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

Arun Thenappan, Vivek Shukla, Feras J Abdul Khalek, Ying Li, Kirti Shetty, Pu Liu, Lu Li, Randy L. Johnson, Lynt Johnson, Lopa Mishra

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1641-1650
Number of pages10
JournalHepatology
Volume53
Issue number5
DOIs
StatePublished - May 2011
Externally publishedYes

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Spectrin
Liver Regeneration
Transforming Growth Factors
Cell Cycle
Proteins
Liver Neoplasms
S 0139
DNA Damage
Hepatocytes
Cyclin A
Cyclin E
Nuclear Antigens
G2 Phase
Liver
Cyclin D1
Hepatectomy
S Phase
Genetic Markers
Cell Division
Body Weight

ASJC Scopus subject areas

  • Hepatology

Cite this

Thenappan, A., Shukla, V., Khalek, F. J. A., Li, Y., Shetty, K., Liu, P., ... Mishra, L. (2011). Loss of transforming growth factor β adaptor protein β-2 spectrin leads to delayed liver regeneration in mice. Hepatology, 53(5), 1641-1650. https://doi.org/10.1002/hep.24111

Loss of transforming growth factor β adaptor protein β-2 spectrin leads to delayed liver regeneration in mice. / Thenappan, Arun; Shukla, Vivek; Khalek, Feras J Abdul; Li, Ying; Shetty, Kirti; Liu, Pu; Li, Lu; Johnson, Randy L.; Johnson, Lynt; Mishra, Lopa.

In: Hepatology, Vol. 53, No. 5, 05.2011, p. 1641-1650.

Research output: Contribution to journalArticle

Thenappan, A, Shukla, V, Khalek, FJA, Li, Y, Shetty, K, Liu, P, Li, L, Johnson, RL, Johnson, L & Mishra, L 2011, 'Loss of transforming growth factor β adaptor protein β-2 spectrin leads to delayed liver regeneration in mice', Hepatology, vol. 53, no. 5, pp. 1641-1650. https://doi.org/10.1002/hep.24111
Thenappan, Arun ; Shukla, Vivek ; Khalek, Feras J Abdul ; Li, Ying ; Shetty, Kirti ; Liu, Pu ; Li, Lu ; Johnson, Randy L. ; Johnson, Lynt ; Mishra, Lopa. / Loss of transforming growth factor β adaptor protein β-2 spectrin leads to delayed liver regeneration in mice. In: Hepatology. 2011 ; Vol. 53, No. 5. pp. 1641-1650.
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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.",
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AU - Shetty, Kirti

AU - Liu, Pu

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