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Vol. 16, Issue 12, 5621-5629, December 2005

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Critical Role of the Ubiquitin Ligase Activity of UHRF1, a Nuclear RING Finger Protein, in Tumor Cell Growth

Yonchu Jenkins ^*, Vadim Markovtsov ^*, Wayne Lang ^*, Poonam Sharma ^*, Denise Pearsall ^*, Justin Warner ^*, Christian Franci ^*, Betty Huang ^*, Jianing Huang ^*, George C. Yam ^*, Joseph P. Vistan ^*, Erlina Pali ^*, Jorge Vialard , Michel Janicot , James B. Lorens ^* , Donald G. Payan ^*, and Yasumichi Hitoshi ^*

^* Rigel Pharmaceuticals, South San Francisco, CA 94080; Johnson and Johnson Pharmaceutical Research and Development, B-2340 Beerse, Belgium

Submitted March 8, 2005; Accepted September 15, 2005
Monitoring Editor: William Tansey

Early cellular events associated with tumorigenesis often include loss of cell cycle checkpoints or alteration in growth signaling pathways. Identification of novel genes involved in cellular proliferation may lead to new classes of cancer therapeutics. By screening a tetracycline-inducible cDNA library in A549 cells for genes that interfere with proliferation, we have identified a fragment of UHRF1 (ubiquitin-like protein containing PHD and RING domains 1), a nuclear RING finger protein, that acts as a dominant negative effector of cell growth. Reduction of UHRF1 levels using an UHRF1-specific shRNA decreased growth rates in several tumor cell lines. In addition, treatment of A549 cells with agents that activated different cell cycle checkpoints resulted in down-regulation of UHRF1. The primary sequence of UHRF1 contains a PHD and a RING motif, both of which are structural hallmarks of ubiquitin E3 ligases. We have confirmed using an in vitro autoubiquitination assay that UHRF1 displays RING-dependent E3 ligase activity. Overexpression of a GFP-fused UHRF1 RING mutant that lacks ligase activity sensitizes cells to treatment with various chemotherapeutics. Taken together, our results suggest a general requirement for UHRF1 in tumor cell proliferation and implicate the RING domain of UHRF1 as a functional determinant of growth regulation.

Abbreviations used: GFP, green fluorescent protein; tTA, tetracycline regulatable transactivator; siRNA, short interfering ribonucleic acid; shRNA, short hairpin ribonucleic acid; BrdU, bromodeoxyuridine; HMECs, human mammary epithelial cells; PrECs, human prostate epithelial cells.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Present address: Department of Biomedicine, University of Bergen School of Medicine, N-5009 Bergen, Norway.

Address correspondence to: Yonchu Jenkins (yjenkins{at}rigel.com).

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