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Low expression of the Lsp1 gene in early mouse T-lymphomas induced by N-methyl-N-nitrosourea
Arthoritis Centre-Research Unit, The Toronto Hospital Research Institute and Department of Immunology, University of Toronto Toronto, Ontario M5T 2S8, Canada
1To whom correspondence should be addressed at: Toronto Hospital Western Division, Room 13–419, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada
The mouse Lspl gene encodes a 330 amino acid intracellular F-actin binding protein. Previously we showed that the mouse and human Lspl genes are expressed in normal B-cells and T-cells, including Thyl+ thymocytes and in normal macrophages and neutrophils. No or little LSP1 RNA and protein was found in a series of transformed mouse and human T-lymphoma cell lines, although normal antigen and lymphokine dependent T-cell lines expressed the Lspl gene. Here we show by Northern analysis that three mature antigen independent T-cell lines (CTLL-2, HT-2 and 532.10) which grow in the presence of lymphokine only, do not express LSP1 RNA, while mature resting and activated lymph node T-cells express high levels of LSP1 RNA. To determine whether the down-regulation of LSP1 expression is an early event which occurs in vivo in the tumor, rather than as a consequence of in vitro propagation of T-lymphoma cells, we analyzed LSP1 expression in primary T-lymphomas induced in AKR/J or AKR/J x BALB/cJ mice by a single intraperitoneal (i.p.) injection with 75 mg N-methyl-N-nitrosourea (MNU) per kg body-weight. Two-color Fluorescence Activated Cell Sorter (FACS) analysis showed that all tumors had an immature CD4+/CD8+ double positive (DP) phenotype. Many tumors contained a substantial population of CD4+ single positive (SP) cells. Since these cells may be infiltrating lymphocytes which can be expected to express the Lspl gene at a high level these tumors were not included in our analysis. Nineteen tumors were analyzed for Lspl gene expression and 13 contained reduced levels of LSPl RNA, ranging from 4% to 44% of those found in age-matched normal thymus. Six tumors showed either no or only a small reduction in LSP1 RNA. These tumors had developed later than those expressing low levels of LSPl. The level of LSP1 RNA in tumors developing <110 days after injection of MNU was 19.1% ± 5.2 (mean ± SEM), while the level of LSPl in later tumors was 78.4% ± 13.0 (P = 0.004). Similar data were obtained when the expression of LSPl protein was analyzed. These findings extend our previous data in several ways. First, they suggest a correlation between the down-regulation of LSPl expression and abnormal regulation of growth or survival of immature and mature T-lymphocytes. Second, they show that down regulation of the Lsp1 gene in transformed T-cells is not the result of prolonged in vitro culture, but occurs in the majority of primary tumors. Third, they show that there are two classes of T-lymphoma, which differ in their expression of LSP1RNA and that the down-regulation of LSP1 is specifically associated with the early appearance of T-lymphoma after injection with MNU. This strongly suggests that the absence or reduced expression of LSP1 contributes to the transformation process and argues against the possibility that loss of LSP1 expression is a mere inconsequential epigenetic event.
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