Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In rheumatoid arthritis (RA), breakdown of self-tolerance and onset of clinical disease are separated in time and space, supporting a multi-hit model in which emergence of autoreactive T cells is a pinnacle pathogenic event. Determining factors in T cell differentiation and survival include antigen recognition, but also the metabolic machinery that provides energy and biosynthetic molecules for cell building. Studies in patients with RA have yielded a disease-specific metabolic signature, which enables naive CD4 T cells to differentiate into pro-inflammatory helper T cells that are prone to invade into tissue and elicit inflammation through immunogenic cell death. A typifying property of RA CD4 T cells is the shunting of glucose away from glycolytic breakdown and mitochondrial processing toward the pentose phosphate pathway, favoring anabolic over catabolic reactions. Key defects have been localized to the mitochondria and the lysosome; including instability of mitochondrial DNA due to the lack of the DNA repair nuclease MRE11A and inefficient lysosomal tethering of AMPK due to deficiency of N-myristoyltransferase 1 (NMT1). The molecular taxonomy of the metabolically reprogrammed RA T cells includes glycolytic enzymes (glucose-6-phosphate dehydrogenase, phosphofructokinase), DNA repair molecules (MRE11A, ATM), regulators of protein trafficking (NMT1), and the membrane adapter protein TSK5. As the mechanisms determining abnormal T cell behavior in RA are unraveled, opportunities will emerge to interject autoimmune T cells by targeting their metabolic checkpoints.
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PMID:Immunometabolism in the development of rheumatoid arthritis. 3198 19

CD4 T-cell depletion is a hallmark of HIV/AIDS, but the underlying mechanism is still unclear. We have recently shown that ataxia-telangiectasia-mutated (ATM) deficiency in CD4 T cells accelerates DNA damage, telomere erosion, and cell apoptosis in HIV-infected individuals on antiretroviral therapy (ART). Whether these alterations in ART-treated HIV subjects occur in vitro in HIV-infected CD4 T cells remains unknown. In this study, we employed a cellular model of HIV infection to characterize the mechanisms underlying CD4 T-cell destruction by analyzing the telomeric DNA damage response (DDR) and cellular apoptosis in highly permissive SupT1 cells, followed by the validation of our observations in primary CD4 T cells with active or drug-suppressed HIV infection. Specifically, we established an in vitro HIV T-cell culture system with viral replication and raltegravir (RAL; an integrase inhibitor) suppression, mimicking active and ART-controlled HIV infection in vivo We demonstrated that HIV-induced, telomeric DDR plays a pivotal role in triggering telomere erosion, premature T-cell aging, and CD4 T-cell apoptosis or depletion via dysregulation of the PI3K/ATM pathways. This in vitro model provides a new tool to investigate HIV pathogenesis, and our results shed new light on the molecular mechanisms of telomeric DDR and CD4 T-cell homeostasis during HIV infection.IMPORTANCE The hallmark of HIV infection is a gradual depletion of CD4 T cells, with a progressive decline of host immunity. How CD4 T cells are depleted in individuals with active and virus-suppressed HIV infection remains unclear. In this study, we employed a cellular model of HIV infection to characterize the mechanisms underlying CD4 T-cell destruction by analyzing the chromosome end (telomere) DNA damage response (DDR) and cellular apoptosis in a T-cell line (highly permissive SupT1 cells), as well as in primary CD4 T cells with active or drug-suppressed HIV infection. We demonstrated that HIV-induced telomeric DDR plays a critical role in inducing telomere loss, premature cell aging, and CD4 T-cell apoptosis or depletion via dysregulation of the PI3K/ATM pathways. This study sheds new light on the molecular mechanisms of telomeric DDR and its role in CD4 T-cell homeostasis during HIV infection.
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PMID:Telomere and ATM Dynamics in CD4 T-Cell Depletion in Active and Virus-Suppressed HIV Infections. 3290 75

Tumor-infiltrating T-lymphocytes are defined as T-lymphocytes that infiltrated into tumor tissues; however, their composition, clinical significance, and underlying mechanism in hepatocellular carcinoma (HCC) and adjacent non-tumor tissues are still not completely understood. Herein, we collected marker genes of T cell subpopulations from a previous study and estimated their relative infiltrating levels in HCC and adjacent non-tumor tissues. Specifically, the infiltrating levels of all the T cells were significantly reduced in HCC as compared with non-tumor tissues. Unsupervised clustering of the HCC samples by the T cell infiltrating levels revealed that the HCC samples could be clearly classified into two groups. The driver genes, including PTK2B, ATM, PIK3C2B, and KIT, and several CNAs were observed to be associated with reduced T cell infiltrating levels. Particularly, deletion of TP53 more frequently occurred in low T cell infiltration HCC samples and resulted in its downregulation and cell cycle progression, indicating that cell cycle progression was closely associated with reduced T cell infiltration. In contrast, for the samples with high infiltration T cells, its immune evasion might be regulated by the immune checkpoint regulators, such as PD-1/PD-L1 and CTLA4. Moreover, Olaparib, one of the PARP inhibitors, and immune checkpoint inhibitors might be therapeutic candidates for the samples from the two T cell infiltrating clusters. Clinically, the tumor-infiltrating levels of cytotoxic CD4 cell, Mucosal associated invariant T (MAIT) cell, and exhausted CD8+ T cell might be used as predictors for vascular invasion, recurrence, and overall survival. Collectively, we systematically evaluated the clinical significance and potential molecular mechanisms of tumor-infiltrating T cell subpopulations in hepatocellular carcinoma, which might broaden our insights into the immunological features of HCC and provide potential immunotherapeutic targets.
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PMID:Functional and Clinical Characterization of Tumor-Infiltrating T Cell Subpopulations in Hepatocellular Carcinoma. 3313 70

Non-small cell lung cancer (NSCLC) is the predominant subtype of lung cancers. KRAS mutation is the second most prevalent mutation in NSCLC. KRAS mutant cancer cells suppress the anti-tumor T cell response. However, the underlying mechanism is still unknown. Here, we analyzed the differential expression of acetyl-CoA acyltransferase 1 (ACAA1) in various types of cancers using the TIMER database and validated the results in the NSCLC cell line H1944. We silenced oncogenic KRAS by siRNA targeting KRASG13D, and employed an MAPK signaling pathway inhibitor to clarify the possible regulatory pathway. Moreover, we analyzed the correlation of ACAA1 expression level with B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells. Correlations between expression of ACAA1 and several biomarkers of mutation burden were also tested. Finally, we evaluated the prognostic value of ACAA1 in a wide range of cancers using the Kaplan-Meier Plotter Database. We found lower expression of ACAA1 in tumor tissue than in adjacent normal tissue in various cancers. This result was confirmed using a GEO dataset. Knock-down of mutant KRAS resulted in increased ACAA1 mRNA level in H1944 cells. ACAA1 mRNA level was significantly upregulated in H1944 after treatment with MAPK pathway inhibitor sorafenib, indicating that oncogenic KRAS may downregulate ACAA1 through MAPK signaling. ACAA1 was negatively correlated with biomarkers of tumor mutation burden, including BRCA1, ATM, ATR, CDK1, PMS2, MSH2, and MDH6. Conversely, ACAA1 expression was positively correlated with infiltrating CD4+ cells and with Th1, Th2, Treg cells in the lung tumor microenvironment. Finally, we showed that ACAA1 is a predictive factor for survival in several cancer types. In summary, decreased ACAA1 expression is correlated with poor prognosis and decreases immune infiltration of CD4+ T cells in LUAD and LUSC. ACAA1 also predicts T cell exhaustion in LUSC. The mechanism underlying KRAS/ACAA1 axis-mediated regulation of immune cell infiltration requires further investigation.
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PMID:ACAA1 Is a Predictive Factor of Survival and Is Correlated With T Cell Infiltration in Non-Small Cell Lung Cancer. 3319 42


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