Leach S D, Scatena C D, Keefer C J, Goodman H A, Song S Y, Yang L, Pietenpol J A
Department of Surgery, The Vanderbilt Cancer Center, Nashville Veterans Affairs Medical Center, Tennessee 37232, USA.
Cancer Res. 1998 Aug 1;58(15):3231-6.
The G2 cell cycle checkpoint protects cells from potentially lethal mitotic entry after DNA damage. This checkpoint involves inhibitory phosphorylation of Cdc2 at the tyrosine-15 (Y15) position, mediated in part by the Wee1 protein kinase. Recent evidence suggests that p53 may accelerate mitotic entry after DNA damage and that the override of the G2 checkpoint may play a role in the induction of apoptosis by p53. To determine the biochemical mechanism by which p53 inactivates the G2 checkpoint, the effects of p53 activation on Wee1 expression, Cdc2-Y15 phosphorylation, and cyclin B1-associated Cdc2 kinase activity were examined. Under conditions of either growth arrest or apoptosis, p53 activation resulted in the down-regulation of Wee1 expression and dephosphorylation of Cdc2. A parallel increase in cyclin B1/Cdc2 kinase activity was observed during p53-mediated apoptosis. Negative regulation of the Wee1 expression and Cdc2 phosphorylation by p53 was also evident in thymus tissue from p53+/+ mice but not from p53-/- mice. Inactivation of the G2 checkpoint may contribute to the tumor suppressor activity of p53.
G2细胞周期检查点可保护细胞在DNA损伤后避免进入可能具有致死性的有丝分裂。该检查点涉及Cdc2在酪氨酸15（Y15）位点的抑制性磷酸化，部分由Wee1蛋白激酶介导。最近的证据表明，p53可能会在DNA损伤后加速有丝分裂的进入，并且G2检查点的越过可能在p53诱导的细胞凋亡中起作用。为了确定p53使G2检查点失活的生化机制，研究了p53激活对Wee1表达、Cdc2-Y15磷酸化以及细胞周期蛋白B1相关的Cdc2激酶活性的影响。在生长停滞或细胞凋亡的条件下，p53激活导致Wee1表达下调和Cdc2去磷酸化。在p53介导的细胞凋亡过程中，观察到细胞周期蛋白B1/Cdc2激酶活性平行增加。p53对Wee1表达和Cdc2磷酸化的负调控在p53+/+小鼠的胸腺组织中也很明显，但在p53-/-小鼠中则不明显。G2检查点的失活可能有助于p53的肿瘤抑制活性。
