These authors contributed equally to this work.

  • Feras J. Abdul Khalek,

    1. Cancer Genetics, Digestive Diseases, and Developmental Molecular Biology, Department of Surgery, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC
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  • Ying Li,

    1. Cancer Genetics, Digestive Diseases, and Developmental Molecular Biology, Department of Surgery, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC
    2. Department of Gastroenterology, Hepatology, and Nutrition, University of Texas MD Anderson Cancer Center, Houston, TX
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  • Kirti Shetty,

    1. Institute of Transplantation, Hepatobiliary Diseases and Surgery, Georgetown University Medical Center, Washington, DC
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  • Pu Liu,

    1. Department of Biochemistry and Molecular Biology, University of Texas MD Anderson Cancer Center, Houston, TX
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  • Lu Li,

    1. Department of Biochemistry and Molecular Biology, University of Texas MD Anderson Cancer Center, Houston, TX
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  • Randy L. Johnson,

    1. Department of Biochemistry and Molecular Biology, University of Texas MD Anderson Cancer Center, Houston, TX
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  • Lynt Johnson,

    1. Cancer Genetics, Digestive Diseases, and Developmental Molecular Biology, Department of Surgery, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC
    2. Institute of Transplantation, Hepatobiliary Diseases and Surgery, Georgetown University Medical Center, Washington, DC
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  • Lopa Mishra

    Corresponding author
    1. Cancer Genetics, Digestive Diseases, and Developmental Molecular Biology, Department of Surgery, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC
    2. Department of Gastroenterology, Hepatology, and Nutrition, University of Texas MD Anderson Cancer Center, Houston, TX
    • Del & Dennis McCarthy Distinguished Professor and Chair, Department of Gastroenterology, Hepatology, and Nutrition, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1466, Houston, TX, 77030
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    • fax: (202) 687-0992


  • Potential conflict of interest: Dr. Shetty is on the speakers' bureau of Merck and Salix. She is also on the speakers' bureau of, and received grants from Gilead.

Abstract

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 G2/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. (HEPATOLOGY 2011;)

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