Shungo Adachi

Role of a BCL9-Related β-Catenin-Binding Protein, B9L, in Tumorigenesis Induced by Aberrant Activation of Wnt Signaling

Wnt signaling plays a crucial role in a number of developmental processes and in tumorigenesis. β-Catenin is stabilized by Wnt signaling and associates with the TCF/LEF family of transcription factors, thereby activating transcription of Wnt target genes. Constitutive activation of β-catenin-TCF–mediated transcription resulting from mutations in adenomatous polyposis coli (APC), β-catenin, or Axin is believed to be a critical step in tumorigenesis among divergent types of cancers. Here we show that the transactivation potential of the β-catenin-TCF complex is enhanced by its interaction with a BCL9-like protein, B9L, in addition to BCL9. We found that B9L is required for enhanced β-catenin-TCF–mediated transcription in colorectal tumor cells and for β-catenin–induced transformation of RK3E cells. Furthermore, expression of B9L was aberrantly elevated in about 43% of colorectal tumors, relative to the corresponding noncancerous tissues. These results suggest that B9L plays an important role in tumorigenesis induced by aberrant activation of Wnt signaling.

Identification of a link between Wnt/β-catenin signalling and the cell fusion pathway

Cell fusion has a critical role in various developmental processes, immune response, tissue homeostasis and regeneration, and possibly, in cancer. However, the signals that regulate cell fusion remain poorly understood. In a screen for novel targets of Wnt/β-catenin signalling, we identified glial cells missing 1 (GCM1), which encodes a transcription factor that is involved in epigenetic regulation and is critical for the fusion of syncytiotrophoblast (ST) cells. Here we show that β-catenin/BCL9-Like (BCL9L)/T-cell factor 4 (TCF4) signalling directly targets the GCM1/syncytin pathway and thereby regulates the fusion of human choriocarcinoma cells. Furthermore, we show that the GCM1/syncytin-B pathway is significantly downregulated in the placenta of BCL9L-deficient mice and that the fusion and differentiation of ST-II cells are blocked. Our results demonstrate a signal transduction pathway that regulates cell fusion, and may provide intriguing perspectives into the various biological and pathological processes that involve cell fusion.

Up‐regulation of a BCL9‐related β‐catenin‐binding protein, B9L, in different stages of sporadic colorectal adenoma

Aberrant activation of Wnt signaling is a critical event in the development of human colorectal tumors. The aim of this study was to elucidate the role of B9L and its association with β‐catenin in each stage of the adenoma‐carcinoma sequence of human colorectal tumorigenesis. We investigated the expression levels of B9L in sporadic colorectal adenomas and carcinomas, categorized according to the Vienna classification, using real‐time quantitative polymerase chain reaction (RTQ‐PCR) and immunohistochemical analysis. B9L was expressed in the nuclei of non‐neoplastic colonic mucosa cells and was overexpressed in the nuclei of neoplasias and invasive carcinoma cells. Immunoreactivity to B9L protein was correlated with the progressive grades of colorectal neoplasias, as was the expression of B9L mRNA. A high level of immunoreactivity to nuclear B9L was present in 27% of low‐grade neoplasias and in more than 50% of high‐grade neoplasias and invasive carcinomas, whereas a high level of nuclear B9L immunoreactivity was not observed in any of the non‐neoplastic mucosa samples. The expression of B9L was dramatically increased in low‐grade neoplasias compared with that in non‐neoplastic mucosa. B9L may play an important role in tumorigenesis induced by aberrant activation of Wnt signaling and may act as a key protein in the progressive dysplasia of adenoma. (Cancer Sci 2007; 98: 83–87)

Immunohistochemical expression of the β-catenin-interacting protein B9L is associated with histological high nuclear grade and immunohistochemical ErbB2/HER-2 expression in breast cancers

B9L/BCL9‐2, a novel β‐catenin‐interacting protein, plays an important role in colorectal carcinogenesis by translocating β‐catenin to the nucleus and enhancing β‐catenin–T‐cell factor‐mediated transcription. To elucidate the role of B9L in breast cancers, we studied B9L expression in ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) of the breast immunohistochemically and compared it to the immunohistochemical expression of known proteins involved in breast carcinogenesis. In breast tissues, B9L immunoreactivity was present exclusively in the nuclei of normal and neoplastic ductal cells. In DCIS, immunohistochemical B9L expression was significantly associated with the tumor nuclear grade, comedo necrosis and the expression of ErbB2/HER‐2, c‐myc and p53. In IDC, B9L expression was correlated with ErbB2/HER‐2 expression and tumor nuclear grade only. In both DCIS and IDC, immunohistochemical B9L expression was not related to the expression of cytoplasmic β‐catenin. We demonstrated that nuclear B9L expression was closely associated with the high nuclear grade cancer phenotype and the expression of ErbB2/HER‐2 in breast cancers. (Cancer Sci 2007; 98: 484–490)

Binding of the human homolog of the Drosophila discs large tumor suppressor protein to the mitochondrial ribosomal protein MRP-S34

The human homolog of the Drosophila discs large tumor suppressor protein (hDLG) functions as a scaffolding protein that facilitates the transmission of diverse downstream signals. Here we show that hDLG interacts through its PDZ domains with the carboxy-terminal S/TXV motif of the mitochondrial ribosomal protein S-34 (MRP-S34). Our results suggest that hDLG interacts with MRP-S34 prior to entry of MRP-S34 into the mitochondria and may be involved in the trafficking of MRP-S34.