CUX1

Official Full Name

cut like homeobox 1

Organism

Homo sapiens

GeneID

1523

Background

The protein encoded by this gene is a member of the homeodomain family of DNA binding proteins. It may regulate gene expression, morphogenesis, and differentiation and it may also play a role in the cell cycle progession. Several alternatively spliced transcript variants encoding different isoforms have been identified.[provided by RefSeq, Feb 2011]

Synonyms

CDP; CUX; p75; CASP; CDP1; COY1; Clox; GDDI; p100; p110; p200; CUTL1; GOLIM6; CDP/Cut; Cux/CDP; Nbla10317;

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Detailed Information

Recent Research Progress

The homeobox transcription factor CUX1 (CUTL1, CDP) is an evolutionarily highly conserved protein that contains up to four DNA binding domains, including a cleaved homology domain. Initially, CUX1 was thought to be expressed only in embryonic tissues and involved in embryonic development and cell differentiation. However, recent studies have demonstrated that CUX1 is highly expressed in several tumor types and plays an important role in mediating tumor progression, both as stimulators of tumor cell migration and invasiveness, and as an inhibitor of drug-induced apoptosis.

The DNA repair function of CUX1 contributes to radioresistance.

About half of cancer patients receive ionizing radiation as part of their treatment. Recently, studies have found that cancer cell survival after ionizing radiation is reduced by CUX1 knockdown and is increased by higher CUX1 expression. However, CUX1 knockdown is by itself sufficient to reduce the viability of many cancer cell lines that exhibit high levels of reactive oxygen species (ROS). Thus, the results of colony expression relative to that of non-irradiated cells that CUX1 knockdown has no or moderate radiosensitivity to cancer cells with high ROS. Recombinant proteins containing only two CUT domains are sufficient to rapidly recruit DNA damage, accelerate DNA repair and increase survival after irradiation. Consistent with these findings, 8-oxoguanine DNA glycosylase (OGG1) knockout and treatment of cells with OGG1 inhibitors made cancer cells sensitive to radiation. Taken together, these results validate CUX1 and more specifically the CUT domain as a therapeutic target.

CUX1 regulates the polarization of tumor-associated macrophages by antagonizing NF-kB signaling.

CUX1 is not only highly expressed in tumor cells, but also highly expressed in tumor-associated macrophages (TAM) (Figure 1). CUX1 down-regulates several NF-kB-regulated chemokines, such as CXCL10, which are involved in M1 polarization and inhibition of angiogenesis and tumor progression. It has been demonstrated that CUX1 interacts with NF-kB p65, resulting in reduced binding of NF-kB p65 to the chemokine promoter. Furthermore, CUX1 reduces the acetylation of NF-kB p65 at K310 by recruiting HDAC1. Functionally, CUX1 expression in TAM antagonizes T cell attraction and enhances angiogenesis in vitro. CUX1 was identified as an important regulator of TAM phenotype and function by modulating NF- kB -dependent cytokines.

Figure 1. Schematic depiction of the proposed action of CUX1 in TAMs during tumorigenesis and tumor progression. (Hnemuth, et al, Oncogene, 2015)

Cux1 achieves hemispherical connectivity of II/III neurons by modulating Kv1-dependent firing.

It has been demonstrated that TF Cux1 controls the formation of the layer II/III corpus callosum (CC) projections through the developmental transcriptional regulation of the Kv1 voltage-dependent potassium channel and the resulting postnatal conversion to a Kv1-dependent excitation pattern. Loss of Cux1 function results in decreased expression of the Kv1 transcript, abnormal discharge response, and selective loss of CC contralateral innervation. Rescue firing and innervation by re-expressing post-natal reactivation of Kv1 or Cux1. Knockdown of Kv1 mimics Cux1-mediated loss of CC axons.

Gene dose effects of CUX1 in a murine model disrupt HSC homeostasis and control the severity and mortality of MDS.

Monosomy 7 (27) and del (7q) are high-risk cytogenetic abnormalities common in bone marrow malignancies. In diseased mice, recovery of CUX1 expression is sufficient to reverse the disease. CUX1 knockdown bone marrow transplant recipients exhibit transient hematopoietic expansion followed by a reduction in hematopoietic stem cells (HSC) and fatal bone marrow failure in a dose-dependent manner. RNA sequencing after CUX1 knockdown in human CD341 cells identified 27/del (7q) MDS gene signatures and altered differentiation, proliferation and phosphatidylinositol 3-kinase (PI3K) signaling pathways. In functional assays, CUX1 maintains HSC quiescence and inhibits proliferation. These steady-state changes coincide with a decrease in the expression of the PI3K inhibitor, Pik3ip1, and an increase in PI3K/AKT signaling after CUX1 knockdown. CUX1 knockdown promotes PI3K signaling, prompting HSC to exit quiescence and proliferation, and causing HSC to be depleted. Furthermore, reducing the single 7q gene Cux1 is sufficient to cause MDS in mice.

The function of CUX1 in oxidative DNA damage repair is needed to prevent premature senescence of mouse embryo fibroblasts.

Despite having long telomeres, mouse embryonic fibroblasts (MEF) age faster than human diploid fibroblasts due to accumulation of oxidative DNA damage. It has recently been discovered that CUX1 homeodomain proteins prevent RAS-driven cancer cells from senescence, resulting in high levels of reactive oxygen species. It is reported that Cux1^-/- MEF cannot proliferate in atmospheric (20%) oxygen, although they can normally proliferate at physiological (3%) oxygen levels. CUX1 contains three fields called Cut repeats. Structural/functional analysis determines that a single Cut repeat domain can stimulate DNA binding of 8-oxoguanine DNA glycosylase 1, OGG1, Schiff base formation, glycosylation enzyme and AP-lyase activity. Strikingly, OGG1 exhibited potent AP-lyase activity in the case of repeated cleavage. Repair of oxidative DNA damage and proliferation in 20% oxygen was rescued in Cux1^-/- MEF by ectopic expression of CUX1 or recombinant Cut repeat protein that stimulates OGG1 but lacks transcriptional activation potential. These findings reinforce the causal relationship between oxidative DNA damage and cellular senescence and suggest that the role of CUX1 as a cofactor in DNA repair is critical in the physiological state of generating higher levels of reactive oxygen species.

In summary, CUX1 plays an important role in many cellular processes, including cell cycle progression and cell proliferation, enhances spindle assembly checkpoints, and establishes transcriptional programs, cell migration and invasion that enable efficient DNA damage responses. Decreased CUX1 expression promotes tumor progression, while increased expression promotes cancer cell survival and tumor progression. Therefore, further study of the function of CUX1 and its important role in the mechanism of tumorigenesis is of great significance and value for the diagnosis and treatment of cancer.

References:

Zubaidah M, et al. The DNA repair function of CUX1 contributes to radioresistance. Oncotarget, 2017, 8(12): 19021-19038.
Hnemuth, et al. CUX1 modulates polarization of tumor-associated macrophages by antagonizing NF-kB signaling. Oncogene, 2015, 34: 177–187.
Beatriz Cubelos, et al. Cux1 and Cux2 Selectively Target Basal and Apical Dendritic Compartments of Layer II-III Cortical Neurons. Develop Neurobiol, 2015, 75: 163–172.
Rodrı´guez-Tornos, et al. Cux1 Enables Interhemispheric Connections of Layer II/III Neurons by Regulating Kv1-Dependent Firing. Neuron, 2016, 89: 494–506.
Ningfei An, et al. Gene dosage effect of CUX1 in a murine model disrupts HSC homeostasis and controls the severity and mortality of MDS. Blood, 2018,131(24):2682-2697.
Zubaidah M, et al. The function of CUX1 in oxidative DNA damage repair is needed to prevent premature senescence of mouse embryo fibroblasts. Oncotarget, 2015, 6:6.

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