SSBP2 is an in vivo tumor suppressor and regulator of LDB1 stability

SSBP proteins bind and stabilize transcriptional cofactor Lim Domain Binding protein1 (LDB1) from proteosomal degradation to promote tissue specific transcription through an evolutionarily conserved pathway. The human SSBP2 gene was isolated as a candidate tumor suppressor from a critical region of loss in chromosome 5q14.1. By gene targeting, we demonstrate increased predisposition to B cell lymphomas and carcinomas in Ssbp2(−/−) mice. Remarkably, loss of Ssbp2 causes increased LDB1 turnover in the thymus, a pathway exploited in Trp53(−/−) Ssbp2(−/−) mice to develop highly aggressive, immature thymic lymphomas. Using T cell differentiation as a model, we report a stage specific up regulation of Ssbp2 expression which in turn regulates LDB1 turnover under physiological conditions. Furthermore, transcript levels of pTα, a target of LDB1 containing complex, and a critical regulator T cell differentiation is reduced in Ssbp2(−/−) immature thymocytes. Our findings suggest disruption of the SSBP2 regulated pathways may be an infrequent but critical step in malignant transformation of multiple tissues.