1. ¹Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
2. ²Department of Medicine, Washington University School of Medicine, St Louis, MO, USA
3. ³Department of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
4. ⁴OU Cancer Institute, Oklahoma City, OK, USA
5. ⁵Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

Correspondence: Dr S Anant, Departments of Medicine and Cell Biology, University of Oklahoma Health Sciences Center, 970 Stanton L. Young Boulevard, WP1360, Oklahoma City, OK 73126, USA. E-mail: shrikant-anant@ouhsc.edu

⁶These authors contributed equally to this work.

Received 31 October 2007; Revised 15 January 2008; Accepted 1 March 2008; Published online 21 April 2008.

Abstract

RNA-binding proteins play a key role in post-transcriptional regulation of mRNA stability and translation. We have identified that RBM3, a translation regulatory protein, is significantly upregulated in human tumors, including a stage-dependent increase in colorectal tumors. Forced RBM3 overexpression in NIH3T3 mouse fibroblasts and SW480 human colon epithelial cells increases cell proliferation and development of compact multicellular spheroids in soft agar suggesting the ability to induce anchorage-independent growth. In contrast, downregulating RBM3 in HCT116 colon cancer cells with specific siRNA decreases cell growth in culture, which was partially overcome when treated with prostaglandin E₂, a product of cyclooxygenase (COX)-2 enzyme activity. Knockdown also resulted in the growth arrest of tumor xenografts. We have also identified that RBM3 knockdown increases caspase-mediated apoptosis coupled with nuclear cyclin B1, and phosphorylated Cdc25c, Chk1 and Chk2 kinases, implying that under conditions of RBM3 downregulation, cells undergo mitotic catastrophe. RBM3 enhances COX-2, IL-8 and VEGF mRNA stability and translation. Conversely, RBM3 knockdown results in loss in the translation of these transcripts. These data demonstrate that the RNA stabilizing and translation regulatory protein RBM3 is a novel proto-oncogene that induces transformation when overexpressed and is essential for cells to progress through mitosis.