TheC. elegansCBFβ homologue BRO-1 interacts with the Runx factor, RNT-1, to promote stem cell proliferation and self-renewal

Abstract

In this report, we investigate the C. elegans CBFβ homologue,BRO-1. bro-1 mutants have a similar male-specific sensory ray loss phenotype to rnt-1 (the C. elegans homologue of the mammalian CBFβ-interacting Runx factors), caused by failed cell divisions in the seam lineages. Our studies indicate that BRO-1 and RNT-1 form a cell proliferation-promoting complex, and that BRO-1 increases both the affinity and specificity of RNT-1-DNA interactions. Overexpression of bro-1,like rnt-1, leads to an expansion of seam cell number and co-overexpression of bro-1 and rnt-1 results in massive seam cell hyperplasia. Finally, we find that BRO-1 appears to act independently of RNT-1 in certain situations. These studies provide new insights into the function and regulation of this important cancer-associated DNA-binding complex in stem cells and support the view that Runx/CBFβ factors have oncogenic potential.

miR-145 induces caspase-dependent and -independent cell death in urothelial cancer cell lines with targeting of an expression signature present in Ta bladder tumors

“…A chromosomal abnormality, inv(16)(p13q22), found in 10% of acute myeloid leukemia cases results in the fusion of CBFB with MYH11, which generates the fusion oncoprotein CBFB-MYH11 (reviewed in Hart and Foroni, 2002). In Caenorhabditis elegans, overexpression of the CBFB homolog BRO-1 leads to massive hyperplasia (Kagoshima et al, 2007). These findings show that CBFB has a significant function in oncogenesis.…”

The nuclear receptor NHR-25 cooperates with the Wnt/β-catenin asymmetry pathway to control differentiation of the T seam cell inC. elegans

“…To specify T-seam-cell polarity, RNT-1 cooperates with BRO-1 (Kagoshima et al, 2007b;Xia et al, 2007). Because mutant phenotypes of rnt-1 or bro-1 resemble impaired function of nhr-25, we examined genetic interaction between nhr-25 and the two genes.…”

“…The interaction of nhr-25 with the genes encoding the transcription factor RNT-1 and its cofactor BRO-1 results in almost a fully penetrant T-seam-cell polarity defect. In addition to their role in the T seam cell, RNT-1 and BRO-1 promote V-cell divisions, and therefore rnt-1 and bro-1 mutations reduce the total number of seam cells (Nimmo et al, 2005;Kagoshima et al, 2007b;Xia et al, 2007). Although this phenotype is opposite to the effect of NHR-25 deficiency (extra seam cells) (Chen et al, 2004;Silhankova et al, 2005) (and this study), we have not detected interaction between nhr-25 and rnt-1 or bro-1 genes that would restore the normal seam-cell number (data not shown).…”

“…Impaired function of RNT-1/RUNX or its coactivator BRO-1/CBFβ abolishes the neural fate in the T.p lineage, i.e. the same T-seam-cell polarity defect as that caused by mutation of tlp-1 (Kagoshima et al, 2005;Kagoshima et al, 2007a;Kagoshima et al, 2007b). In addition to the T seam cell, RNT-1/RUNX and BRO-1/CBFβ also act in the V seam cells as rate-limiting regulators of proliferative divisions.…”

“…In addition to the T seam cell, RNT-1/RUNX and BRO-1/CBFβ also act in the V seam cells as rate-limiting regulators of proliferative divisions. Their loss-and gain-of-function effects are reciprocal, resulting in missing or extra seam cells, respectively (Ji et al, 2004;Kagoshima et al, 2005;Nimmo et al, 2005;Kagoshima et al, 2007a;Kagoshima et al, 2007b;Xia et al, 2007). This phenotype reflects the fact that RNT-1/RUNX and BRO-1/CBFβ promote cell-cycle progression by downregulating expression of a cyclin-dependent kinase inhibitor CKI-1 (Nimmo et al, 2005;Kagoshima et al, 2007a;Xia et al, 2007).…”