The zinc finger protein cKrox directs CD4 lineage differentiation during intrathymic T cell positive selection

2005 ◽  
Vol 6 (4) ◽  
pp. 373-381 ◽  
Author(s):  
Guangping Sun ◽  
Xiaolong Liu ◽  
Peter Mercado ◽  
S Rhiannon Jenkinson ◽  
Magdalini Kypriotou ◽  
...  
Keyword(s):  
T Cell ◽  
Positive Selection ◽  
Zinc Finger ◽  
Zinc Finger Protein ◽  
Lineage Differentiation ◽  
Finger Protein

IL-7R–dependent survival and differentiation of early T-lineage progenitors is regulated by the BTB/POZ domain transcription factor Miz-1

Blood ◽  
2011 ◽  
Vol 117 (12) ◽  
pp. 3370-3381 ◽  
Author(s):  
Ingrid Saba ◽  
Christian Kosan ◽  
Lothar Vassen ◽  
Tarik Möröy
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
Zinc Finger ◽  
Zinc Finger Protein ◽  
Strong Reduction ◽  
Expression Levels ◽  
Cell Numbers ◽  
Finger Protein

Abstract T cells originate from early T lineage precursors that have entered the thymus and differentiate through well-defined steps. Mice deficient for the BTB/POZ domain of zinc finger protein-1 (Miz-1) almost entirely lack early T lineage precursors and have a CD4−CD8− to CD4+CD8+ block causing a strong reduction in thymic cellularity. Miz-1ΔPOZ pro-T cells cannot differentiate in vitro and are unable to relay signals from the interleukin-7R (IL-7R). Both STAT5 phosphorylation and Bcl-2 up-regulation are perturbed. The high expression levels of SOCS1 found in Miz-1ΔPOZ cells probably cause these alterations. Moreover, Miz-1 can bind to the SOCS1 promoter, suggesting that Miz-1 deficiency causes a deregulation of SOCS1. Transgenic overexpression of Bcl-2 or inhibition of SOCS1 restored pro-T cell numbers and their ability to differentiate, supporting the hypothesis that Miz-1 is required for the regulation of the IL-7/IL-7R/STAT5/Bcl-2 signaling pathway by monitoring the expression levels of SOCS1.

scholarly journals Zinc finger protein Zfp335 is required for the formation of the naïve T cell compartment

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Brenda Y Han ◽  
Shuang Wu ◽  
Chuan-Sheng Foo ◽  
Robert M Horton ◽  
Craig N Jenne ◽  
...  
Keyword(s):  
T Cell ◽  
Zinc Finger ◽  
Target Genes ◽  
Zinc Finger Protein ◽  
Cell Maturation ◽  
Developmental Defect ◽  
Finger Protein ◽  
T Cell Maturation ◽  
Naïve T Cell ◽  
Naive T Cell

The generation of naïve T lymphocytes is critical for immune function yet the mechanisms governing their maturation remain incompletely understood. We have identified a mouse mutant, bloto, that harbors a hypomorphic mutation in the zinc finger protein Zfp335. Zfp335bloto/bloto mice exhibit a naïve T cell deficiency due to an intrinsic developmental defect that begins to manifest in the thymus and continues into the periphery, affecting T cells that have recently undergone thymic egress. The effects of Zfp335bloto are multigenic and cannot be attributed to altered thymic selection, proliferation or Bcl2-dependent survival. Zfp335 binds to promoter regions via a consensus motif, and its target genes are enriched in categories related to protein metabolism, mitochondrial function, and transcriptional regulation. Restoring the expression of one target, Ankle2, partially rescues T cell maturation. These findings identify Zfp335 as a transcription factor and essential regulator of late-stage intrathymic and post-thymic T cell maturation.

scholarly journals Gfi-1 encodes a nuclear zinc finger protein that binds DNA and functions as a transcriptional repressor.

1996 ◽  
Vol 16 (8) ◽  
pp. 4024-4034 ◽  
Author(s):  
P A Zweidler-Mckay ◽  
H L Grimes ◽  
M M Flubacher ◽  
P N Tsichlis
Keyword(s):  
T Cell ◽  
Binding Site ◽  
Electrophoretic Mobility ◽  
Zinc Finger ◽  
Binding Sites ◽  
Zinc Finger Protein ◽  
Zinc Fingers ◽  
Mobility Shift ◽  
Finger Protein ◽  
Electrophoretic Mobility Shift Assays

The Gfi-1 proto-oncogene encodes a zinc finger protein with six C2H2-type, C-terminal zinc finger motifs and is activated by provirus integration in T-cell lymphoma lines selected for interleukin-2 independence in culture and in primary retrovirus-induced thymomas. Gfi-1 expression in adult animals is restricted to the thymus, spleen, and testis and is enhanced in mitogen-stimulated splenocytes. In this report, we show that Gfi-1 is a 55-kDa nuclear protein that binds DNA in a sequence-specific manner. The Gfi-1 binding site, TAAATCAC(A/T)GCA, was defined via random oligonucleotide selection utilizing a bacterially expressed glutathione S-transferase-Gfi-1 fusion protein. Binding to this site was confirmed by electrophoretic mobility shift assays and DNase I footprinting. Methylation interference analysis and electrophoretic mobility shift assays with mutant oliginucleotides defined the relative importance of specific bases at the consensus binding site. Deletion of individual zinc fingers demonstrated that only zinc fingers 3, 4, and 5 are required for sequence-specific DNA binding. Potential Gfi-1 binding sites were detected in a large number of eukaryotic promoter-enhancers, including the enhancers of several proto-oncogenes and cytokine genes and the enhancer of the human cytomegalovirus (HCMV) major immediate-early promoter, which contains two such sites. HCMV major immediate-early-chloramphenicol acetyltransferase reporter constructs, transfected into NIH 3T3 fibroblasts, were repressed by Gfi-1, and the repression was abrogated by mutation of critical residues in the two Gfi-1 binding sites. These results suggest that Gfi-1 may play a role in HCMV biology and may contribute to oncogenesis and T-cell activation by repressing the expression of genes that inhibit these processes.

scholarly journals Zinc finger protein GFI-1 has low oncogenic potential but cooperates strongly with pim and myc genes in T-cell lymphomagenesis

Oncogene ◽  
1998 ◽  
Vol 17 (20) ◽  
pp. 2661-2667 ◽  
Author(s):  
Thorsten Schmidt ◽  
Holger Karsunky ◽  
Eva Gau ◽  
Branko Zevnik ◽  
Hans-Peter Elsässer ◽  
...  
Keyword(s):  
T Cell ◽  
Zinc Finger ◽  
Zinc Finger Protein ◽  
Oncogenic Potential ◽  
Finger Protein

scholarly journals Progression of interleukin-2 (IL-2)-dependent rat T cell lymphoma lines to IL-2-independent growth following activation of a gene (Gfi-1) encoding a novel zinc finger protein.

1993 ◽  
Vol 13 (3) ◽  
pp. 1759-1768 ◽  
Author(s):  
C B Gilks ◽  
S E Bear ◽  
H L Grimes ◽  
P N Tsichlis
Keyword(s):  
T Cell ◽  
Cell Line ◽  
Cell Lines ◽  
Zinc Finger ◽  
Zinc Finger Protein ◽  
Cell Lymphoma ◽  
Interleukin 2 ◽  
T Cell Lymphoma ◽  
Finger Protein ◽  
Cell Clones

During progression of Moloney murine leukemia virus (Mo-MuLV)-induced rat T cell lymphomas, growth selection results in the expansion of cell clones carrying increasing numbers of integrated proviruses. These new provirus insertions reproducibly contribute to enhanced growth, allowing the emergence of cell clones from the initially heterogeneous population of tumor cells. The Mo-MuLV-induced rat T cell lymphoma lines 2780d and 5675d, which are dependent on interleukin-2 (IL-2) for growth in culture (IL-2d), were placed in IL-2-free medium to select for IL-2-independent (IL-2i) mutants. Southern blot analysis of genomic DNA from these mutants, which was hybridized to a Mo-MuLV long terminal repeat probe, revealed that all mutants carried new provirus insertions (from one to four new proviruses per cell line). A locus of integration identified through cloning of the single new provirus detected in one of the IL-2i mutants, 2780i.5, was found to be the target of provirus insertion in 1 additional IL-2i cell line of 24 tested. A full-length cDNA of a gene (growth factor independence-1 [Gfi-1]) activated by promoter insertion in the 2780i.5 cells was cloned and shown to encode a novel zinc finger protein. Gfi-1 is expressed at low levels in IL-2d cell lines cultured in IL-2-containing medium and at high levels in most IL-2i cell lines, including the two harboring a provirus at this locus. Gfi-1 expression in adult animals is restricted to the thymus, spleen, and testis. In mitogen-stimulated splenocytes, Gfi-1 expression begins to rise at 12 h after stimulation and reaches very high levels after 50 h, suggesting that it may be functionally involved in events occurring after the interaction of IL-2 with its receptor, perhaps during the transition from the G1 to the S phase of the cell cycle. In agreement with this, Gfi-1 does not induce the expression of IL-2. Expression of Gfi-1 in 2780d cells following transfer of a Gfi-1/LXSN retrovirus construct contributes to the emergence of the IL-2i phenotype.

scholarly journals Author response: Zinc finger protein Zfp335 is required for the formation of the naïve T cell compartment

2014 ◽  
Author(s):  
Brenda Y Han ◽  
Shuang Wu ◽  
Chuan-Sheng Foo ◽  
Robert M Horton ◽  
Craig N Jenne ◽  
...  
Keyword(s):  
T Cell ◽  
Zinc Finger ◽  
Zinc Finger Protein ◽  
Author Response ◽  
Cell Compartment ◽  
Finger Protein ◽  
Naïve T Cell ◽  
Naive T Cell

Progression of interleukin-2 (IL-2)-dependent rat T cell lymphoma lines to IL-2-independent growth following activation of a gene (Gfi-1) encoding a novel zinc finger protein

1993 ◽  
Vol 13 (3) ◽  
pp. 1759-1768
Author(s):  
C B Gilks ◽  
S E Bear ◽  
H L Grimes ◽  
P N Tsichlis
Keyword(s):  
T Cell ◽  
Cell Line ◽  
Cell Lines ◽  
Zinc Finger ◽  
Zinc Finger Protein ◽  
Cell Lymphoma ◽  
Interleukin 2 ◽  
T Cell Lymphoma ◽  
Finger Protein ◽  
Cell Clones

During progression of Moloney murine leukemia virus (Mo-MuLV)-induced rat T cell lymphomas, growth selection results in the expansion of cell clones carrying increasing numbers of integrated proviruses. These new provirus insertions reproducibly contribute to enhanced growth, allowing the emergence of cell clones from the initially heterogeneous population of tumor cells. The Mo-MuLV-induced rat T cell lymphoma lines 2780d and 5675d, which are dependent on interleukin-2 (IL-2) for growth in culture (IL-2d), were placed in IL-2-free medium to select for IL-2-independent (IL-2i) mutants. Southern blot analysis of genomic DNA from these mutants, which was hybridized to a Mo-MuLV long terminal repeat probe, revealed that all mutants carried new provirus insertions (from one to four new proviruses per cell line). A locus of integration identified through cloning of the single new provirus detected in one of the IL-2i mutants, 2780i.5, was found to be the target of provirus insertion in 1 additional IL-2i cell line of 24 tested. A full-length cDNA of a gene (growth factor independence-1 [Gfi-1]) activated by promoter insertion in the 2780i.5 cells was cloned and shown to encode a novel zinc finger protein. Gfi-1 is expressed at low levels in IL-2d cell lines cultured in IL-2-containing medium and at high levels in most IL-2i cell lines, including the two harboring a provirus at this locus. Gfi-1 expression in adult animals is restricted to the thymus, spleen, and testis. In mitogen-stimulated splenocytes, Gfi-1 expression begins to rise at 12 h after stimulation and reaches very high levels after 50 h, suggesting that it may be functionally involved in events occurring after the interaction of IL-2 with its receptor, perhaps during the transition from the G1 to the S phase of the cell cycle. In agreement with this, Gfi-1 does not induce the expression of IL-2. Expression of Gfi-1 in 2780d cells following transfer of a Gfi-1/LXSN retrovirus construct contributes to the emergence of the IL-2i phenotype.

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