The genetic programs directing CD4 or CD8 T cell differentiation in the thymus remain poorly understood. While analyzing gene expression during intrathymic T cell selection, we found that Zfp67, encoding the zinc finger transcription factor cKrox, was upregulated during the differentiation of CD4(+) but not CD8(+) T cells. Expression of a cKrox transgene impaired CD8 T cell development and caused major histocompatibility complex class I-restricted thymocytes to differentiate into CD4(+) T cells with helper properties rather than into cytotoxic CD8(+) T cells, as normally found. CD4 lineage differentiation mediated by cKrox required its N-terminal BTB (bric-a-brac, tramtrack, broad complex) domain. These findings identify cKrox as a chief CD4 differentiation factor during positive selection.

Elevated levels of the calcium-binding protein S100A4 are associated with poor patient survival in breast cancer patients and induce metastasis in rodent models. To investigate the effects of S100A4 on different components of the metastatic process, epithelial cells lines have been isolated from nonmalignant tumours in neu transgenic mice and from malignant tumours in neu/S100A4 double transgenic mice. Additional cell lines expressing both Neu and S100A4 have also been derived by transfection of rat S100A4 cDNA into tumour cell lines cloned from neu single transgenic mice. Using these cells in transfilter migration assays, it has been shown that increases in either motility or invasive properties correlate with each other and with the level of S100A4 protein. Injection of three of the cell lines separately into the mammary fat pads of nude mice showed that elevated levels of S100A4 correlated with the degree of metastasis to the lungs. In contrast, changes in cell proliferation and cell -substrate adhesion did not correlate with S100A4 levels. Neither motility nor invasiveness correlated with proteolytic degradation of gelatin as measured by zymography. Thus, the results suggest that the main effect of increases in S100A4 levels in metastasis is to generate increased cell motility and invasion and that this latter change is not dependent upon an increased ability to degrade the intercellular matrix. The processes by which solid primary tumours, such as those of the breast, are able to disseminate and establish growth at a secondary site are still poorly understood. Tumour metastasis is complex, probably requiring both gain and loss of functions, enabling escape from the primary tumour, and growth at a secondary site. This has led to the search for metastasis-associated genes, which, unlike oncogenes, are unable to initiate tumour formation but are able to induce a metastatic phenotype in previously tumorigenic cells (Davies et al, 1993(Davies et al, , 1996Oates et al, 1996). One such metastasis-associated gene is that for the calciumbinding protein S100A4 (Barraclough et al, 1987). Increased levels of S100A4 have been shown to induce a metastatic phenotype in several rodent models of mammary carcinogenesis (Davies et al, 1993;Grigorian et al, 1996). Moreover, elevated expression of S100A4 has been shown to correlate with early patient demise of one group of breast cancer patients (Rudland et al, 2000), presumably due to metastatic spread of the primary tumour.A transgenic murine model that represents human metastatic breast disease in both its pathology and development of metastasis has previously been established by mating MMTV-neu transgenic mice with S100A4 transgenic mice (Davies et al, 1996). The resultant neu/S100A4 transgenic offspring develop both mammary gland tumours and lung metastases, in contrast to the parental transgenic MMTV-neu strain, which develops only mammary gland tumours (Bouchard et al, 1989;Davies et al, 1996), and to the S100A4 transgenic strain, which shows no pathology (Davies et al, ...