Expression of the proto-oncogene rhombotin-2 is identical to the acute phase response protein metallothionein, suggesting multiple functions.

Rhombotin-2 (RBTN-2) is a LIM domain protein that, with the exception of thymocytes, is widely expressed during fetal development. Although RBTN-2 is crucial for normal erythropoiesis, the ectopic expression of RBTN-2 in T lymphocytes results in T-cell proliferation and leukemogenesis. Thus, while a proliferative function for RBTN-2 has been established in T-cells, neither its role in erythropoiesis nor its function(s) in other tissues are known. We have examined the expression and location of RBTN-2 in normal and malignant cells. Similar to fetal development, RBTN-2 RNA was detected in all normal adult tissues tested with the exception of colon and thymocytes. RBTN-2 RNA was not detected in all primary tumors and tumor cell lines, indicating RBTN-2 expression is not ubiquitous in proliferating cells. Using polyclonal antisera, RBTN-2 was detected predominantly in the nucleus of human hematopoietic cells. Significantly, human leukemic T cells with disruption of the RBTN-2 locus and thymocytes from transgenic mice with enforced expression of RBTN-2 showed similar nuclear location of RBTN-2 protein, consistent with the notion that RBTN-2 acts as a transcriptional regulator in T-cell proliferation. Surprisingly, in normal tissues, RBTN-2 showed a strikingly similar distribution to that of metallothionein-1, having both nuclear and cytoplasmic localization that suggested that RBTN-2 may be involved in the acute phase response. Indeed, similar to metallothionein-1, RBTN-2 mRNA was induced in thymocytes of mice exposed to zinc and in human thymocytes treated with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate. Since the LIM domain permits binding of multiple protein partners, the specific function of RBTN-2 may depend upon subcellular sequestration through interaction with different cofactors. Thus, in addition to its roles in erythropoiesis and T-cell leukemia, RBTN-2 may also be involved in the acute phase response.