Lymphoid Enhancer Factor-1 Blocks Adenomatous Polyposis Coli-mediated Nuclear Export and Degradation of β-Catenin

Abstract

The oncogenic protein ␤-catenin is overexpressed in many cancers, frequently accumulating in nuclei where it forms active complexes with lymphoid enhancer factor-1 (LEF-1)/T-cell transcription factors, inducing genes such as c-myc and cyclin D1. In normal cells, nuclear ␤-catenin levels are controlled by the adenomatous polyposis coli (APC) protein through nuclear export and cytoplasmic degradation. Transient expression of LEF-1 is known to increase nuclear ␤-catenin levels by an unknown mechanism. Here, we show that APC and LEF-1 compete for nuclear ␤-catenin with opposing consequences. APC can export nuclear ␤-catenin to the cytoplasm for degradation. In contrast, LEF-1 anchors ␤-catenin in the nucleus by blocking APC-mediated nuclear export. LEF-1 also prevented the APC/CRM1-independent nuclear export of ␤-catenin as revealed by in vitro assays. Importantly, LEF-1-bound ␤-catenin was protected from degradation by APC and axin in SW480 colon cancer cells. The ability of LEF-1 to trap ␤-catenin in the nucleus was down-regulated by histone deacetylase 1, and this correlated with a decrease in LEF1 transcription activity. Our findings identify LEF-1 as key regulator of ␤-catenin nuclear localization and stability and suggest that overexpression of LEF-1 in colon cancer and melanoma cells may contribute to the accumulation of oncogenic ␤-catenin in the nucleus.␤-Catenin accumulates to excessive levels in different cancers, including melanomas, colon cancer, breast cancer, and hepatocarcinomas (1-3). Whether overexpressed in cancer (2, 3), in transfected cells (4), or in transgenic mice (5), the induced ␤-catenin accumulates throughout the cell with frequent concentration in the nucleus. ␤-Catenin is thought to be the key mediator of the Wnt signaling pathway (3), and when overexpressed it can cause cell transformation (6). The oncogenic potential of ␤-catenin is mediated by its association with a class of related (but not identical) transcription factors that include lymphoid enhancer factor-1 (LEF-1), 1 and the T cell factors including TCF-1, -3, and -4 (3). Of these, LEF-1 is of particular interest as it is overexpressed in colon cancer cell lines (7) and colon tumors (8), and in metastatic melanoma cells (9), and is known to form nuclear ␤-catenin-LEF-1 complexes in vivo, which activate transcription of various transforming genes, including cyclin D1 (10) and c-myc (11). ␤-Catenin overexpression results from stabilizing cancer mutations within the ␤-catenin gene (see Ref. 2) or in genes that regulate its degradation such as APC and axin (see Ref.3). Recently, we and others showed that the nuclear build-up of ␤-catenin is normally prevented by a combination of nuclear export and cytoplasmic degradation (12-14). ␤-Catenin can exit the nucleus by two distinct pathways: the CRM1 export pathway, which requires its association with the shuttling protein APC (12)(13)(14), and an alternative CRM1-independent export route (15, 16). Despite the ability of ␤-catenin to efficiently exit the nucleus of SW480 colon cancer c...

Signal Transducers and Activators of Transcription 3 Activation Is Involved in Nuclear Accumulation of β-Catenin in Colorectal Cancer

“…In addition, p-STAT3 and h-catenin did not coimmunoprecipitate, ruling out the possibility that activated STAT3 directly shuttles h-catenin from the cytoplasm and/or membrane to the nucleus. Other molecules, APC and lymphoid enhancer binding factor (LEF)-1, shuttle h-catenin between the cytoplasm and nucleus (18,19). However, APC gene is mutated in SW480 cells, and immunofluorescence did not detect any changes in the intracellular localization of LEF-1 (data not shown).…”

Effects of histone deacetylase inhibitors on estradiol-induced proliferation and hyperplasia formation in the mouse uterus

“…Direct interactions between -catenin and histone deacetylases were documented (Billin et al 2000). It was also shown that -catenin led to a loss of activity of histone deacetylases (Henderson et al 2002, Baek et al 2003. A function of -catenin is compromised by fusion to a transcriptional repressor domain from histone deacetylase (Cong et al 2003).…”

Nucleo-cytoplasmic distribution of β-catenin is regulated by retention

“…Nuclear and cytoplasmic retention factors could compete for binding to ␤-catenin as has been demonstrated in several studies (Hamada and Bienz, 2004;Henderson et al, 2002;Hulsken et al, 1994;Lee et al, 2001;Tolwinski and Wieschaus, 2001). Such competition could fine-tune the outcome of Wnt signalling at different steps along the pathway.…”