Abstract
The proto-oncogene LIM-domain only 2 (lmo2) was traditionally considered to be a pivotal transcriptional regulator in hematopoiesis and leukemia. Recently, the cytosolic localization of LMO2 was revealed in multiple epithelial tissues and a variety of solid tumors. However, the function of LMO2 in these epithelia and solid tumors remains largely unclear. The Wnt signaling pathway is a crucial determinant of development, and abnormalities in several key segments of this pathway contribute to oncogenesis. The current study demonstrated that LMO2 participates in the regulation of canonical Wnt signaling in the cytoplasm by binding to Dishevelled-1/2 (DVL-1/2) proteins. These interactions occurred at the PDZ domain of Dishevelled, and LMO2 subsequently attenuated the activation of the key factor β-catenin in the canonical Wnt signaling pathway. Meanwhile, significantly decreased expression of LMO2 was detected in breast and colorectal cancers, and the downregulation of LMO2 in these cells increased cell proliferation and reduced apoptosis. Taken together, the data in this study revealed a novel crosstalk between LMO2 and the Wnt signaling pathway during tumorigenesis and suggested that LMO2 might be a tumor suppressor in certain solid tumors, in contrast to its traditional oncogenic role in the hematopoietic system.
Highlights
The proto-oncogene LIM-domain only 2 was traditionally considered to be a pivotal transcriptional regulator in hematopoiesis and leukemia
The current study revealed that LMO2 plays a role in regulating the Wnt signaling pathway by targeting Dishevelled-1 and -2 proteins, which function upstream of the β-catenin degradation complex, and thereby attenuating the activation of β-catenin
A previous study revealed that the β-catenin co-transcriptional factor LEF1 directly interacts with LMO2 in the nucleus of DLBCB26
Summary
The proto-oncogene LIM-domain only 2 (lmo2) was traditionally considered to be a pivotal transcriptional regulator in hematopoiesis and leukemia. The current study demonstrated that LMO2 participates in the regulation of canonical Wnt signaling in the cytoplasm by binding to Dishevelled-1/2 (DVL-1/2) proteins These interactions occurred at the PDZ domain of Dishevelled, and LMO2 subsequently attenuated the activation of the key factor β-catenin in the canonical Wnt signaling pathway. The data in this study revealed a novel crosstalk between LMO2 and the Wnt signaling pathway during tumorigenesis and suggested that LMO2 might be a tumor suppressor in certain solid tumors, in contrast to its traditional oncogenic role in the hematopoietic system. The canonical Wnt pathway is activated by the binding of the ligand Wnt to a Frizzled family receptor, which transmits the signal to Dishevelled proteins (DVLs) inside the cell This leads to the accumulation and nuclear translocation of β-catenin, where it functions a co-activator of the transcription factor TCF/LEF15,16. The results revealed that LMO2 could attenuate tumor progression by blocking the Wnt signaling pathway, suggesting a novel tumor suppressor role for LMO2 in contrast to its traditional oncogenic function in the hematopoietic system
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