Abstract
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 show 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 upregulation 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 are reduced in Ssbp2/immature thymocytes. Our findings suggest that disruption of the SSBP2-regulated pathways may be an infrequent but critical step in malignant transformation of multiple tissues.
Original language | English (US) |
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Pages (from-to) | 3044-3053 |
Number of pages | 10 |
Journal | Oncogene |
Volume | 29 |
Issue number | 21 |
DOIs | |
State | Published - May 27 2010 |
Keywords
- LIM code
- Lymphoma
- Null mouse
- P53
- SSBP2
- Tumor suppressor
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Cancer Research
MD Anderson CCSG core facilities
- Genetically Engineered Mouse Facility