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Results for “Resting Phase, Cell Cycle”

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PubMed2003

ANG II stimulates PKC-dependent ERK activation, DNA synthesis, and cell division in intestinal epithelial cells.

PKC, a major target for the tumor-promoting phorbol esters, has been implicated in the signal transduction pathways that mediate important functions in intestinal epithelial cells, including proliferation and carcinogenesis. With the use of IEC-18 cells arrested in G0/G1, addition of phorbol esters resulted in a modest increase in [3H]thymidine incorporation and a slight shift toward the S and G2/M phases of the cell cycle, whereas the combination of EGF and phorbol 12,13-dibutyrate (PDB) synergistically stimulated DNA synthesis. To investigate the effects of receptor-mediated PKC activation on mitogenesis, we demonstrated that ANG II induced ERK activation, a response completely blocked by pretreatment with mitogen/extracellular signal-regulated kinase inhibitors or specific PKC inhibitors. Furthermore, ANG II stimulated an over threefold increase in [3H]thymidine incorporation that was corroborated by flow cytometric analysis of the cell cycle to levels comparable to that achieved by the combination of EGF and PDB. Taken together, our results indicate that receptor-mediated PKC activation, as induced by ANG II, transduces mitogenic signals leading to DNA synthesis and cell proliferation in IEC-18 cells.

Angiotensin II↗

PubMed2003

SPRR1B overexpression enhances entry of cells into the G0 phase of the cell cycle.

Many studies have established the role of SPRR1B during squamous differentiation of skin and respiratory epithelial cells. However, its role in nonsquamous cells is largely unknown. We reported that expression of SPRR1B in Chinese hamster ovary (CHO) cells is increased as they enter the G0 phase of the cell cycle. The purpose of this study was to further investigate the SPRR1B expression pattern in nonsquamous tumors and to study its role in these cells. Expression of SPRR1B was detected by Northern blotting in a higher percentage of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced compared with beryllium metal-induced rat lung adenocarcinomas. In situ hybridizations confirmed that SPRR1B is expressed in individual or clusters of cells of nonsquamous cells from mouse, rat, and human adenocarcinomas. The same pattern of expression was observed in adenocarcinomas formed in nude mice from cell lines established from adenocarcinomas. SPRR1B expression was downregulated in the cell lines derived from adenocarcinoma when cells were enriched in G0 at low confluence. Tetraploidy was induced in CHO, mouse, and human tumor cell lines by stably overexpressing SPRR1B, whereas control cells showed no change in ploidy. Inducible expression of this protein for shorter periods using the ecdyson system did not affect growth rate or the ploidy of CHO cells but accelerated entry into G0/G1 compared with controls. These findings indicate that SPRR1B is likely coupled primarily to signals responsible for withdrawal from the proliferative state rather than the final stages of cellular quiescence and that its overexpression for prolonged periods may disrupt the normal progression of mitosis.

Adenocarcinoma↗

PubMed2006

Quiescence induced by iron challenge protects neuroblastoma cells from oxidative stress.

The brain uses massive amounts of oxygen, generating large quantities of reactive oxygen species (ROS). Because of its lipid composition, rich in unsaturated fatty acids, the brain is especially vulnerable to ROS. Furthermore, oxidative damage in the brain is often associated with iron, which has pro-oxidative properties. Iron-mediated oxidative damage in the brain is compounded by the fact that brain iron distribution is non-uniform, being particularly high in areas sensitive to neurodegeneration. This work was aimed to further our understanding of the cellular mechanisms by which SHSY5Y neuroblastoma cells adapt to, and survive increasing iron loads. Using an iron accumulation protocol that kills about 50% of the cell population, we found by cell sorting analysis that the SHSY5Y sub-population that survived the iron loading arrested in the G(0) phase of the cell cycle. These cells expressed neuronal markers, while their electrical properties remained largely unaltered. These results suggest that upon iron challenge, neuroblastoma cells respond by entering the G(0) phase, somehow rendering them resistant to oxidative stress. A similar physiological condition might be involved in neuronal survival in tissues known to accumulate iron with age, such as the hippocampus and the substantia nigra pars compacta.

Cell Line, Tumor↗

PubMed2000

The growth inhibitory effect of p21 adenovirus on human bladder cancer cells.

PURPOSE: To evaluate whether p21 (WAF-1/CIP1) should be considered a potential candidate for human bladder cancer gene therapy, we determined: (1) the basal level of p21 expression in bladder cancer cell lines, (2) the response of bladder cancer cells to increased p21 expression following p21 adenovirus infection, and (3) the mechanism of growth inhibition produced by p21 overexpression. MATERIALS AND METHODS: Five established human bladder cancer cell lines and one primary culture derived from an invasive transitional cell carcinoma were used in this study. To examine the effect of p21 protein on the growth of human bladder cancer cells, a recombinant adenovirus vector system containing p21 cDNA, under the control of cytomegalovirus promoter, was constructed. A control virus containing p21 in an antisense orientation was used to eliminate potential artifacts caused by viral toxicity. RESULTS: Human bladder cancer cell lines exhibit variable endogenous p21 levels which correlate with the in vitro growth status. Significant, but highly variable increases in the steady-state level of p21 were detected in p21 adenovirus infected cells. Human bladder cancer cell lines responded heterogeneously to p21 adenovirus infection. Growth of the WH cell line was substantially inhibited in a dose and time-course dependent fashion. The mechanism of p21 growth inhibition was found to be due to G0/G1 arrest and not the induction of apoptosis. In contrast, p21 adenovirus failed to inhibit the growth of T24 bladder cancer cells because T24 cells were resistant to viral infection. The 253J bladder cancer cells exhibited marked sensitivity to adenovirus; substantial growth inhibition was seen with both sense and antisense p21 very early in the time course of infection. CONCLUSIONS: We found significant variation in the basal level of p21 protein expression in several human bladder cancer cell lines. Increased p21 expression as a result of adenoviral infection may be a potent growth suppressor in some human bladder cancer because it elicits cell cycle arrest in G0/G1 stage, but not the induction of apoptosis. Bladder cancer cells exhibit a wide spectrum of sensitivity to adenoviral infection that may be caused by the presence of viral receptor heterogeneity. This wide spectrum of sensitivity has significant basic scientific and clinical implications and warrants further study.

Adenoviridae↗

PubMed2004

The induction of prostaglandin E2 production, interleukin-6 production, cell cycle arrest, and cytotoxicity in primary oral keratinocytes and KB cancer cells by areca nut ingredients is differentially regulated by MEK/ERK activation.

There are about 200-600 million betel quid (BQ) chewers in the world. BQ chewing is one of the major risk factor of hepatocarcinoma, oropharyngeal, and esophagus cancers in Taiwan, India, and Southeast Asian countries. Thus, the precise molecular mechanisms deserve investigation. We used cultured primary keratinocytes and KB cells, RT-PCR, flow cytometry, Western blotting, and ELISA to evaluate whether alterations in early gene expression is crucial in the carcinogenic processes of BQ. We observed the induction of c-Fos mRNA expression in human gingival keratinocyte (GK) and KB carcinoma cells by areca nut (AN) extract and arecoline. A maximal increment in c-fos gene expression was shown at about 30 min after challenge. AN extract (100-800 microg/ml) and arecoline (0.1-0.8 mM) also stimulated ERK1/ERK2 phosphorylation with a maximal stimulation at 5-10 min of exposure. Pretreatment by U0126 (30 microM), a MEK inhibitor, markedly inhibited the c-Fos, cyclooxygenase-2 (COX-2), and IL-6 mRNA expression of the KB epithelial cells. In addition, U0126 and PD98059 (50 microM) also decreased AN extract- and arecoline-associated PGE2 and IL-6 production in GK and KB cells. However, U0126 by itself arrested the cells in G0/G1 phase, but was not able to prevent AN- and arecoline-induced cell death or apoptosis. In contrast, U0126 enhanced the AN-induced apoptosis of KB cells. AN ingredients thus play a significant role in the pathogenesis of oropharyngeal cancer by activation of MEK1/ERK/c-Fos pathway, which promotes keratinocyte inflammation, cell survival, and affects cell cycle progression.

Apoptosis↗

PubMed2006

Identification of a terphenyl derivative that blocks the cell cycle in the G0-G1 phase and induces differentiation in leukemia cells.

To further explore the SAR of resveratrol-related trans-stilbene derivatives, here we describe the synthesis of (a) a series of 3,5-dimethoxy analogues in which a variety of substituents were introduced at positions 2', 3', 4', and 5' of the stilbene scaffold and (b) a second group of derivatives (2-phenylnaphthalenes and terphenyls) that incorporate a phenyl ring as a bioisosteric replacement of the stilbene alkenyl bridge. We thoroughly characterized all of the new compounds with respect to their apoptosis-inducing activity and their effects on the cell cycle. One of the new derivatives, 13g, behaved differently from the others, as it was able to block the cell cycle in the G(0)-G(1) phase and also to induce differentiation in acute myelogenous leukemia HL60 cells. Compared to resveratrol, the synthetic terphenyl 13g showed a more potent apoptotic and differentiating activity. Moreover, it was active on both multidrug resistance and Bcr-Abl-expressing cells that were resistant to resveratrol.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

Modulation of endothelial cell growth arrest and apoptosis by vascular endothelial growth inhibitor.

Vascular endothelial growth inhibitor (VEGI), a new member of the tumor necrosis factor family, is an endothelial cell-specific gene and a potent inhibitor of endothelial cell proliferation, angiogenesis, and tumor growth. We report here that VEGI mediates the following two activities in endothelial cells: early G(1) arrest in G(0)/G(1) cells responding to growth stimuli, and programmed death in proliferating cells. G(0)/G(1)-synchronized bovine aortic endothelial cells were treated with VEGI before and after the onset of the growth cycle. When the cells were stimulated with growth conditions but treated simultaneously with VEGI, a reversible, early-G(1) growth arrest occurred, evidenced by the lack of late G(1) markers such as hyperphosphorylation of the retinoblastoma gene product and upregulation of the c-myc gene. Additionally, VEGI treatment led to inhibition of the activities of cyclin-dependent kinases CDK2, CDK4, and CDK6. In contrast, VEGI treatment of cells that had entered the growth cycle resulted in apoptotic cell death, as evidenced by terminal deoxytransferase labeling of fragmented DNA, caspase 3 activation, and annexin V staining, all of which were lacking in nonproliferating cells treated with VEGI. Additionally, stress-signaling proteins p38 and JNK were not as fully activated by VEGI in quiescent as compared with proliferating populations. These findings suggest a dual role for VEGI, the maintenance of growth arrest and induction of apoptosis, in the modulation of the endothelial cell cycle.

Animals↗

PubMed1998

CA 125 is dominantly expressed by arrest of G0/G1 phase in uterine cervical adenocarcinoma cell line.

Our purpose is to evaluate at which phase of the cell cycle CA 125 is dominantly expressed in a uterine cervical adenocarcinoma cell line (CAC-1). By a flow cytometric analysis of CA 125 expression, approximately 50% of the cells treated with interferon-gamma (IFN) were positive after 24 h. In cell cycle, the G0/G1 arrest was observed in cells treated with IFN after 24 h. The pattern for the transition of the relative rate of CA 125 expression was similar to that of the population of G0/G1. Furthermore, in the G0/G1 phase, the positive rate of CA 125 expression in cells treated with IFN was 80% of the expression in all cells after 24 h. Additionally, flow cytometry with Ki-67 demonstrated that G1 arrest occurred at 24 h, and then G0 arrest was induced by IFN after 48 h of incubation. The increased expression of CA 125 appeared mainly in the G1 phase rather than in G0.

Adenocarcinoma↗

PubMed2003

Redox factor-1 contributes to the regulation of progression from G0/G1 to S by PDGF in vascular smooth muscle cells.

Redox factor-1 (Ref-1/APE), a multifunctional DNA base excision repair and redox regulation enzyme, plays an important role in oxidative signaling, transcription factor regulation, and cell cycle control. We hypothesized that Ref-1 plays a regulatory role in smooth muscle cell (SMC) proliferation induced by PDGF. Ref-1 antisense oligodeoxynucleotides (AODN), which diminished the level of Ref-1 protein in SMCs by approximately 50%, inhibited PDGF-BB (composed of the homodimer of B-polypeptide chain)-induced [3H]thymidine incorporation compared with control oligodeoxynucleotides. Ref-1 AODN inhibited PDGF-BB-induced S phase entry by approximately 63%, which was overcome by overexpression of Ref-1 by adenoviral-mediated gene transfer. Overexpression of Ref-1 alone without PDGF enhanced SMC entry into the S phase. Furthermore, decreasing Ref-1 protein by treatment of SMCs with Ref-1 AODN, or by immunodepletion of Ref-1 from nuclear extracts, inhibited PDGF-BB-induced activator protein-1 (AP-1) DNA binding activity. Chemical reduction restored the AP-1 DNA binding in Ref-1-depleted nuclear extracts. These results suggest that Ref-1 contributes to the regulation of PDGF-BB-stimulated cell cycle progression from G0/G1 to S in SMCs, with one of the possible steps being redox-regulation of AP-1 by Ref-1 protein.

Angiogenesis Inducing Agents↗

PubMed2004

Effect of glucose stress conditions in BL6T murine melanoma cells.

Elevated expression of stress proteins can be a characteristic of human cancer and may be involved in the development of resistance to some types of chemotherapeutic agent. In this paper, the effect of physiological stress conditions, such as glucose deprivation, was investigated in overexpressing nPKCdelta murine melanoma BL6 (BL6T) cells. Glucose stress conditions decreased the proliferative capacity, increasing the percentage of BL6T cells in the G0/G1 phase of the cell cycle. Furthermore, under such conditions, nPKCdelta, whose subcellular localization is cell cycle dependent, showed a cytoplasmic and perinuclear localization by immunohistochemistry, this being typical for cells in G0/G1 phase. Moreover, these cells expressed GRP-78, a known stress protein. On the other hand, glucose depletion enhanced intracellular melanin as well as tyrosinase activity and expression. In summary, these data demonstrate that stress conditions can modify the biological characteristics of BL6T cells, and therefore can select a quiescent cellular population.

Animals↗

PubMedDate not supplied

Ethanol induces transient arrest of cell division (G2 + M block) followed by G0/G1 block: dose effects of short- and longer-term ethanol exposure on cell cycle and cell functions.

To study the cytophysiological effects of ethanol systematically, L929 cells, a fibroblastic cell line derived from mouse connective tissue, were exposed to various concentrations of ethanol (12.5, 50, 100 and 200 mM) for short (3 and 6 h) and longer (24 or 26 h) durations. Ethanol-induced cellular responses were analysed by a combination of the following assays: number of cells, amounts of DNA and protein, MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay and cell cycle. Ethanol dose-dependently suppressed these cellular functions, except that 12.5 mM exposures for both 6 and 26 h increased the amount of protein in spite of almost no change in other cellular functions, compared to the control. The most marked dose-dependency was observed in a reduction of formazan product in an MTT assay after both 6 and 26 h exposures to ethanol, being independent of the number of cells and probably reflecting dose-dependent depression of mitochondrial respiration. A G2 + M block in the cell cycle, an inhibition of cell division, was induced after short-term exposures (3 and 6 h) to 100 and 200 mM ethanol, but the block was released before 24 h had passed. Alternatively, prolonged exposures (24 h) to 50-200 mM ethanol induced a G0/G1 block, resulting in a decrease in the amount of DNA below the control value. Moreover, the percentage of the S phase was decreased gradually and dose-dependently throughout the 24 h exposure. Thus, high concentrations of ethanol (50, 100 and 200 mM) perturbed the cell cycle progression by causing both a transient G2 + M block (an inhibition of mitosis) and a continuous G0/G1 block, though the latter was masked by the G2 + M block during short-term exposure. The cells seem finally to acquire some tolerance to ethanol so as to pass through mitosis, but much less tolerance to pass through the checkpoint from the G1 to the S phase, which results in a decline in proliferation.

Animals↗

PubMed2004

Caffeine inhibits cell proliferation by G0/G1 phase arrest in JB6 cells.

Caffeine is a major biologically active constituent in coffee and tea. Because caffeine has been reported to inhibit carcinogenesis in UVB-exposed mice, the cancer-preventing effect of caffeine has attracted considerable attention. In the present study, the effect of caffeine in quiescent (G0 phase) cells was investigated. Pretreatment with caffeine suppressed cell proliferation in a dose-dependent manner 36 h after addition of fetal bovine serum as a cell growth stimulator. Analysis by flow cytometry showed that caffeine suppressed cell cycle progression at the G0/G1 phase, i.e., 18 h after addition of fetal bovine serum, the percentages of cells in G0/G1 phase in 1 mM caffeine-treated cells and in caffeine-untreated cells were 61.7 and 29.0, respectively. The percentage of cells in G0/G1 phase at 0 h was 75.5. Caffeine inhibited phosphorylation of retinoblastoma protein at Ser780 and Ser807/Ser811, the sites where retinoblastoma protein has been reported to be phosphorylated by cyclin-dependent kinase 4 (cdk4). Furthermore, caffeine inhibited the activation of the cyclin D1-cdk4 complex in a dose-dependent manner. However this compound did not directly inhibit the activity of this complex. In addition, caffeine did not affect p16INK4 or p27Kip1 protein levels, but inhibited the phosphorylation of protein kinase B (Akt) and glycogen synthase kinase 3beta. Our results showed that caffeine suppressed the progression of quiescent cells into the cell cycle. The inhibitory mechanism may be due to the inhibition of cell growth signal-induced activation of cdk4, which may be involved in the inhibition of carcinogenesis in vivo.

Animals↗

PubMed2003

Downregulation of c-Jun expression and cell cycle regulatory molecules in acute myeloid leukemia cells upon CD44 ligation.

In the present study, we investigated the mechanism of CD44 ligation with the anti-CD44 monoclonal antibody A3D8 to inhibit the proliferation of human acute myeloid leukemia (AML) cells. The effects of A3D8 on myeloid cells were associated with specific disruption of cell cycle events and induction of G0/G1 arrest. Induction of G0/G1 arrest was accompanied by an increase in the expression of p21, attenuation of pRb phosphorylation and associated with decreased Cdk2 and Cdk4 kinase activities. Since c-Jun is an important regulator of proliferation and cell cycle progression, we analysed its role in A3D8-mediated growth arrest. We observed that A3D8 treatment of AML patient blasts and HL60/U937 cells led to the downregulation of c-Jun expression at mRNA and protein level. Transient transfection studies showed the inhibition of c-jun promoter activity by A3D8, involving both AP-1 sites. Furthermore, A3D8 treatment caused a decrease in JNK protein expression and a decrease in the level of phosphorylated c-Jun. Ectopic overexpression of c-Jun in HL60 cells was able to induce proliferation and prevent the antiproliferative effects of A3D8. In summary, these data identify an important functional role of c-Jun in the induction of cell cycle arrest and proliferation arrest of myeloid leukemia cells because of the ligation of the cell surface adhesion receptor CD44 by anti-CD44 antibody. Moreover, targeting of G1 regulatory proteins and the resulting induction of G1 arrest by A3D8 may provide new insights into antiproliferative and differentiation therapy of AML.

Acute Disease↗

PubMedDate not supplied

Growth regulatory effects of transforming growth factor-beta 1 and interleukin-2 on IL-2 dependent CD4+T lymphoblastoid cell line.

Transforming growth factor-beta 1 (TGF-beta 1) is an immuno-modulatory cytokine which has been shown to modulate the activity of T and B cells. We show here that human TGF-beta 1 inhibited stationary cultures of IL-2 dependent CD4+ bovine lymphoblastoid T cells (BLTC) by down-regulating their IL-2 receptor (IL-2R) expression, arresting cells in the G0/G1 compartment of the cell cycle, and inducing these cells to undergo apoptosis. These events were reversed by the addition of a minimal concentration of IL-2 (2U/ml). In the presence of exogenous IL-2, TGF-beta 1 was found to augment the proliferative response of BLTC through up-regulation of IL-2R expression, allow progression of normal cell cycle, and significantly prevent apoptosis. Our data clearly show that IL-2 and TGF-beta 1, when present alone, have contrasting effects on BLTC. TGF-beta 1 down regulates events that are associated with IL-2 mediated signal. But when present together, IL-2 and TGF-beta 1 upregulate activation signals and proliferation of rapidly dividing CD4+T cells.

Animals↗

PubMed2003

C16 ceramide accumulates following androgen ablation in LNCaP prostate cancer cells.

BACKGROUND: Adenocarcinoma of the prostate is the most frequently diagnosed non-cutaneous cancer and the second leading cause of cancer-related deaths among men in the United States. The most successful therapies to date for this tumor have involved some form of androgen ablation. However, these therapies become ineffective as the tumor evolves to an androgen-insensitive state. Ceramide is a lipid second messenger that has been shown to mediate growth arrest or cell death when added exogenously to prostate cancer cells. As a first step toward understanding the events that lead to the transition of prostate cancer cells to an androgen-independent state, we considered investigating the effect of androgen ablation on endogenous ceramide levels in androgen-sensitive and androgen-insensitive prostate cancer cells. METHODS: To investigate the mechanisms of growth arrest/apoptosis in androgen-sensitive (LNCaP) and insensitive (DU-145, PC-3) cells, we used various methods including nonyl acridine orange (NAO) staining, propidium iodide (PI) staining/cell-cycle analysis, lipid analysis, and Western blotting assays. RESULTS: In this study, we demonstrate that androgen ablation drives G(0)/G(1)-phase cell-cycle arrest followed by progressive apoptosis in vitro, in LNCaP cells. Lipid analysis indicated an increase in C16 ceramide, which was generated via the de novo pathway as revealed by blockade of ceramide synthase by fumonisin B1. The addition of 5alpha-dihydrotestosterone (DHT) or fumonisin B1 rescued LNCaP cells from apoptosis induced by androgen ablation, and decreased levels of intracellular C16 ceramide. Neither apoptosis nor an increase in C16 ceramide was observed in androgen-independent cell lines following androgen ablation.

Adenocarcinoma↗

PubMed2002

Oestrogens induce G(1) arrest in benzo[a]pyrene-treated MCF-7 breast cells whilst enhancing genotoxicity and clonogenic survival.

Carcinogens, such as benzo[a]pyrene (B[a]P), allow cells to evade G(1) arrest (the stealth property), thus increasing the chance that DNA damage will ultimately result in transformation. In this study we have investigated the effects of B[a]P in MCF-7 cells incubated in the presence or absence of oestrogens (beta-oestradiol, oestrone or oestriol). The cytokinesis block micronucleus assay was used to examine cells for chromosomal damage. Micronuclei were scored in 500 binucleate cells per treatment. Increased micronucleus formation (3-fold) occurred following 24 h treatment with 10(-6) M B[a]P alone. Following co-treatment with either 10(-9) M beta-oestradiol, 10(-8) M oestrone or 10(-8) M oestriol, 2- to 3-fold increases in micronuclei were observed with 10(-8) M B[a]P. When MCF-7 cells were pre-incubated for 96 h with 10(-9) M beta-oestradiol, 10(-8) M oestrone or 10(-8) M oestriol prior to the addition of B[a]P for 24 h, up to a 5-fold enhanced sensitivity to micronucleus formation was observed with beta-oestradiol and oestrone, while oestriol appeared to reduce levels of micronucleus formation. B[a]P-induced decreases in cell proliferation (per cent binucleate cells) and plating efficiency were reversed by all three oestrogens. Analysis of cell cycle distributions revealed that treatment with oestrogens or B[a]P alone did not induce marked effects on cell cycle distributions. However, in combination oestrogen and B[a]P induced increases in G(0)/G(1), decreases in S phase and increases in G(2)/M. This work suggests that whilst oestrogens appear to enhance carcinogen-induced DNA damage, they also appear, paradoxically, to trigger mechanisms that facilitate clonogenic survival, which may be relevant to breast cancer initiation.

Benzo(a)pyrene↗

PubMed1996

Regulation of T-cell activation in the lung: isolated lung T cells exhibit surface phenotypic characteristics of recent activation including down-modulated T-cell receptors, but are locked into the G0/G1 phase of the cell cycle.

Peripheral lung tissue contains large numbers of T cells, strategically located for immune surveillance at the blood-air interface. Given the intensity of antigenic exposure at this site, it is clear that local T-cell activation events require strict control, in order to maintain tissue homeostasis. How this control is achieved in this unique tissue microenvironment is unknown, and the present study sought to elucidate the process via detailed analysis of the surface phenotypic characteristics of freshly isolated lung T cells. We report below that these cells display typical characteristic of 'postactivation', notably elevated basal Ca2+ concentrations, down-modulated T-cell receptors, expression of Ia and 'late' activation antigens and concomitant CD4/CD8. However, levels of interleukin-2 receptor and CD2 expression were below those expected of 'activated' T-cell populations, and virtually all of the cells were found to be in the G0/G1 phases of the cell cycle. These properties bear a remarkable similarity to those of T cells activated in the presence of endogenous tissue (alveolar) macrophages from the lung (see accompanying paper). We hypothesize that they reflect the in vivo operation of an endogenous macrophage-mediated T-cell anergy-induction process, the function of which is to limit the local clonal expansion of T cells in peripheral lung tissue after in situ activation.

Animals↗

PubMed1998

Radiation-induced micronucleus induction in lymphocytes identifies a high frequency of radiosensitive cases among breast cancer patients: a test for predisposition?

Enhanced sensitivity to the chromosome-damaging effects of ionizing radiation is a feature of many cancer-predisposing conditions. We previously showed that 42% of an unselected series of breast cancer patients and 9% of healthy control subjects showed elevated chromosomal radiosensitivity of lymphocytes irradiated in the G2 phase of the cell cycle. We suggested that, in addition to the highly penetrant genes BRCA1 and BRCA2, which confer a very high risk of breast cancer and are carried by about 5% of all breast cancer patients, there are also low-penetrance predisposing genes carried by a much higher proportion of breast cancer patients, a view supported by recent epidemiological studies. Ideally, testing for the presence of these putative genes should involve the use of simpler methods than the G2 assay, which requires metaphase analysis of chromosome damage. Here we report on the use of a simple, rapid micronucleus assay in G0 lymphocytes exposed to high dose rate (HDR) or low dose rate gamma-irradiation, with delayed mitogenic stimulation. Good assay reproducibility was obtained, particularly with the HDR protocol, which identified 31% (12 out of 39) of breast cancer patients compared with 5% (2 out of 42) of healthy controls as having elevated radiation sensitivity. In the long term, such cytogenetic assays may have the potential for selecting women for intensive screening for breast cancer.

Adult↗