Previous studies have shown that BMI-1026 is a potent inhibitor of the cyclin-dependent kinases (cdk). In cell culture, the compound also arrests G2/M strongly and G1/S and S weakly. Two key kinases, cdk1 (p34cdc2 kinase) and mitogen-activated protein (MAP) kinase (erk1 and 2), perform crucial roles during oocyte maturation and, later, metaphase II (MII) arrest. In mammalian oocytes, both kinases are activated gradually around the time of germinal vesicle breakdown (GVBD) and maintain high activity in eggs arrested at metaphase II. In this study, we examined the effects of BMI-1026 on GVBD and MII arrest in mouse oocytes. BMI-1026 inhibited GVBD of immature oocytes and activated MII-arrested oocytes in a concentration-dependent manner, with more than 90% of oocytes exhibiting GVBD inhibition and MII activation at 100 nM. This is approximately 500～1,000 times more potent than the activity reported for the cdk inhibitors roscovitine (~50 M) and butyrolactone (～100 M). Based on the results of previous in vitro kinase assays, we expected BMI-1026 to inhibit only cdk1 activation in oocytes and eggs, not MAP kinase. However, in our cell-based system, it inhibited the activity of both kinases. We also found that the effect of BMI-1026 is reversible. Our results suggest that BMI-1026 inhibits GVBD and activates MII-arrested oocytes efficiently and reversibly and that it also inhibits both cdk1/histone H1 kinase and MAP kinase in mouse oocytes.

미성숙의 Germinal Vesicle(GV 단계에서 성숙한 Metaphase II(MII) 단계가 되는 난자성숙 과정은 핵과 세포질의 성숙을 통해 이루어지며, 이를 통해 수정과 배 발달을 할 수 있는 능력을 갖게 된다. GV 난자는 prophase I 단계에 arrest 되어 있다가 meiosis 과정을 거쳐 성숙한 MII로 되는데 이를 조절하는 기작에 대해서는 거의 알려져 있지 않다. 따라서 본 연구는 미성숙 난자와 성숙 난자간의 유전자 발현의 차이