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Loss of transforming growth factor β adaptor protein β‐2 spectrin leads to delayed liver regeneration in mice
Author(s) -
Thenappan Arun,
Shukla Vivek,
Khalek Feras J. Abdul,
Li Ying,
Shetty Kirti,
Liu Pu,
Li Lu,
Johnson Randy L.,
Johnson Lynt,
Mishra Lopa
Publication year - 2011
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.24111
Subject(s) - biology , liver regeneration , cell cycle , proliferating cell nuclear antigen , cyclin d1 , cell growth , cancer research , microbiology and biotechnology , endocrinology , medicine , apoptosis , regeneration (biology) , biochemistry , genetics
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. (H EPATOLOGY 2011;)