Zinc regulates the ability of Cdc25C to activate MPF/cdk1

Zn(2+) is an essential micronutrient for the growth and development of multicellular organisms, as Zn(2+) deficiencies lead to growth retardation and congenital malformations (Vallee, BL, Falchuk, KH. 1993. Physiol Rev., 73:79-118). At the cellular level Zn(2+) depravation results in proliferation defects in many cell types (Vallee, BL, Falchuk, KH. 1993. Physiol Rev., 73:79-118), however the molecular pathways involved remain poorly defined. Here we show that the transition metal chelator TPEN (N,N,N',N'-tetrakis(2-pyridylmethyl) ethylene diamine) blocks the G2/M transition of the meiotic cell cycle by inhibiting Cdc25C-cdk1 activation. ICP-MS analyses reveal that Cdc25C is a Zn(2+)-binding metalloprotein, and that TPEN effectively strips Zn(2+) away from the enzyme. Interestingly, although apo-Cdc25C (Zn(2+)-deficient) remains fully catalytically active, it is compromised in its ability to dephosphorylate and activate MPF/cdk1. Thus, Zn(2+) is an important regulator of Cdc25C function in vivo. Because of the conserved essential role of the Cdc25C-cdk1 module in the eukaryotic cell cycle, these studies provide fundamental insights into cell cycle regulation.