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.
Sun
Lu
L
Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
Chai
Yingtao
Y
Hannigan
Robyn
R
Bhogaraju
Venkata K
VK
Machaca
Khaled
K
D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002614:Chelating Agents / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005029:Ethylenediamines / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D016200:Maturation-Promoting Factor / Q000378:metabolism*; D008540:Meiosis / Q000187:drug effects; D009865:Oocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014981:Xenopus; D029867:Xenopus Proteins / Q000378:metabolism; D015032:Zinc / Q000378:metabolism*; D020687:cdc25 Phosphatases / Q000378:metabolism*
D018797:Cell Cycle Proteins; D002614:Chelating Agents; D005029:Ethylenediamines; D011993:Recombinant Fusion Proteins; D029867:Xenopus Proteins; D016203:CDC2 Protein Kinase; D016200:Maturation-Promoting Factor; D020687:cdc25 Phosphatases; D015032:Zinc; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine