Elsevier

Gene

Volume 497, Issue 1, 10 April 2012, Pages 18-26
Gene

Review
CUX1 transcription factors: From biochemical activities and cell-based assays to mouse models and human diseases

https://doi.org/10.1016/j.gene.2012.01.039Get rights and content

Abstract

ChIP-chip and expression analyses indicated that CUX1 transcription factors regulate a large number of genes and microRNAs involved in multiple cellular processes. Indeed, in proliferating cells CUX1 was shown to regulate several genes involved in DNA replication, progression into S phase and later, the spindle assembly checkpoint that controls progression through mitosis. siRNA-mediated knockdown established that CUX1 is required for cell motility. Moreover, higher expression of short CUX1 isoforms, as observed in many cancers, was shown to stimulate cell migration and invasion. In parallel, elevated expression particularly in higher grade tumors of breast and pancreatic cancers implicated CUX1 in tumor initiation and progression. Indeed, transgenic mouse models demonstrated a causal role of CUX1 in cancers originating from various cell types. These studies revealed that higher CUX1 expression or activity not only stimulates cell proliferation and motility, but also promotes genetic instability. CUX1 has also been implicated in the etiology of polycystic kidney diseases, both from a transgenic approach and the analysis of CUX1 activity in multiple mouse models of this disease. Studies in neurobiology have uncovered a potential implication of CUX1 in cognitive disorders, neurodegeneration and obesity. CUX1 was shown to be expressed specifically in pyramidal neurons of the neocortex upper layers where it regulates dendrite branching, spine development, and synapse formation. In addition, modulation of CUX1 expression in neurons of the hypothalamus has been associated with changes in leptin receptor trafficking in the vicinity of the primary cilium resulting in altered leptin signaling and ultimately, eating behavior. Overall, studies in various fields have allowed the development of several cell-based assays to monitor CUX1 function and have extended the range of organs in which CUX1 plays an important role in development and tissue homeostasis.

Highlights

► CUX1 accelerates the start of DNA replication and promotes genetic instability. ► CUX1 stimulates cell migration and invasion. ► CUX1 expression is elevated in breast and pancreatic tumors of higher grade. ► CUX1 stimulates dendrite branching and synapse formation in the neocortex. ► CUX1 may regulate leptin signaling and obesity via its effect on the primary cilium.

Introduction

The literature on cut goes back to 1931 (Hertweck, 1931). The term “cut” was derived from the “cut wing” phenotype observed in a mutant of Drosophila melanogaster (Blanc, 1942). In mammals, a CCAAT-displacement activity was first described in DNA binding assays (Barberis et al., 1987). Sequence analysis of the cDNA for the CCAAT-displacement protein (CDP) then revealed that this protein was the mammalian ortholog of Drosophila Cut (Neufeld et al., 1992). The gene and proteins have variously been called CDP, Cut-like 1 (CUTL1) and more recently Cut homeobox 1 (CUX1).

The present review will focus on studies published since 2008, although references to previous work will be made to provide background information. Previous reviews have detailed the tissue-specific functions and genetic interactions in Drosophila as well as the early characterization of the CDP in mammalian cells (Nepveu, 2001), expression and activity of CUX1 in the myeloid cell lineage (Skalnik, 2002), multiple CUX1 isoforms, modes of DNA binding, early mouse models and cell-based assays (Sansregret and Nepveu, 2008), roles of CUX1 in kidney development and homeostasis (Alcalay and Vanden Heuvel, 2009), mechanisms by which CUX1 stimulates cell migration and invasion (Kedinger and Nepveu, 2010), and roles of CUX1 and CUX2 in neurons of the cortex upper layer (Cubelos and Nieto, 2010). In addition, a number of commentaries present more specific views and speculations (Chapman, 2004, Goulet and Nepveu, 2004, Michl and Downward, 2006, Sansregret and Nepveu, 2011).

Section snippets

CUX1 isoforms, biochemical activities and cell-based assays

Multiple CUX1 isoforms have been described (Neufeld et al., 1992, Vandenheuvel et al., 1996, Moon et al., 2001, Goulet et al., 2002, Maitra et al., 2006, Truscott et al., 2007; reviewed in Sansregret and Nepveu, 2008). While the full-length p200 CUX1 protein has been implicated in transcriptional repression only, the shorter p110 and p75 isoforms, respectively generated by proteolytic processing or from an alternate mRNA, can participate in transcriptional activation or repression depending on

Continued expression of CUX1 during osteoblastic differentiation

In osteoblastic cells, CUX1 was found to interact with the vitamin D-receptor (VDR) in a ligand-dependent manner (Ochiai et al., 2010). Further analysis showed that CUX1 increased the recruitment of VDR to one of its targets, the CYP24 gene, and potentiated VDR-mediated transcriptional activation. Moreover, in SaM-1 human osteoblastic cells, vitamin D3-induced osteoblastogenesis was stimulated following adenovirus-driven CUX1 expression, but was inhibited by CUX1 siRNA. These findings were

CUX1 controls dendrite branching, spine development and synapse formation in cortical neurons

In Drosophila, cut was shown to specify cell-type identity in the sensory organs (Bodmer et al., 1987, Blochlinger et al., 1990). Subsequent work in Drosophila implicated cut in the regulation of dendrite branching pattern (Grueber et al., 2003, Jinushi-Nakao et al., 2007, Komiyama and Luo, 2007, Moore, 2008). A similar function in the brain of mammals has now been established (Cubelos and Nieto, 2010, Li et al., 2010). In the mouse, ferret and human, CUX1 was shown to be selectively expressed

Transgenic mouse models demonstrate a causal role of CUX1 in cancer

Accumulating evidence indicates that CUX1 expression and activities are altered in cancer. Elevated CUX1 mRNA and protein expression was reported in primary tumors and cancer cell lines of various types (De Vos et al., 2002, Moon et al., 2002, Tsutsumi et al., 2003, Michl et al., 2005, Ripka et al., 2007, Ripka et al., 2010a). In breast cancers, increased CUX1 expression inversely correlated with relapse-free and overall survival (Michl et al., 2005). Molecular analysis revealed that expression

Concluding remarks and remaining questions

As predicted from genetic studies on cut in Drosophila melanogaster, CUX1 proteins are expressed ubiquitously in mammals and play essential roles in development and tissue homeostasis. Not surprisingly, a number of pathological conditions have been associated with alterations in CUX1 expression or regulation. Histopathological studies as well as mouse models have confirmed the implication of CUX1 in the etiology of certain diseases, notably cancer and kidney diseases, while cell-based assays

Acknowledgments

A.N. is the recipient of a James McGill scholarship. This research was supported by grants #19411 from the Canadian Cancer Society, #019389 from the Canadian Breast Cancer Research Alliance and #MOP-98010 from the Canadian Institute of Health Research of Canada to A.N.

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