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J. Biol. Chem., Vol. 283, Issue 9, 5477-5485, February 29, 2008

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Identification of Cyclin A₂ as the Downstream Effector of the Nuclear Phosphatidylinositol 4,5-Bisphosphate Signaling Network^*

Ka-Kei Ho, Alexandra A. Anderson, Erika Rosivatz, Eric W.-F. Lam, Rüdiger Woscholski, and David J. Mann¹

From the Division of Cell and Molecular Biology, Imperial College London, Exhibition Road, London SW7 2AZ, United Kingdom and Cancer Research UK, Department of Oncology, Imperial College London, Du Cane Road, London W12 0NN, United Kingdom

In addition to the well characterized phosphoinositide second messengers derived from the plasma membrane, increasing evidence supports the existence of a nuclear phosphoinositide signaling network. The aim of this investigation was to dissect the role played by nuclear phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P₂) in cell cycle progression and to determine the cell cycle regulatory component(s) that are involved. A number of cytosolic/nuclear PtdIns(4,5)P₂-deficient Swiss 3T3 cell lines were established, and their G₀/G₁/S cell cycle phase transitions induced by defined mitogens were examined. Our results demonstrate that nuclear PtdIns(4,5)P₂ down-regulation caused a delay in phorbol ester-induced S phase entry and that this was at least in part channeled through cyclin A₂ at the transcriptional level. In summary, these data identify cyclin A₂ as a downstream effector of the nuclear PtdIns(4,5)P₂ signaling network and highlight the importance of nuclear PtdIns(4,5)P₂ in the regulation of mammalian mitogenesis.

Received for publication, August 9, 2007 , and in revised form, December 4, 2007.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental "Experimental Procedures" and Figs. S1-S6.

¹ To whom correspondence should be addressed. Tel.: 44-20-7594-5314; E-mail: d.mann{at}imperial.ac.uk.

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