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PubMed2007

The Bloom's syndrome helicase is critical for development and function of the alphabeta T-cell lineage.

Bloom's syndrome is a genetic disorder characterized by increased incidence of cancer and an immunodeficiency of unknown origin. The BLM gene mutated in Bloom's syndrome encodes a DNA helicase involved in the maintenance of genomic integrity. To explore the role of BLM in the immune system, we ablated murine Blm in the T-cell lineage. In the absence of Blm, thymocytes were severely reduced in numbers and displayed a developmental block at the beta-selection checkpoint that was partially p53 dependent. Blm-deficient thymocytes rearranged their T-cell receptor (TCR) beta genes normally yet failed to survive and proliferate in response to pre-TCR signaling. Furthermore, peripheral T cells were reduced in numbers, manifested defective homeostatic and TCR-induced proliferation, and produced extensive chromosomal damage. Finally, CD4(+) and CD8(+) T-cell responses were impaired upon antigen challenge. Thus, by ensuring genomic stability, Blm serves a vital role for development, maintenance, and function of T lymphocytes, suggesting a basis for the immune deficiency in Bloom's syndrome.

Adenosine Triphosphatases↗
PubMed2026

Next-generation macrophage engineering in cancer therapy: From TAM reprogramming to CAR-macrophages.

Macrophages are central regulators of the tumor microenvironment (TME), shaping immune suppression, angiogenesis, metabolism, and therapeutic resistance in solid cancers. While early strategies sought to deplete tumor-associated macrophages (TAMs) or block monocyte recruitment, limited efficacy and compensatory mechanisms revealed the need for functional reprogramming rather than elimination. Recent advances in viral vectors, CRISPR-Cas genome editing, and RNA-based delivery platforms have enabled precise genetic modification of macrophages, giving rise to chimeric antigen receptor macrophages (CAR-Ms) and related engineered products. Beyond antigen targeting, effective macrophage engineering requires stabilization of pro-inflammatory identity, resistance to tumor-induced repolarization, metabolic reinforcement, and integration of checkpoint modulation pathways. This review synthesizes current strategies across DNA, mRNA, and siRNA-based platforms, highlighting convergent design principles that connect TAM reprogramming with CAR-M development. We discuss reshaping phagocytosis checkpoints, metabolic and transcriptional stabilization, cytokine augmentation, and synthetic receptor architecture, emphasizing combinatorial and context-aware engineering, while proposing new candidate gene targets. Engineered macrophages are thus evolving from simple effector cells into programmable immune coordinators capable of converting immunologically "cold" tumors into inflamed, therapy-responsive niches.

CAR-M↗
PubMed1997

In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death.

Gene targeting experiments have demonstrated that the expression of immunoglobulin heavy chain in the pre-B cell receptor (pBCR) and of heavy and light chains in the B cell antigen receptor (BCR) marks checkpoints in early B cell development that the cells have to pass to survive. To investigate whether the persistence of mature B cells in the peripheral immune system also depends on BCR expression, we have generated a transgenic mouse in which the BCR can be inducibly ablated through V region gene deletion. Ablation leads to rapid death of mature B lymphocytes, which is preceded by down-regulation of MHC antigens and up-regulation of CD95 (Fas) and can be delayed by constitutive bcl-2 expression.

Animals↗
PubMed2005

Balancing diversity and tolerance: lessons from patients with systemic lupus erythematosus.

The autoimmune disease systemic lupus erythematosus (SLE) is caused by a failure of B cell tolerance. Recent studies in mouse models of SLE have identified several distinct tolerance checkpoints that must each function appropriately to protect against disease. However, studies of B cell repertoire selection in humans are essential to understand which checkpoints are defective in human autoimmune diseases.

Animals↗
PubMed2004

[The emergent role of p38 MAPKs in the regulation of cell cycle].

The p38 MAPKs are members of the MAPK family. Its pathway has been traditionally associated with the stress and immune response. More recently, it has been reported that the p38 MAPKs pathway can also regulate apoptosis and some differentiation process. It can regulate cellular growth and cell cycle checkpoints in different ways depending on the cell type and the stimulus.

Animals↗
PubMed1996

Proliferation markers.

Types of growth include embryonic, fetal, neonatal, juvenile and mature. Until full differentiation is achieved, cells grow through proliferation from progenitor cells. At maturity, the cellular genome is fixed with committed patterns of cell cycle duration and adaptation, ranging from static to renewing type 3. The static cell type cannot proliferate and adapts through hypertrophy. The renewing type continuously proliferates even without stimulus. In all cell types the processes of differentiation and proliferation are mutually exclusive. Cellular kinetics involve (a) the duration of the cell cycle, (b) the birth rate of cells, and (c) the growth rate fractions. The duration of the cell cycle is 2-4 days. All growth factors (GF) exert their influence during G1 phase. Release a GF by one cell type can influence the proliferation of another (= paracrine stimulation). At the end of G1 is the point of highest sensitivity to toxicity. Tumor suppressor genes act here through tyrosine phosphorylation. During S, the cell replicates its chromosomes. During G2 the immune surveillance and DNA damage repair mechanisms operate. Injured cells stay here longer enabling repair of their damaged DNA. Cell division involves both nuclear (mitosis) and cytoplasmic (cytokinesis) phases giving rise to 2 new cells. The cell cycle has 2 checkpoints. The first involves the G1-S transition and the second the G2-M transition. The types of cell cycle inhibition include (a) cycle- and phase-specific inhibition; (b) cycle-and nonphase-specific inhibition; (c) noncycle-and nonphase-specific inhibition, and finally (d) noncycle, nonphase-, and nonorgan-specific inhibition. Proliferation is a circadian process and it is stimulated by a variety of stimuli which include (1) interference with hormonal feedback pathways; (2) inhibition of the tissue trophic activity; (3) sustained presence of antigenic substances; (4) tissue ischemia; (5) changes of conditions luminally or on surfaces of tissues; (6) sustained cytotoxicity; (7) cell death; and (8) surgical resection. Proliferation can be arrested through senescence, apoptosis, injury or even during the development of immune cells. In the past, tissue/cell kinetics have been studied by tritiated thymidine histoautoradiography. Recently, monoclonal antibodies to proliferation-associated antigens, have been successfully employed. These antigens are cycle-associated proteins and include (1) PCNA; (2) p53; (3) Ki67; (4) AGNOR; (5) Statin; and (6) BrdU. Practical examples are given comparing PCNA and BrdU markers from 3 tissues, i.e. liver, glandular stomach, and uterus, across 2 or 3 strains of rats. Mean values of labeling indices are cited. Within the PCNA marker, 2 different clones are compared from the glandular stomach of SD rats of 2 different ages. Gender and across species comparisons are also made. All these comparisons denote that in every study where markers are used (a) there is a need for a concurrent study control group of the same age; (b) there is a need for in-house control data for this particular organ by species, strain, gender and age; (c) there is ancillary assessment of the trophic status of the target tissue; (d) there is a need for at least 2 different time points during assessment; (e) there is a need for such proliferation data prior to commencing the 2 year rodent bioassay; and (f) that PCNA is the most reliable and versatile of all markers used, capable of rendering good results even from archival specimens.

Animals↗
PubMed2005

Defective B cell tolerance checkpoints in systemic lupus erythematosus.

A cardinal feature of systemic lupus erythematosus (SLE) is the development of autoantibodies. The first autoantibodies described in patients with SLE were those specific for nuclei and DNA, but subsequent work has shown that individuals with this disease produce a panoply of different autoantibodies. Thus, one of the constant features of SLE is a profound breakdown in tolerance in the antibody system. The appearance of self-reactive antibodies in SLE precedes clinical disease, but where in the B cell pathway tolerance is first broken has not been defined. In healthy humans, autoantibodies are removed from the B cell repertoire in two discrete early checkpoints in B cell development. We found these checkpoints to be defective in three adolescent patients with SLE. 25-50% of the mature naive B cells in SLE patients produce self-reactive antibodies even before they participate in immune responses as compared with 5-20% in controls. We conclude that SLE is associated with abnormal early B cell tolerance.

Adolescent↗
PubMed2026

Multi-level Transcriptomic and Machine-learning Analyses Identify MZT1 as a Proliferation-associated Prognostic Marker in Lung Adenocarcinoma.

BACKGROUND/AIM: Lung adenocarcinoma (LUAD) exhibits substantial molecular heterogeneity and variable clinical outcomes, highlighting the need for biomarkers that reflect core tumor biological processes. Centrosome-associated proteins regulate mitotic fidelity and genome stability, yet their roles in LUAD remain incompletely defined. In this study, we systematically characterized mitotic spindle organizing protein 1 (MOZART1; MZT1) and related family members in LUAD. MATERIALS AND METHODS: We performed integrated analyses combining bulk transcriptomic datasets, survival modeling, gene set enrichment, immune deconvolution, machine-learning based prognostic modeling, and single-cell RNA sequencing. Expression patterns and clinical associations of MZT family genes were evaluated across pan-cancer and LUAD cohorts. RESULTS: MZT family genes were consistently upregulated in tumor tissues, with MZT1 showing the most robust expression pattern. Elevated MZT1 expression was significantly associated with reduced overall survival. Functional analyses revealed coordinated activation of proliferative and genome maintenance pathways, including G2/M checkpoint regulation, E2F and MYC signaling, and DNA repair. A multivariable analysis indicated that the prognostic association of MZT1 was reduced after adjusting for canonical proliferation markers, suggesting partial overlap with established proliferation signals. The LASSO-based Cox model demonstrated stable time-dependent predictive performance at 1-, 3-, and 5-year survival. Immune analyses indicated associations between MZT1 expression and tumor microenvironmental features. Single-cell analysis showed that MZT1 expression was predominantly enriched in malignant epithelial cells and associated with proliferative cellular states. Protein-level validation supported concordance with transcriptomic findings. CONCLUSION: MZT1 is a proliferation-associated marker that integrates clinical risk, transcriptional programs, cellular heterogeneity, and predictive modeling in LUAD, providing a potential framework for biomarker development and risk stratification.

Humans↗
PubMed1999

Absence of mutations in ATM, the gene responsible for ataxia telangiectasia in patients with cerebellar ataxia.

Ataxia-telangiectasia (AT) is an autosomal recessive multisystem disorder presenting in childhood with progressive cerebellar ataxia, oculocutaneous telangiectasia, immune deficiency, radiosensitivity, and cancer predisposition. The gene for AT, designated ATM (AT, mutated) encodes a protein with a carboxy-terminal phosphoinositide-3 kinase domain which is involved in cell cycle checkpoints and other responses to genotoxic stress. Most of the patients with the classical AT phenotype are homozygous or compound heterozygous for severe mutations causing truncation or destabilization of the ATM protein. Patients with a milder forms of disease, called AT variants, have been found to be either homozygous for milder mutations or compound heterozygotes for null alleles and mild mutations. In order to define the clinical phenotype of patients homozygous (or compound heterozygotes) for other, milder mutations, we decided to search for ATM mutations in patients with either sporadic or familial idiopathic ataxia. Thirty-four patients with idiopathic cerebellar ataxia, aged 3-77 years, were screened for mutations in the ATM coding region. There were 12 familial cases. None of the patients had abnormal immunoglobulin or alpha-fetoprotein levels, and none had mutations in the ATM coding region. In this heterogeneous group of patients with cerebellar ataxia we found no mutations in the ATM gene. We conclude that mutations in the ATM gene are probably not a common cause for cerebellar ataxia other than AT.

Adolescent↗
PubMed1999

Mechanisms of apoptosis avoidance in cancer.

Defects in the programmed cell death mechanisms can extend cell lifespan, contributing to neoplastic cell expansion independently of cell division. Deficiencies in apoptosis also contribute to carcinogenesis by creating a permissive environment for genetic instability and accumulation of gene mutations, permitting disobeyance of cell cycle checkpoints which would normally induce apoptosis, facilitating growth factor- and hormone-independent cell survival, supporting anchorage-independent survival during metastasis, reducing dependence on oxygen and nutrients, promoting resistance to immune-based destruction, and conferring resistance to cytotoxic anticancer drugs and radiation. Though much remains to be learned, identification of gene families that control the physiological cell death pathway has provided the basis for improved understanding of tumor biology. This review describes some of the recent progress made towards delineating the biochemistry and molecular biology of apoptosis control, and briefly summarizes the progress in identifying specific road blocks to apoptosis induction in cancers. These advances are beginning to reveal novel strategies for combating cancer by restoring apoptosis sensitivity.

Apoptosis↗
PubMed2000

Nuclear localization and cell cycle-specific expression of CtIP, a protein that associates with the BRCA1 tumor suppressor.

The BRCA1 tumor suppressor has been implicated in a diverse spectrum of cellular processes, including transcriptional regulation, DNA repair, and cell cycle checkpoint control. CtIP was recently identified as a protein that associates with BRCA1 and two other nuclear factors, CtBP1 and Rb1. To understand the functions of CtIP, we have evaluated its biological properties with respect to those of BRCA1. Our results show that CtIP, like its associated factors, is predominantly a nuclear protein. A subset of the endogenous pool of CtIP polypeptides exists in a protein complex that includes both BRCA1 and the BRCA1-associated RING domain protein (BARD1). At the protein level, CtIP expression varies with cell cycle progression in a pattern identical to that of BRCA1. Thus, the steady-state levels of CtIP polypeptides, which remain low in resting cells and G(1) cycling cells, increase dramatically as dividing cells traverse the G(1)/S boundary. In contrast to BRCA1, however, the G(1)/S induction of CtIP expression is mediated primarily by post-transcriptional mechanisms. Finally, the interaction between CtIP and BRCA1 is shown to be stable in the face of genotoxic stress elicited by treatment with UV light, adriamycin, or hydrogen peroxide. Together, these results indicate that CtIP can potentially modulate the functions ascribed to BRCA1 in transcriptional regulation, DNA repair, and/or cell cycle checkpoint control.

Animals↗
PubMed2006

The use of genomewide ENU mutagenesis screens to unravel complex mammalian traits: identifying genes that regulate organ-specific and systemic autoimmunity.

T-cell development is perhaps one of the best understood processes of mammalian cell differentiation, as many of the genes and pathways have been identified. By contrast, relatively little is known about the genes and pathways involved in immunological tolerance to self-antigens. Here, we describe the challenges associated with a genomewide screen designed at identifying new immune regulatory genes that uses a model of organ-specific autoimmunity leading to type 1 diabetes. The successful propagation and identification of the new gene variants will shed light on the various developmental checkpoints in lymphocyte development that are crucial for establishing tolerance to self-antigens.

Animals↗
PubMed2003

Lack of patent liver autoimmunity after breakage of tolerance in a mouse model.

We report in this work that a cellular and humoral autoreactive response can be induced against liver-specific self-determinants by repeated immunization with a chimeric tissue-specific self-antigen carrying a heterologous T(h) epitope. Epitope spreading rendering the autoimmune reaction independent of the presence of the cognate heterologous help is also demonstrated. Although neutrophil infiltrates can be demonstrated in the livers of treated mice, no clinical sign of organ damage is observed. These findings suggest that breakage of tolerance by this means leads the process only up to the next checkpoint in the progression of autoimmune disease and that further events are required to precipitate functional organ impairment.

Animals↗
PubMed2006

MDC1 maintains genomic stability by participating in the amplification of ATM-dependent DNA damage signals.

MDC1 functions in checkpoint activation and DNA repair following DNA damage. To address the physiological role of MDC1, we disrupted the MDC1 gene in mice. MDC1-/- mice recapitulated many phenotypes of H2AX-/- mice, including growth retardation, male infertility, immune defects, chromosome instability, DNA repair defects, and radiation sensitivity. At the molecular level, H2AX, MDC1, and ATM form a positive feedback loop, with MDC1 directly mediating the interaction between H2AX and ATM. MDC1 binds phosphorylated H2AX through its BRCT domain and ATM through its FHA domain. Through these interactions, MDC1 accumulates activated ATM flanking the sites of DNA damage, facilitating further ATM-dependent phosphorylation of H2AX and the amplification of DNA damage signals. In the absence of MDC1, many downstream ATM signaling events are defective. These results suggest that MDC1, as a signal amplifier of the ATM pathway, is vital in controlling proper DNA damage response and maintaining genomic stability.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Expression of the T cell antigen receptor zeta chain following activation is controlled at distinct checkpoints. Implications for cell surface receptor down-modulation and re-expression.

The multisubunit T cell antigen receptor (TCR) is involved in antigen recognition and signal transduction, leading to T cell activation and rapid down-modulation of the cell surface expressed TCRs. Although the levels of TCR cell surface expression are pivotal to the efficiency and duration of the immune response, the molecular mechanisms controlling TCR down-modulation and re-expression upon activation, remain obscure. Here, we provide a biochemical characterization of the regulatory mechanisms governing TCR expression following long-term T cell activation. We focused primarily on the TCR zeta chain, as this is considered the limiting factor in TCR complex formation and transport to the cell surface. We found that following TCR-mediated activation zeta mRNA is up-regulated by a transcription-dependent mechanism. Concomitantly, zeta protein levels are modified according to a biphasic pattern: rapid degradation coinciding with TCR cell surface down-regulation, followed by a rebound to normal levels 24 h subsequent to T cell activation. Even though there are adequate levels of all the TCR subunits within the cell following 24 h of activation, TCR cell surface expression remained very low, provided the activating antibody is continuously present. Correlative with the latter, we detected a previously undescribed monomeric form of the zeta chain. This form could be indicative of adverse endoplasmic reticulum conditions affecting correct protein folding, dimerization, and TCR assembly, all critical for optimal receptor surface re-expression. Cumulatively, our results indicate that the levels of TCR expression following activation, are tightly controlled at several checkpoints.

Animals↗
PubMed2006

B cell tolerance checkpoints that restrict pathways of antigen-driven differentiation.

Autoreactive B cells can be regulated by deletion, receptor editing, or anergy. Rheumatoid factor (RF)-expressing B lymphocytes in normal mice are not controlled by these mechanisms, but they do not secrete autoantibody and were presumed to ignore self-Ag. Surprisingly, we now find that these B cells are not quiescent, but instead are constitutively and specifically activated by self-Ag. In BALB/c mice, RF B cells form germinal centers (GCs) but few Ab-forming cells (AFCs). In contrast, autoimmune mice that express the autoantigen readily generate RF AFCs. Most interestingly, autoantigen-specific RF GCs in BALB/c mice appear defective. B cells in such GCs neither expand nor are selected as efficiently as equivalent cells in autoimmune mice. Thus, our data establish two novel checkpoints of autoreactive B cell regulation that are engaged only after initial autoreactive B cell activation: one that allows GCs but prevents AFC formation and one that impairs selection in the GC. Both of these checkpoints fail in autoimmunity.

Animals↗
PubMed2004

Direct regulation of CREB transcriptional activity by ATM in response to genotoxic stress.

Ataxia-telangiectasia (A-T) is a syndrome of cancer susceptibility, immune dysfunction, and neurodegeneration that is caused by mutations in the A-T-mutated (ATM) gene. ATM has been implicated as a critical regulator of cellular responses to DNA damage, including the activation of cell cycle checkpoints and induction of apoptosis. Although defective cell cycle-checkpoint regulation and associated genomic instability presumably contribute to cancer susceptibility in A-T, the mechanism of neurodegeneration in A-T is not well understood. In addition, although ATM is required for the induction of the p53 transcriptional program in response to DNA damage, the identities of the relevant transcription factors that mediate ATM-dependent changes in gene expression remain largely undetermined. In this article, we describe a signal transduction pathway linking ATM directly to the Ca(2+)/cAMP response element-binding protein, CREB, a transcription factor that regulates cell growth, homeostasis, and survival. ATM phosphorylated CREB in vitro and in vivo in response to ionizing radiation (IR) and H(2)O(2) on a stress-inducible domain. IR-induced phosphorylation of CREB correlated with a decrease in CREB transactivation potential and reduced interaction between CREB and its transcriptional coactivator, CREB-binding protein (CBP). A CREB mutant containing Ala substitutions at ATM phosphorylation sites displayed enhanced transactivation potential, resistance to inhibition by IR, and increased binding to CBP. We propose that ATM-mediated phosphorylation of CREB in response to DNA damage modulates CREB-dependent gene expression and that dysregulation of the ATM-CREB pathway may contribute to neurodegeneration in A-T.

Amino Acid Sequence↗
PubMed2003

Global gene profiling analysis of mouse uterus during the oestrous cycle.

Many genes related to the cyclic changes of the uterus during the oestrous cycle have been identified using a one-by-one approach. In the present study, cDNA microarray technology was applied to investigate the global profile of gene expression of mouse uterus at the oestrous and dioestrous stages. At a certain stage of the oestrous cycle, the uteri of mature CD-1 mice (n=10) were removed, pooled and snap-frozen in liquid nitrogen. Total RNA was extracted to synthesize cDNA probes for microarray assay. By screening 8192 mouse genes and expressed sequence tags (ESTs), 51 upregulated and 51 downregulated genes were identified in oestrous uterus, of which 62 are well characterized and 40 are ESTs. The known genes were assigned to various gene categories according to their main function. The microarray was performed three times with three independent sets of uterine tissue pools. The results of northern blot analysis for small proline-rich protein 2 (Sprr2), 17beta-hydroxysteroid dehydrogenase type 2 (17betaHSD-2), high mobility group 2 (Hmg2), mitotic checkpoint component 2 (Mad2) and an EST AW555366 mRNA were consistent with that of microarray analysis. In situ hybridization was performed to localize the transcript of the EST AW555366. Most of the upregulated genes encode secreted immune-related proteins, proteinases and their inhibitors, indicating their potential involvement in sperm viability as well as capacitation. The downregulated genes mainly encode cell cycle-related factors, implying the active proliferation of uterus at dioestrus.

Animals↗