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J. Biol. Chem., Vol. 283, Issue 20, 13992-14001, May 16, 2008

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Phospholipase C-₁ Expression Is Linked to Proliferation, DNA Synthesis, and Cyclin E Levels^*

Jonathan D. Stallings, Yue X. Zeng, Francisco Narvaez, and Mario J. Rebecchi¹

From the Department of Clinical Investigation, Madigan Army Medical Center, Tacoma, Washington 98431 and the Department of Anesthesiology, State University of New York, Stony Brook, New York 11794

We previously reported that phospholipase C-₁ (PLC-₁) accumulates in the nucleus at the G₁/S transition, which is largely dependent on its binding to phosphatidylinositol 4,5-bisphosphate ( Stallings, J. D., Tall, E. G., Pentyala, S., and Rebecchi, M. J. (2005) J. Biol. Chem. 280, 22060-22069[Abstract/Free Full Text] ). Here, using small interfering RNA (siRNA) that specifically targets rat PLC-1, we investigated whether this enzyme plays a role in cell cycle control. Inhibiting expression of PLC-₁ significantly decreased proliferation of rat C6 glioma cells and altered S phase progression. [³H]Thymidine labeling and fluorescence-activated cell sorting analysis indicated that the rates of G₁/S transition and DNA synthesis were enhanced. On the other hand, knockdown cultures released from the G₁/S boundary were slower to reach full G₂/M DNA content, consistent with a delay in S phase. The levels of cyclin E, a key regulator of the G₁/S transition and DNA synthesis, were elevated in asynchronous cultures as well as those blocked at the G₁/S boundary. Epifluorescence imaging showed that transient expression of human phospholipase C-₁, resistant to these siRNA, suppressed expression of cyclin E at the G₁/S boundary despite treatment of cultures with rat-specific siRNA. Although whole cell levels of phosphatidylinositol 4,5-bisphosphate were unchanged, suppression of PLC-₁ led to a significant rise in the nuclear levels of this phospholipid at the G₁/S boundary. These results support a role for PLC-₁ and nuclear phospholipid metabolism in regulating cell cycle progression.

Received for publication, January 29, 2008 , and in revised form, March 21, 2008.

^* 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 Fig. 1.

¹ To whom correspondence should be addressed: Dept. of Anesthesiology, Health Sciences Center Level 4, Rm. 075, SUNY @ Stony Brook, NY 11794-8480. Tel.: 631-444-8178; Fax: 631-444-2907; E-mail: mrebecchi{at}notes.cc.sunysb.edu.

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