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Cellular & Molecular Immunology Oct 2021Acute viral infection causes illness and death. In addition, an infection often results in increased susceptibility to a secondary infection, but the mechanisms behind...
Acute viral infection causes illness and death. In addition, an infection often results in increased susceptibility to a secondary infection, but the mechanisms behind this susceptibility are poorly understood. Since its initial identification as a marker for resident memory CD8 T cells in barrier tissues, the function and regulation of CD103 integrin (encoded by ITGAE gene) have been extensively investigated. Nonetheless, the function and regulation of the resident CD103CD8 T cell response to acute viral infection remain unclear. Although TGFβ signaling is essential for CD103 expression, the precise molecular mechanism behind this regulation is elusive. Here, we reveal a TGFβ-SKI-Smad4 pathway that critically and specifically directs resident CD103CD8 T cell generation for protective immunity against primary and secondary viral infection. We found that resident CD103CD8 T cells are abundant in both lymphoid and nonlymphoid tissues from uninfected mice. CD103 acts as a costimulation signal to produce an optimal antigenic CD8 T cell response to acute viral infection. There is a reduction in resident CD103CD8 T cells following primary infection that results in increased susceptibility of the host to secondary infection. Intriguingly, CD103 expression inversely and specifically correlates with SKI proto-oncogene (SKI) expression but not R-Smad2/3 activation. Ectopic expression of SKI restricts CD103 expression in CD8 T cells in vitro and in vivo to hamper viral clearance. Mechanistically, SKI is recruited to the Itgae loci to directly suppress CD103 transcription by regulating histone acetylation in a Smad4-dependent manner. Our study therefore reveals that resident CD103CD8 T cells dictate protective immunity during primary and secondary infection. Interfering with SKI function may amplify the resident CD103CD8 T cell response to promote protective immunity.
Topics: Animals; CD8-Positive T-Lymphocytes; DNA-Binding Proteins; Immunologic Memory; Mice; Proto-Oncogene Proteins; Proto-Oncogenes; Transforming Growth Factor beta; Virus Diseases
PubMed: 32612153
DOI: 10.1038/s41423-020-0495-7 -
Molecular Therapy : the Journal of the... Jun 2006The experience of the past 3 years, since the first case of leukemia was reported in a child cured of X-linked severe combined immunodeficiency (X-SCID) by gene therapy,... (Review)
Review
The experience of the past 3 years, since the first case of leukemia was reported in a child cured of X-linked severe combined immunodeficiency (X-SCID) by gene therapy, indicates that the potential genotoxicity of retroviral integration in hematopoietic cells will remain a consideration in evaluating the relative risks versus benefits of gene therapy for specific blood disorders. Although many unique variables may have contributed to an increased risk in X-SCID patients, clonal dominance or frank neoplasia in animal models, clonal dominance in humans with chronic granulomatous disease, and the ability of retroviral integration to immortalize normal bone marrow cells or convert factor-dependent cells to factor independence suggest that transduction of cells with an integrating retrovirus has the potential for altering their subsequent biologic behavior. The selective pressure imposed during in vitro culture or after engraftment may uncover a growth or survival advantage for cells in which an integration event has affected gene expression. Such cells then carry the risk that subsequent mutations may lead to neoplastic evolution of individual clones. Balancing that risk is that the vast majority of integration events seem to be neutral and that optimizing vector design may diminish the probability of altering gene expression by an integrated vector genome. Several cell culture systems and animal models designed to empirically evaluate the safety of vector systems are being developed and should provide useful data for weighing the relative risks and benefits for specific diseases and patient populations. Gene therapy interventions continue to have enormous potential for the treatment of disorders of the hematopoietic system. The future of such efforts seems bright as we continue to evolve and improve various strategies to make such interventions both effective and as safe as possible.
Topics: Adaptor Proteins, Signal Transducing; Animals; Cells, Cultured; DNA-Binding Proteins; Disease Models, Animal; Enhancer Elements, Genetic; Genetic Therapy; Genetic Vectors; Hematopoietic System; Humans; LIM Domain Proteins; Leukemia; Lymphoproliferative Disorders; Metalloproteins; Mice; Mutagenicity Tests; Promoter Regions, Genetic; Proto-Oncogene Proteins; Proto-Oncogenes; Retroviridae; Severe Combined Immunodeficiency; Virus Integration
PubMed: 16624621
DOI: 10.1016/j.ymthe.2006.03.001 -
Environmental Health Perspectives Nov 1987Proto-oncogenes are cellular genes that are expressed during normal growth and developmental processes. Altered versions of normal proto-oncogenes have been implicated... (Review)
Review
Proto-oncogenes are cellular genes that are expressed during normal growth and developmental processes. Altered versions of normal proto-oncogenes have been implicated in the development of human neoplasia. In this report, we show the detection of activated proto-oncogenes in various spontaneous and chemically induced rodent tumors. The majority of activated proto-oncogenes found in these tumors are members of the ras gene family and have been activated by a point mutation. Characterization of the activating mutation may be useful in determining whether this proto-oncogene was activated by direct interaction of the chemical with the DNA. Comparison of activating lesions in spontaneous versus chemically induced tumors should be helpful in determining whether the chemical acts via a genotoxic or a nongenotoxic mechanism. All of this information may be helpful in the assessment of potential carcinogenic hazards of human exposure to chemicals.
Topics: Animals; Carcinogens; Cell Transformation, Neoplastic; Gene Amplification; Genes, ras; Humans; Neoplasms, Experimental; Oncogenes; Proto-Oncogene Mas; Proto-Oncogenes
PubMed: 3319570
DOI: 10.1289/ehp.877581 -
Oncotarget Jul 2011Recent studies have demonstrated the significance of the leukemia oncogene Evi1 as the regulator of hematopoietic stem cells and marker of poor clinical outcomes in... (Review)
Review
Recent studies have demonstrated the significance of the leukemia oncogene Evi1 as the regulator of hematopoietic stem cells and marker of poor clinical outcomes in myeloid malignancies. Evi1-mediated leukemogenic activities include a wide array of functions such as the induction of epigenetic modifications, transcriptional control, and regulation of signaling pathways. We have recently succeeded in comprehensively elucidating the oncogenic function of Evi1 in a model of the polycomb-Evi1-PTEN/AKT/mTOR axis. These results may provide us with novel therapeutic approaches to conquer the poor prognosis associated with Evi1-activated leukemia or other solid tumors with high Evi1 expression. Here, we review the current understanding of the role of Evi1 in controlling the development of leukemia and highlight potential modalities for targeting factors involved in Evi1-regulated signaling.
Topics: Animals; DNA-Binding Proteins; Epigenesis, Genetic; Hematopoietic Stem Cells; Humans; Leukemia, Myeloid; MDS1 and EVI1 Complex Locus Protein; Mice; Molecular Targeted Therapy; Phosphatidylinositol 3-Kinases; Prognosis; Proto-Oncogene Proteins c-akt; Proto-Oncogenes; Signal Transduction; TOR Serine-Threonine Kinases; Transcription Factors; Transcription, Genetic; Treatment Outcome
PubMed: 21795762
DOI: 10.18632/oncotarget.304 -
Environmental Health Perspectives Jun 1991DNA transfection experiments using the NIH 3T3 mouse fibroblast cell line have demonstrated that chemically induced tumors and chemically transformed cell lines... (Review)
Review
DNA transfection experiments using the NIH 3T3 mouse fibroblast cell line have demonstrated that chemically induced tumors and chemically transformed cell lines frequently contain dominant transforming genes. Although many of the genes detected using the NIH 3T3 transfection-transformation assay are activated versions of H-ras, K-ras, and N-ras, in some experimental systems activated forms of genes such as met and neu that are unrelated to ras have been observed. The activated met gene was originally detected in a human cell line that had been transformed by exposure to N-methyl-N'-nitro-N-nitrosoguanidine. Subsequent studies demonstrated that the met proto-oncogene encodes a novel growth factor receptor and that gene activation involves the production of a chimeric gene in which the regions of met encoding the extracellular and transmembrane domains of the receptor are replaced by the 5'-region of an unrelated gene called trp. The activated neu gene was detected in tumors of the nervous system that arose in mice following transplacental exposure to N-ethyl-N-nitrosourea. The neu gene also encodes a novel growth factor receptor but, in contrast to met, its activation involves a single T:A----A:T point mutation in the region of the neu gene encoding the receptor transmembrane domain. The presence of genetic alterations in chemically induced malignancies has also been assessed in cytogenetic studies and by Southern analysis of DNA from neoplastic cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: 3T3 Cells; Amino Acid Sequence; Animals; Carcinogens; Cell Line, Transformed; Cell Transformation, Neoplastic; Cocarcinogenesis; DNA; DNA, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Gene Rearrangement; Genes, Immunoglobulin; Genes, ras; Humans; Mice; Mice, Inbred Strains; Molecular Sequence Data; Mutation; Neoplasms; Neoplasms, Experimental; Oncogene Proteins, Fusion; Plasmacytoma; Pregnancy; Protein-Tyrosine Kinases; Proto-Oncogene Mas; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-met; Proto-Oncogene Proteins c-mos; Proto-Oncogenes; Rats; Receptor, ErbB-2; Receptors, Cell Surface; Transcriptional Activation; Transfection
PubMed: 1685444
DOI: 10.1289/ehp.919333 -
Zhong Nan Da Xue Xue Bao. Yi Xue Ban =... Jan 2024Malignant tumors continue to pose a significant threat to human life and safety and their development is primarily due to the activation of proto-oncogenes and the...
Malignant tumors continue to pose a significant threat to human life and safety and their development is primarily due to the activation of proto-oncogenes and the inactivation of suppressor genes. Among these, the activation of proto-oncogenes possesses greater potential to drive the malignant transformation of cells. Targeting oncogenes involved in the malignant transformation of tumor cells has provided a novel approach for the development of current antitumor drugs. Several preclinical and clinical studies have revealed that the development pathway of B cells, and the malignant transformation of mature B cells into tumors have been regulated by oncogenes and their metabolites. Therefore, summarizing the key oncogenes involved in the process of malignant transformation of mature B cells and elucidating the mechanisms of action in tumor development hold significant importance for the clinical treatment of malignant tumors.
Topics: Humans; B-Lymphocytes; Proto-Oncogenes; Neoplasms
PubMed: 38615172
DOI: 10.11817/j.issn.1672-7347.2024.230304 -
Cancer Control : Journal of the Moffitt... 2000Medullary thyroid cancer (MTC) is a distinct C-cell tumor of the thyroid. We review the oncogenesis and management of both sporadic tumors and those tumors arising as... (Review)
Review
Medullary thyroid cancer (MTC) is a distinct C-cell tumor of the thyroid. We review the oncogenesis and management of both sporadic tumors and those tumors arising as part of specific inherited syndromes. The RET proto-oncogene plays a role in the development of inherited forms of MTC and has become important in the clinical management of patients and their families. The recognition of the high rate of regional nodal involvement has led to lymphadenectomy being strongly considered for patients undergoing thyroidectomy for MTC.
Topics: Carcinoma, Medullary; Cell Transformation, Neoplastic; Humans; Lymph Node Excision; Lymphatic Metastasis; Prognosis; Proto-Oncogene Mas; Proto-Oncogenes; Thyroid Neoplasms; Thyroidectomy
PubMed: 10832112
DOI: 10.1177/107327480000700305 -
Molecular Therapy : the Journal of the... Jan 2004Recently, unusual forms of leukemias have developed as complications following retroviral transfer of potentially therapeutic genes into hematopoietic cells. A crucial... (Review)
Review
Recently, unusual forms of leukemias have developed as complications following retroviral transfer of potentially therapeutic genes into hematopoietic cells. A crucial component in the pathogenesis of these complications was the upregulation of a cellular proto-oncogene by random insertion of the retroviral gene transfer vector. These findings have great implications for the genetic manipulation of somatic stem cells in medicine. This review discusses the extent to which the random oncogene activation may have required disease-specific stimuli of the transgene and the hematopoietic milieu to become leukemogenic. Based on these considerations, we propose approaches to risk prediction and prevention.
Topics: Adaptor Proteins, Signal Transducing; Animals; DNA-Binding Proteins; Genetic Therapy; Genetic Vectors; Hematopoietic Stem Cell Transplantation; Humans; LIM Domain Proteins; Leukemia, T-Cell; Leukemia-Lymphoma, Adult T-Cell; Metalloproteins; Mice; Mutagenesis, Insertional; Proto-Oncogene Mas; Proto-Oncogene Proteins; Proto-Oncogenes; Retroviridae; Risk Assessment; Up-Regulation
PubMed: 14741772
DOI: 10.1016/j.ymthe.2003.10.013 -
Seminars in Immunology Oct 1993Protooncogenes are the normal forms of cellular genes that when altered in their expression or coding sequences can contribute to neoplastic transformation. As these... (Review)
Review
Protooncogenes are the normal forms of cellular genes that when altered in their expression or coding sequences can contribute to neoplastic transformation. As these genes often are important for normal cellular growth control, we explored the possibility that protein kinases encoded by particular protooncogenes could participate in signal transduction pathways regulated by the T cell growth factor, interleukin-2 (IL-2). In this review we summarize our findings to date regarding Raf-1, a serine/threonine-specific kinase that becomes phosphorylated on tyrosine residues and enzymatically activated in response to IL-2 stimulation. In addition, we describe our investigations of Lck and Lyn, two closely related protein tyrosine kinases of the src gene family that physically associate with the IL-2 receptor complex and whose activities are regulated by IL-2 in at least some T cells and B cells, respectively.
Topics: Animals; Gene Transfer Techniques; Humans; Interleukin-2; Lymphocyte Specific Protein Tyrosine Kinase p56(lck); Phosphorylation; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-raf; Proto-Oncogenes; Receptors, Interleukin-2; Signal Transduction
PubMed: 8260649
DOI: 10.1006/smim.1993.1039 -
A novel interaction between the proto-oncogene Evi1 and histone methyltransferases, SUV39H1 and G9a.FEBS Letters Aug 2008The transcription factor ecotropic viral integration site 1 (Evi1) is associated with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) in patients due to...
The transcription factor ecotropic viral integration site 1 (Evi1) is associated with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) in patients due to chromosomal aberration of chromosome 3. Here we show that Evi1 interacts with the histone methyltransferase SUV39H1. The interaction requires the N-terminal part of Evi1 and the H3-specific histone methyltransferase domain, SET, of SUV39H1 without Evi1 having an inhibitory effect on SUV39H1 methyltransferase activity. Presence of SUV39H1 enhances Evi1 transcriptional repression in a dose dependent manner. In addition, Evi1 also interacts with another histone methyltransferase, G9a, but not with SET9. Our data establish an epigenetic role of Evi1 in cell transformation by recruiting higher order chromatin remodeling complexes.
Topics: Amino Acid Sequence; Animals; Cell Line; DNA-Binding Proteins; Gene Expression Regulation; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Humans; MDS1 and EVI1 Complex Locus Protein; Methyltransferases; Molecular Sequence Data; Protein Methyltransferases; Protein Structure, Tertiary; Proto-Oncogene Mas; Proto-Oncogenes; Repressor Proteins; Transcription Factors; Transcription, Genetic; Zinc Fingers
PubMed: 18619962
DOI: 10.1016/j.febslet.2008.06.056