Department of Surgery, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
Hepatology. 2011 May;53(5):1641-50. doi: 10.1002/hep.24111.
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.
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.
肝再生，肝部分切除（PHx）后，通过精确控制和同步的细胞增殖发生，其中静止的肝细胞经历一到两轮复制，恢复肝质量和功能。我们之前的研究表明，Smad3/4 衔接蛋白β-2 spectrin（β2SP）的缺失与更快地进入 S 期和肝细胞癌形成有关。这些观察结果促使我们进一步研究β2SP 在体内细胞周期进展中的作用。在β2SP（+/-）小鼠中进行的肝再生研究表明，与野生型小鼠相比，在 PHx 后 48 小时，β2SP（+/-）小鼠的肝/体重比显著降低。在 PHx 后 48 小时，我们还观察到细胞周期蛋白 E（2.4 倍，P < 0.05）、Cdk1（7.2 倍，P < 0.05）、细胞周期蛋白 A、pRb（Ser249/Thr252）、增殖细胞核抗原（PCNA）、细胞周期蛋白 D1 的水平降低，而 pCdk1（Thr14）的水平升高（3.6 倍，P < 0.05）。引人注目的是，在 24 小时时，p53（4 倍，P < 0.05）、磷酸化 p53（ser15 和 ser20）和 p21（200 倍，P < 0.05）的水平升高持续到 PHx 后 48 小时，与 DNA 损伤标志物 pChk2（Thr68）和 γH2AX（S139）的表达升高相关。然而，β2SP 的缺失导致细胞周期进程受损，PHx 后 48 小时肝再生延迟，但不依赖于 p53。β2SP 的缺失可能增加对 DNA 损伤的易感性，损害细胞周期进程，并最终导致肝细胞癌。
