Department of Gastroenterology, Endocrinology, University of Marburg, Marburg, Germany
Studies indicate that the pro-proliferative effects of CUX1 are mainly mediated by the p110 isoform. This isoform is produced by proteolytic cleavage of the full length protein occuring during G1/S-transition in the cell cycle (Goulet et al., 2004; Moon et al., 2001). Cells stably transfected with p110 CUX1 showed increased proliferation due to a shortened G1-phase whereas embryonic fibroblasts obtained from CUX1 knockout mice showed elongated G1-phase and less proliferation compared to cells isolated from wild-type mice (Sansregret et al., 2006).
A genome-wide location array for p110 CUX1 binding sites in transformed and non-transformed cell lines identified numerous CUX1 target genes that are related to proliferation and cell cycle progression (Harada et al., 2008). Most of these genes are activated by p110 CUX1 including DNA polymerase-alpha, cyclin A2 and cyclin E2. In contrast, other genes are repressed such as the CDK-inhibitor p21 (Truscott et al., 2003; Nishio and Walsh, 2004; Harada et al., 2008).
First evidence that CUX1 plays a role in cell motility originates from knockdown studies in fibroblasts and a panel of human cancer cell lines that revealed that depletion of CUX1 leads to decreased cell migration and invasion (Michl et al., 2005). In agreement with this, cells stably expressing p110 and p75 CUX1 show increased cell migration and invasion (Kedinger et al., 2009; Cadieux et al., 2009). Additionally, tail vein injection of cells stably expressing shRNA against CUX1 resulted in reduced formation of lung metastases, whereas injection of cells stably overexpressing CUX1 led to increased lung metastases (Michl et al., 2005; Cadieux et al., 2009).
The molecular basis for these effects on cell motility was in part elucidated in a genome-wide location analysis in several cell lines (Kedinger et al., 2009). In this study, CUX1 was found to inhibit the expression of genes that repress cell migration (e.g. E-cadherin, occludin) and to turn on the expression of genes that promote cell migration (e.g. FAK, N-cadherin, vimentin) (Kedinger et al., 2009). The regulation of these genes seems to be mediated both directly by binding of CUX1 to the gene promoters but also indirectly by modulation of transcription factors and signaling proteins involved in EMT (e.g. SNAI1, SNAI2, Src, Wnt5a) (Kedinger et al., 2009; Aleksic et al., 2007; Ripka et al., 2007). Additionally, several of the CUX1 target genes are known GTPases important for actin-cytoskeleton polymerization (Kedinger et al., 2009).
Studies in pancreatic cancer cell lines showed that depletion of CUX1 by siRNA increases TNFalpha- and TRAIL-induced apoptosis whereas overexpression of CUX1 rescues from apoptosis. Additionally, treatment of xenograft tumours with siRNA for CUX1 lead to retarded tumour growth and increased apoptosis. These effects are at least in part explained by a positive regulation of the antiapoptotic protein BCL2 by CUX1 (Ripka et al., 2010a). Subsequently, the glutamate receptor GRIA3 was identified as another downstream target of CUX1 able to mediate its antiapoptotic effects (Ripka et al., 2010b).
Benjamin Kühnemuth ; Patrick Michl
CUX1 (cut-like homeobox 1)
Atlas Genet Cytogenet Oncol Haematol. 2011-10-01
Online version: http://atlasgeneticsoncology.org/gene/403/cux1