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Dysregulation of the human transforming acidic coiled coil (TACC) genes is thought to be important in the development of multiple myeloma, breast and gastric cancer. However, even though these proteins have been implicated in the control of cell growth and differentiation, the mechanism by which they function still remains to be clarified. Using the yeast two-hybrid assay, we have now identified the histone acetyltransferase (HAT) hGCN5L2 as a TACC2-binding protein. GST pull-down analysis subsequently confirmed that all human TACC family members can bind in vitro to hGCN5L2. The authenticity of these interactions was validated by coimmunoprecipitation assays within the human embryonic kidney cell line HEK293, which identified the TACC2s isoform as a component consistently bound to several different members of HAT family. This raises the possibility that aberrant expression of one or more TACC proteins may affect gene regulation through their interaction with components of chromatin remodeling complexes, thus contributing to tumorigenesis.

A highly specific t(8;13)(p11;q12) translocation has been consistently identified in bone marrow cells from patients with an atypical myeloproliferative disease that is associated with peripheral blood eosinophila and T- or B-cell leukemias. In all patients analysed to date, the translocation event results in a chimeric gene in which the atypical zinc-finger domain of ZNF198 is fused to the N-terminal end of the catalytic domain of the FGFR1 receptor tyrosine kinase. To understand more about the consequences of this rearrangement we have investigated the normal function of the ZNF198 gene. Using yeast two-hybrid analysis we identified HHR6 as a protein binding partner and confirmed this using immunoprecipitation studies. The ZNF198/FGFR1 fusion protein also binds to HHR6. We demonstrate here that the human RAD18 is also present in the ZNF198/HHR6 protein complex, although it does not coimmunoprecipitate with the fusion kinase. Cells expressing the fusion kinase gene show a marked increased sensitivity to UVB irradiation, suggesting that it acts in a dominant-negative way to affect DNA repair. These observations support the idea that ZNF198, through its interaction with HHR6 and RAD18, may be involved in the DNA repair process.

Amplification of several chromosomal regions have been observed in human breast carcinomas. One such region, 8p11, is amplified in 10 – 15% of tumor samples. Although the FGFR1 gene is located close to this region, and is often included within the amplicon, the observation that tumors exhibiting 8p11 amplification do not always overexpress FGFR1 suggests that another gene located close to FGFR1 is involved in the tumorigenic process. We now report the precise location of four expressed sequence tags (ESTs) within this region and the cloning of a novel gene, designated TACC1 (transforming acidic coiled coil gene 1), which encodes an 8 kb transcript and which is expressed at high levels during early embryogenesis. Constitutive expression of this gene under the control of the cytomegalovirus (CMV) promoter in mouse fibroblasts, results in cellular transformation and anchorage independent growth, suggesting that inappropriate expression can impart a proliferative advantage. This observation raises the possibility that amplification of TACC1 could promote malignant growth, thereby making TACC1 an attractive candidate for the gene promoting tumorigenicity as a result of the 8p11 amplification in human breast cancers.