Translation regulatory factor RBM3 is a proto-oncogene that prevents mitotic catastrophe

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 E 2 , 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.

Discovery and validation of colonic tumor-associated proteins via metabolic labeling and stable isotopic dilution

“…Previously, researchers identified RBM-3 as an oncogene whose expression in human colonic adenocarcinomas and colon-derived cell lines is elevated and increases as disease progresses (42). Our observation of decreased RBM-3 expression in adenomas suggests that expression of this protein varies during tumor development, and that high levels of expression may be specific to advanced stages of disease.…”

The RNA-binding protein RBM3 is involved in hypothermia induced neuroprotection

“…Therefore, it is not surprising that several RNA-binding proteins exhibit a common dynamic expression pattern during postnatal brain development (Hambardzumyan et al, 2009;McKee et al, 2005). Previous reports found RBM3 to be associated with ribosomal subunits (Dresios et al, 2005;Smart et al, 2007) and at least one heterogenous ribonucleoprotein (Sureban et al, 2008).…”

“…However, it is unlikely that RBM3 rescues neuronal cells from apoptosis by merely stabilizing the translational machinery. Thus, we propose that in a fashion similar to the specific stabilization of cyclooxygenase-2 (COX-2) mRNA in colon carcinoma cells (Cok et al, 2004;Sureban et al, 2008), a number of specific target mRNAs are stabilized by RBM3 in neuronal cells. The cold inducible protein CIRP, also known as heterogenous ribonucleoprotein A18, shares high homology with RBM3, especially in the RRM (Lleonart, 2010).…”

“…Blocking RBM3 signalling by siRNAs triggers cells mitotic catastrophe in colon carcinoma cells (Sureban et al, 2008) and causes loss of proliferation and ultimately cell death in human embryonic kidney cells (HEK-293) (Wellmann et al, 2010). In contrast, exogenous over-expression of RBM3 inhibits apoptosis in neurons transfected with mutated huntingtin (Kita et al, 2002) and increases protein synthesis in mouse neuroblastoma N2a cells (Dresios et al, 2005;Smart et al, 2007).…”

TNF transactivation of EGFR stimulates cytoprotective COX-2 expression in gastrointestinal epithelial cells

“…7B). It is not clear how EGFR activity is increasing cox-2 expression, but future experiments will determine whether TNF-transactivated EGFR increases cox-2 transcription or regulates the stability of the mRNA through stabilizing factors such as the embryonic lethal abnormal vision (ELAV)-like HuR (15,61,65) or RNA-binding motif (RBM3) (66). Interestingly, TNF consistently stimulated more COX-2 protein induction than did EGF, but these ligands stimulated comparable levels of cox-2 mRNA.…”