CD3-ε Overexpressed in Prothymocytes Acts as an Oncogene

Wang, Baoping; She, Jian; Salio, Mariolina; Allen, Deborah; Lacy, Elizabeth; Lönberg, Nils; Terhorst, Cox

doi:10.1007/bf03401669

Cited by 8 publications

(5 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…CD3 overexpression blocks T cell development at a very early stage preceding T cell receptor (TCR) rearrangement (47). CD3 also acts as an oncogene when overexpressed in prothymocytes (48). These findings are especially relevant to the possible consequences of B29 overexpression as CD3 fulfills the same role in the TCR as B29 does in the B cell receptor.…”

Section: Discussionmentioning

confidence: 99%

Silencer elements controlling the B29 (Igβ) promoter are neither promoter- nor cell-type-specific

Malone

Omori

Wall

1997

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The murine B29 (Ig␤) promoter is B cell specific and contains essential SP1, ETS, OCT, and Ikaros motifs. Flanking 5 DNA sequences inhibit B29 promoter activity, suggesting this region contains silencer elements. Two adjacent 5 DNA segments repress transcription by the murine B29 promoter in a position-and orientationindependent manner, analogous to known silencers. Both these 5 segments also inhibit transcription by several heterologous promoters in B cells, including mb-1, c-fos, and human B29. These 5 segments also inhibit transcription by the c-fos promoter in T cells suggesting they are not B cell-specific elements. DNase I footprint analyses show an approximately 70-bp protected region overlapping the boundary between the two negative regulatory DNA segments and corresponding to binding sites for at least two different DNA-binding proteins. Within this footprint, two unrelated 30-bp cis-acting DNA motifs (designated TOAD and FROG) function as positionand orientation-independent silencers when located directly 5 of the murine B29 promoter. These two silencer motifs act cooperatively to restrict the transcriptional activity of the B29 promoter. Neither of these motifs resembles any known silencers. Mutagenesis of the TOAD and FROG motifs in their respective 5 DNA segments eliminates the silencing activity of these upstream regions, indicating these two motifs as the principal B29 silencer elements within these regions.The B29 gene is strictly B cell-specific and expressed at all stages of B cell differentiation (1). The B29 gene product, also called Ig␤, is disulfide-linked to the mb-1 gene product Ig␣ and this heterodimeric complex is associated with all Ig isotypes to form the B cell-receptor complex (2-5). The B29-mb-1 heterodimer plays a central and critical role in B cell development. Specific events in B cell development that are controlled by B29-mb-1 heterodimers include allelic exclusion (6, 7) and the pre-B cell transition marked by cell surface translocation of IgM (3,4,6,8). Signal transduction through cross-linked IgM is also controlled by B29-mb-1 heterodimers (for review, see ref. 9). In addition, B29 knock-out mice (i.e., Ig␤ Ϫ/Ϫ ) produce pro-B cells that fail to progress beyond the DJ H stage of rearrangement, suggesting B29 is essential for VDJ H recombination resulting in functional chain production (10).We have previously identified and characterized the B29 minimal promoter to resolve the features controlling its B cell specificity (11). The B29 promoter is a TATA-less promoter containing essential cis-acting OCT, ETS, SP1, and Ikaros motifs (11). A similar spectrum of motifs is present in the promoters of other TATA-less genes expressed in lymphocytes including ETS-1 (12), bcl-2 (13), mb-1 (14), TdT (15), VpreB (16), 5 (17), CD19 (18), and pp52 (19). The strict B cell specificity of the B29 minimal promoter is determined by the combinatorial activities of this cassette of different transcription factors (11,20).The current study focuses on the B29 regulatory region 5Ј of the mu...

show abstract

Section: Discussionmentioning

confidence: 99%

Silencer elements controlling the B29 (Igβ) promoter are neither promoter- nor cell-type-specific

Malone

Omori

Wall

1997

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…The invariant preTCRα gene (which acts as a surrogate for TCRα during T-cell development) has been shown to cooperate with Notch signaling to induce lymphomagenesis in mice (10). More directly, mice transgenic for components of the TCR have been shown to undergo lymphomagenesis, including mice that overexpress a TCRα transgene, mice that overexpress CD3ε, and mice that express truncated versions of TCRβ (11)(12)(13). These findings suggest that the TCR signaling pathway can play a role in driving lymphomagenesis and also bring up the question of whether a completely unmodified TCR expressed at normal levels can be oncogenic.…”

mentioning

confidence: 99%

T-cell receptor-driven lymphomagenesis in mice derived from a reprogrammed T cell

Serwold

Hochedlinger

Swindle

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The conversion of mature somatic cells into pluripotent stem cells, both by nuclear transfer and transduction with specific “reprogramming” genes, represents a major advance in regenerative medicine. Pluripotent stem cell lines can now be generated from an individual's own cells, facilitating the generation of immunologically acceptable stem cell-based therapeutics. Many cell types can undergo nuclear reprogramming, leading to the question of whether the identity of the reprogrammed cell of origin has a biological consequence. Peripheral blood, containing a mixture of T, B, NK, and myeloid cell types, represents one potential source of reprogrammable cells. In this study, we describe the unique case of mice derived from a reprogrammed T cell. These mice have prerearranged T-cell receptor (TCR) genes in all cells. Surprisingly, ≈50% of mice with prerearranged TCR genes develop spontaneous T cell lymphomas, which originate in the thymus. The lymphomas arise from developing T cells, and contain activated Notch1, similar to most human and mouse T-cell acute lymphoblastic lymphomas. Furthermore, lymphomagenesis requires the expression of both prerearranged TCRα and TCRβ genes, indicating a critical role for TCR signaling. Furthermore, inhibitors of multiple branches of TCR signaling suppress lymphoma growth, implicating TCR signaling as an essential component in lymphoma proliferation. The lymphomagenesis in mice derived from a reprogrammed T cell demonstrates the deleterious consequences of misregulation of the TCR rearrangement and signaling pathways and illustrates one case of cellular reprogramming where the identity of the cell of origin has profound consequences.

show abstract

“…In addition to the gene knockout approach, transgenic expression of genes has been very informative in elucidating the contribution of TCR/aD3 proteins in T-lymphocyte and NK-cell development (20,21). We generated a series of transgenic mice with genomic constructs containing the CD3-e or CD3-5 genes tinder the transcriptional regulation of their endogenous promoters and enhancers (22)(23)(24), Interestingly, we observed an arrest in T-lymphocyte development in many of the lines derived from CD3-e transgenes. which occurred only when these transgenes were expressed at high levels (23), The earhest block in thymocyte development was found in two homozygous CD3-e-transgenic lines: one termed tge26.…”

Section: Fig I Schematic Diagram Of Thymocyte Developmentmentioning

confidence: 99%

“…Consistently, in the CD3-deficient mice (CD3-e"'" (AP/E1/E2) X CD3-^-'^-), thymocyte development is arrested at the later CD44 CD25+ control point, and these animals stiU have a wild-type level of NK cells (Wang et al unpublished data). Taken together, the studies of the CD3-e-transgenic mice have led us to propose that the arrest in T-and NK-cell development in tge26 mice results from a high level of transgene expression which causes excessive apoptotic signaling (23,24). Using BM transplantation, we examined whether the thymic architecture of tge26 mice could be reconstituted by wild-type thymocyte precursors.…”

Section: Fig I Schematic Diagram Of Thymocyte Developmentmentioning

confidence: 99%

Development and function of T lymphocytes and natural killer cells after bone marrow transplantation of severely immunodeficient mice

Wang

Simpson

Holländer³

et al. 1997

Immunological Reviews

Self Cite

View full text Add to dashboard Cite

Bone marrow (BM) transplantation experiments were performed in a strain of CD3 epsilon-transgenic mice, termed tg epsilon 26, which are completely deficient in T-cell and natural killer (NK) cell development. We found that an interaction of stromal cells and prothymocytes is required for the induction of a cortical thymic microenvironment. This induction takes place in a time window from fetal development to early neonates. Although the thymic environment is not required for NK-cell development, we found that aberrantly educated alpha beta or gamma delta T lymphocytes can influence NK-cell ontogeny. Surprisingly, BM transplantation of tg epsilon 26 fetuses and neonates results in normal T-cell development, but very low levels of NK cells. The poor NK-cell reconstitution in fetal and neonatal stages could be explained by an inefficient migration of hematopoietic progenitor cells to the BM. By contrast, migration of the progenitor cells to the thymus was efficient to initiate T-cell development. BM transplantation of adult tg epsilon 26 mice resulted in abnormal T-cell development which, in turn, caused an inflammatory bowel disease (IBD) in the recipient mice. Studies in these BM chimeras have revealed that both alpha beta and gamma delta T cells can be pathogenic and, further, that Th1-like cytokines produced by these cells are causal factors in the pathogenesis of IBD.

show abstract

CD3-ε Overexpressed in Prothymocytes Acts as an Oncogene

Abstract: Background: Upon engagement of the T cell receptor for antigen, its associated CD3 proteins recruit signal transduction molecules, which in turn regulate T lymphocyte proliferation, apoptosis, and thymocyte development. Because some signal transducing molecules re-

Cited by 8 publications

References 34 publications

Silencer elements controlling the B29 (Igβ) promoter are neither promoter- nor cell-type-specific

Silencer elements controlling the B29 (Igβ) promoter are neither promoter- nor cell-type-specific

T-cell receptor-driven lymphomagenesis in mice derived from a reprogrammed T cell

Development and function of T lymphocytes and natural killer cells after bone marrow transplantation of severely immunodeficient mice

Contact Info

Product

Resources

About