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J. Biol. Chem., Vol. 281, Issue 2, 858-866, January 13, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/2/858    most recent M502693200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Los, A. P. Articles by Divecha, N. Search for Related Content PubMed PubMed Citation Articles by Los, A. P. Articles by Divecha, N. Social Bookmarking                      What's this?

The Retinoblastoma Family Proteins Bind to and Activate Diacylglycerol Kinase^*

Alrik P. Los, Fabian P. Vinke, John de Widt, Matthew K. Topham, Wim J. van Blitterswijk1, and Nullin Divecha2

From the Division of Cellular Biochemistry, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands and Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112

The retinoblastoma protein (pRB) is a tumor suppressor and key regulator of the cell cycle. We have previously shown that pRB interacts with phosphatidylinositol-4-phosphate 5-kinases, lipid kinases that can regulate phosphatidylinositol 4,5-bisphosphate levels in the nucleus. Here, we investigated pRB binding to another lipid kinase in the phosphoinositide cycle, diacylglycerol kinase (DGK) that phosphorylates the second messenger diacylglycerol to yield phosphatidic acid. We found that DGK, but not DGK or DGK, interacts with pRB in vitro and in vivo. Binding of DGK to pRB is dependent on the phosphorylation status of pRB, since only hypophosphorylated pRB interacts with DGK. DGK also binds to the pRB-related pocket proteins p107 and p130 in vitro and in cells. Although DGK did not affect the ability of pRB to regulate E2F-mediated transcription, we found that pRB, p107, and p130 potently stimulate DGK activity in vitro. Finally, overexpression of DGK in pRB-null fibroblasts reconstitutes a cell cycle arrest induced by -irradiation. These results suggest that DGK may act in vivo as a downstream effector of pRB to regulate nuclear levels of diacylglycerol and phosphatidic acid.

Received for publication, March 11, 2005 , and in revised form, November 4, 2005.

^* This work was supported by Dutch Cancer Society Grant NKI 2000-2209. 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.

¹ To whom correspondence may be addressed. Fax: 31-205121989; E-mail: w.v.blitterswijk{at}nki.nl. ²To whom correspondence may be addressed. Fax: 31-205121989; E-mail: n.divecha{at}nki.nl.

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