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PubMed1999

Is the effect of smoking on the risk for coronary heart disease even stronger than was previously thought?

OBJECTIVE: To assess the extent to which smoking cessation among cohort members during the follow-up affects the estimated association between smoking and coronary heart disease (CHD) risk in an observational study with a single determination of the smoking status at baseline. DESIGN: Cross-sectional trend and prospective cohort analyses. SETTINGS: North Karelia and Kuopio provinces in eastern Finland. SUBJECTS: Men (n = 13542) aged 30-59 years who participated in risk factor surveys between 1972 and 1992. Of these, 3937 men belonged to the 1972 cohort with the prospective follow-up. MAIN OUTCOME MEASUREMENTS: Smoking prevalence, CHD mortality, non-CHD mortality, and total mortality. RESULTS: Smoking prevalence in the population decreased from 53% to 37% between 1972 and 1992. In the follow-up of the 1972 study cohort, the association between baseline smoking status and CHD weakened markedly when the follow-up time from the baseline measurement was extended. The risk ratio of cumulative CHD mortality associated with smoking was 6.96 in the first 2-year follow-up and it decreased gradually to 2.06 at the 20-year follow-up. A similar decrease in the risk ratio was observed when the analysis was performed during periods of the follow-up. The association between smoking and non-CHD mortality weakened only slightly when the follow-up time became longer. CONCLUSION: The results from prospective observational studies conducted in populations with a decreasing smoking prevalence may be biased by the misclassification of study subjects during the follow-up as a result of smoking cessation. This results in an underestimation of the risk of CHD caused by smoking. Thus, smoking may be even more harmful for health than the estimates from prospective studies suggest.

Adult↗
PubMed2005

Follicular development and maturation in gilts selected for an index of high ovulation rate and high prenatal survival.

Seventy-one 10th-generation gilts from White Line-1 (WL-1 = randomly selected control line) and White Line-2 (WL-2 = selected for an index of ovulation rate and prenatal survival rate) were used to compare the pattern of follicular development and atresia during the follicular phase of the estrous cycle. Gilts were treated with PGF(2alpha)on d 13 of the estrous cycle (d 0 of induced follicular development) to induce luteolysis and assigned randomly within line and sire for ovary recovery on d 0, 2, 3, 4, 5, and the day after estrus. Ovaries were evaluated for numbers of corpora albicantia and small (2 to 2.9 mm), medium (M1 = 3 to 4.9 mm; M2 = 5 to 6.9 mm), and large (>or=7 mm) follicles. The concentration of estradiol-17beta in follicular fluid was used to classify individual M2 and large follicles as estrogen-active (>or=100 ng of estradiol-17beta/mL) or inactive (<100 ng of estradiol-17beta/mL). The WL-2 gilts had a greater ovulation rate than WL-1 gilts at their pre-treatment estrus (20.4 vs. 13.8 corpora albicantia; P < 0.001). The small and M1 follicle populations decreased rapidly in both lines over time (P < 0.001). The M2 follicle population increased in both lines between d 0 to 4 and then decreased. Mean estradiol concentration of M2 follicles increased in both genetic lines over time (P < 0.02). All large follicles were estrogen-active in both lines; the number of large follicles increased with day (P < 0.001) and was similar in both lines. The number of estrogen-active M2 follicles was similar in both lines, increasing to d 3 and 4 and then decreasing (P < 0.01) thereafter. However, the total number of estrogen-active follicles (sum of estrogen-active M2 and large follicles) was greater in WL-2 than in WL-1 gilts (P < 0.04), increasing to the ovulatory potential by d 3 in WL-1 gilts, but continuing to increase through d 4 in WL-2 gilts. Selection of an additional six ovulatory follicles from the estrogen-active M2 follicle pool after d 5 was required in both lines to achieve the projected ovulation rate, and after estrus, the number of large follicles remained insufficient to attain the ovulatory potential of each line.

Animals↗
PubMed2004

Cell cycle arrest by monochloramine through the oxidation of retinoblastoma protein.

Impairment of cell cycle control has serious effects on inflammation, tissue repair, and carcinogenesis. We report here the G1 cell cycle arrest by monochloramine (NH2Cl), a physiological oxidant derived from activated neutrophils, and its mechanism. When Jurkat cells were treated with NH2Cl (70 microM, 10 min) and incubated for 24 h, the S phase population decreased significantly with a slight increase in the hypodiploid cell population. The G0/ G1 phase and G2/M phase populations did not show marked changes. Three hours after NH2Cl treatment, the retinoblastoma protein (pRB) was dephosphorylated especially at Ser780 and Ser795, both of which are important phosphorylation sites for the G1 checkpoint function. The phosphorylation at Ser807/811 showed no apparent change. The expression of cyclins, cyclin-dependent kinases, and cyclin-dependent kinase inhibitors showed no apparent change. Moreover, the kinase activity that phosphorylates pRB remained constant even after NH2Cl treatment. The protein phosphatase activity that dephosphorylates pRB showed a marginal increase. Notably, when the recombinant pRB was oxidized by NH2Cl in vitro, the oxidized pRB became difficult to be phosphorylated by kinases, especially at Ser780 and Ser795, but not at Ser807/811. Amino acid analysis of oxidized pRB showed methionine oxidation to methionine sulfoxide. The NH2Cl-treated Jurkat cell proteins also showed a decrease in methionine. These observations suggested that direct pRB oxidation was the major cause of NH2Cl-induced cell cycle arrest. In the presence of 2 mM NH4+, NaOCl (200 microM) or activated neutrophils also induced a G1 cell cycle arrest. As protein methionine oxidation has been reported in inflammation and aging, cell cycle modulation by pRB oxidation may occur in various pathological conditions.

Cell Cycle↗
PubMed1985

Homozygosity in a population of variable size and mutation rate.

A formula is obtained for the probability that two genes at a single locus, sampled at random from a population at time t, are of particular types. The model assumed is a diffusion approximation to a neutral Wright-Fisher model in which mutation is not necessarily symmetric and the population size is a function of time. It is shown that for symmetric mutation in a population undergoing a step-function type bottleneck, homozygosity increases with decreasing population size. A formula is given for the distribution of the number of segregating sites occurring in two randomly sampled sequences of completely linked sites, with general mutation at a site and identical mutation structure between sites. We give similar results for a population of fixed size but for which the mutation rate is a function of time, and not necessarily symmetric. We confirm the intuitively clear effect that increasing the mutation rate decreases homozygosity.

Alleles↗
PubMed2005

Cytokine profile of natural killer cells in early human pregnancy.

PROBLEM: To examine whether the NK1/NK2/NK3/NKr1 paradigm can be adapted in natural killer (NK) cells. METHOD OF STUDY: Mononuclear cells were isolated from peripheral blood and/or decidua in healthy non-pregnant women (n = 17), early pregnant women (6-12 weeks of gestation, n = 17) and miscarriage cases (6-11 weeks of gestation, n = 10). We investigated the production of transforming growth factor (TGF)-beta, interleukin (IL)-4, IL-5, IL-10, IL-13, interferon (IFN)-gamma and tumor necrosis factor-alpha from peripheral blood- and decidual-CD56bright NK cells and -CD56dim NK cells by flow cytometry. RESULTS: In the peripheral blood of the non-pregnant subjects, the main populations of CD56bright NK cells and CD56dim NK cells were IFN-gamma-producing NK1 type cells. Populations of IL-10-producing NKr1 type cells in peripheral blood CD56bright NK cells and CD56dim NK cells in early pregnant women were significantly greater compared with those in non-pregnant women, and these cells population decreased in miscarriage cases. In the early pregnancy decidua, the main populations of CD56bright NK cells and CD56dim NK cells were TGF-beta-producing NK3 type cells, and NK1 type cells were rare. NK3 type cells in decidua were significantly decreased in miscarriage cases compared with those in normal pregnant subjects. IL-4-, IL-5- or IL-13-producing NK2 type cells were rare in peripheral blood and decidua. CONCLUSION: These data support the NK1/NK2/NK3/NKr1 hypothesis. NKr1 type cells in peripheral blood and NK3 type cells in decidua might play some important roles in the maintenance of pregnancy by regulation of maternal immune function.

CD56 Antigen↗
PubMed2000

Use of green fluorescent protein (GFP) to study the invasion pathways of Edwardsiella tarda in in vivo and in vitro fish models.

Edwardsiella tarda is a fish pathogen that causes systemic infections in many food and ornamental fish. E. tarda PPD130/91 and PPD125/87 were selected as representatives of the virulent and avirulent groups, respectively, from eight fish isolates, and transformed with plasmids encoding either green fluorescent protein (pGFPuv) or blue fluorescent protein (pBFP2). Two host models were used to study the invasion pathway of E. tarda in vitro and in vivo. Epithelioma papillosum of carp (EPC) was used as the first model. Virulent and avirulent E. tarda strains were found to adhere to and invade EPC cells. Interactions between E. tarda and host cells examined under confocal microscopy and intracellular growth were followed at different time points. Bacterial internalization of PPD130/91 and PPD125/87 involved microfilaments and protein tyrosine kinase since cytochalasin D (an inhibitor of microfilament polymerization) and genistein (an inhibitor of protein tyrosine kinase) prevented internalization. Confocal studies revealed co-localization of polymerized actin with bacteria. Staurosporine, a protein kinase C inhibitor, accelerated internalization of PPD125/87, whereas PD098059, a mitogen-activated protein kinase (MAPK) kinase inhibitor prevented internalization of PPD130/91. In the second model, blue gourami were infected with E. tarda intramuscularly. Mortalities were observed in PPD130/91(pGFPuv)-infected fish with high bacterial numbers detectable in all organs. PPD125/87(pBFP2)-infected fish did not die and the bacterial population decreased over time. Mixed infections comprised of both PPD130/91(pGFPuv) and PPD125/87(pBFP2), where inoculum size was similar to the single infections, caused mortalities in fish. High bacterial populations were noted only in the fish body muscle. The PPD125/87(pBFP2) population in the fish decreased after 5 d. The number of PPD130/91(pGFPuv) also decreased in the fish organs, except for continued high growth in the body muscle. Histology revealed necrosis of the tissue (body muscle and liver) and fluorescent bacteria in fish that were infected with PPD130/91(pGFPuv) but not with PPD125/87(pBFP2). This study showed that fluorescent proteins are a useful tool for investigating bacterial host cell infection, and information elucidated here sheds new light on the interactions between E. tarda and its hosts.

Actins↗
PubMed1979

Immune function in systemic lupus erythematosus. Impairment of in vitro T-cell proliferation and in vivo antibody response to exogenous antigen.

Peripheral blood mononuclear cells from 46 systemic lupus erythematosus (SLE) patients showed reduced ability to proliferate in vitro in response to the soluble antigen, tetanus toxoid, as compared with 96 normal controls. Special studies of 27 untreated SLE patients also revealed significantly decreased blastogenic responses to tetanus toxoid. In both the total and untreated SLE populations, decreased mean tetanus antibody titers also were found as compared with the control population. However, the reduction in antibody titer and blastogenic response was not strictly parallel. A limited immunization program was initiated in low-responding volunteers from the SLE and normal populations. Three out of four SLE patients did not develop a significant blastogenic response despite increases in anti-tetanus titers after immunization, whereas all normals showed significant increases in both blastogenic and antibody responses. The accumulated evidence indicated that the unresponsiveness was the result of a defect in T-cell function. Monocyte reactivity was demonstrated to be normal, and no evidence was found for the presence of suppressor cells, inhibition by immune complexes, or increased prostaglandins to explain the defect.

Antibodies, Bacterial↗
PubMed1991

Heated linoleic acid anilide: toxicity and relevance to toxic oil syndrome.

The present study was undertaken to investigate toxic potentials of linoleic acid anilide (LAA) and heated linoleic acid anilide (HLAA) and their possible role in the etiology of toxic oil syndrome (TOS). Male Sprague-Dawley rats were given 250 mg/kg of LAA or HLAA in mineral oil through gavage, on alternate days for 2 weeks (total 7 doses). Control rats received an equal volume of vehicle only. The animals were sacrificed at day 1, 7 and 28 following the last dose. Ratio of organ weight/body weight showed a significant increase in lung in LAA group at day 7 while spleen showed remarkable increases in both treatment groups at day 1 and 7. On the other hand, this ratio showed decreases in case of liver, brain and heart at some time points. Among blood parameters, red cell counts and hemoglobin content decreased at day 1 in both LAA and HLAA treated groups, while platelet counts showed an increase. Serum LDH, GOT and GPT activities significantly decreased at day 1 and 7 in both LAA and HLAA treated groups, however, these changes were more prominent in the HLAA treated group. Interestingly, at day 28, these serum enzyme levels recovered to control levels. Both LAA and HLAA treated groups showed a decrease in serum IgM levels at day 1, however, at day 7 only the LAA group showed a significant decrease. IgA levels significantly increased in both groups at all the time points studied and were more pronounced in the HLAA treated group. Similarly, IgG levels also showed increases in both the groups. In addition to serum immunoglobulin changes, alterations in the lymphocyte subpopulations were also observed. While T-cell population decreased, B-cell population remained unchanged. Among T-cell subsets, T-helper cells did not show any change while T-suppressor cells decreased significantly at day 1 in the LAA group and at day 1 and 7 in the HLAA group, but regained control levels at day 28. The biochemical and immunological alterations observed in this study as a result of LAA and HLAA exposure and more so by HLAA further support that the fatty acid anilides may play a role in the etiology of TOS.

Anilides↗
PubMed2000

Plant genetic diversity in the Canary Islands: a conservation perspective.

The Canary Islands are an Atlantic volcanic archipelago with a rich flora of ∼570 endemic species. The endemics represent ∼40% of the native flora of the islands, and ∼20% of the endemics are in the E (endangered) category of the International Union for Conservation of Nature. A review of allozyme variation in 69 endemic species belonging to 18 genera and eight families is presented. The average species-level genetic diversity (H(T)) at allozyme loci is 0.186, which is twice as high as the mean reported for endemics of Pacific archipelagos. Possible factors contributing to this higher diversity are discussed, but the reasons remain obscure. An average of 28% of the allozyme diversity within species resides among populations, indicating a high level of interpopulational differentiation. Studies of reproductive biology indicate that many of the endemic species are outcrossers. The high total diversity within species, the relatively high differentiation among populations, and the outcrossing breeding systems have implications for species conservation. Decreased population sizes in outcrossing species would promote biparental inbreeding and increase inbreeding depression. The relatively high proportion of allozyme diversity among populations indicates that the most effective strategy for preserving genetic variation in species is to conserve as many populations as possible. The genetic diversity in many Canary Island endemics is endangered by: (1) overgrazing by introduced animals, such as barbary sheep, goats, mouflons, rabbits, and sheep; (2) interspecific hybridization following habitat disturbance or planting of endemics along roadsides or in public gardens; (3) competition with alien plant species; and (4) decline of population size because of urban development and farming.

Journal Article↗
PubMed1976

Receptors for immune complexes on cells within a non-lymphoid murine tumor.

In this paper we present evidence that antibodies unrelated to the tumor cell can comprise part of the in vivo Ig surface coat of cells derived from the non-lymphoid murine tumor, TA3/St. This was shown by incubating TA3 cells originating from other OA or BSA preimmunized mice with radioiodinated 125I-OA and 131I BSA. Radioiodine-labeled 125I-OA specifically fixed to cells derived from TA3/St tumors originating from OA-preimmunized mice. On the other hand 131I-BSA was specifically fixed by cell populations from BSA-preimmunized mice. Incubation of these cells in vitro at 37 degrees C abolished the specific binding and antibody could subsequently be detected in the tissue culture medium. Radioiodine labeled purified soluble antibody-antigen complexes could also be bound to cells derived from freshly harvested TA3/St tumors but not to their in vitro propagated counterparts. Removal of phagocytic or adherent cells from these cell populations decreased the binding of the complexed antibody on freshly harvested TA3/St populations, but did not eliminate it. Inhibition of complexed antibody binding was obtained when TA3/St cells (an H-2a tumor) were pre-incubated with anti-H2a antiserum. Propagation of the tumor in an F1 hybrid (A X C57BL) in which host cells could be distinguished from tumor cells by using an anti H-2b antiserum showed that binding of the immune complex was mostly limited to host cells infiltrating into the tumor population.

Animals↗
PubMed2001

Modelling viral and CD4 cellular population dynamics in HIV: approaches to evaluate intervention strategies.

Computational models, such as in epidemiology, provide a powerful tool that can be used to systematically examine an array of dynamic interactions among populations as well as to evaluate altemate disease intervention strategies. The specific objectives in this study were to: a/ examine the interaction of cellular (CD4) and HIV population dynamics and evaluate the impact of the use of combination chemotherapies on viral and CD4 populations (Experiment #1), b/ demonstrate how modelling can be used to evaluate the impact of an intervention (condom use) on reducing the rate of HIV/AIDS (Experiment #2). In this study, we used state transition models and conducted simulation experiments to evaluate various alternatives for the control and/or prevention of HIV/AIDS. The result indicated that combination therapy (double or triple drug therapies) was very effective. The HIV viral population decreased rapidly and remained suppressed for years. On the other hand, the CD4 cell population increased above 400 cells per ml and was maintained above that level for many years. Mono-therapy was not as effective; although the viral load decreased rapidly, it increased to its original levels within a few months. Since condom use is one of the key interventions of HIV/AIDS, we evaluated its use in 25%, 50% and 75% of an adult, sexually active population. Increasing condom use by 50% and 75% above an estimated baseline of 25% reduced the incidence of AIDS by 53% in Blacks, 49% in Hispanics and 43% in Whites. The study shows how a cellular/molecular level model can be incorporated within a macro-epidemiologic systems dynamics model to evaluate a variety of scientific questions such as to see if cellular/molecular level interventions reduce morbidity and mortality rates in HIV.

Anti-HIV Agents↗
PubMedDate not supplied

[Angkor. The mystery of the dead city and Anopheles dirus].

The desertion of Angkor, which during more than five centuries was the center of a glorious civilization, has long been a matter of mystery and conjecture. The discovery of the vectorial capacity of the jungle mosquito Anopheles dirus, its epidemiological importance in the emergence and spread of multidrug resistance in Plasmodium falciparum malaria, the wiping out of large populations after transfer or deportation of non-immune Khmers into forest areas can now easily explain the desertion of Angkor. In 1431, Angkor Thom, the capital of the Khmer kingdom surrendered to the Thai conquerors. Soon afterwards, the young king left the city in search of a new capital. As a result of the population decrease large surfaces of rice fields were abandoned and reinvaded by the jungle, the typical biotope of Anopheles dirus. Severe epidemics of Plasmodium falciparum then occurred in the non-immune population with very high mortality decreasing again the number of workers and, thus, creating a vicious circle resulting in the progressive but complete desertion of Angkor.

Animals↗
PubMed2004

A longitudinal study of antioxidant status in phenylketonuric patients.

OBJECTIVES: To investigate the implications of the three main factors of the antioxidant system reported in relation to oxidative damage in phenylketonuric patients: selenium, ubiquinone-10 (Q10) and antioxidant enzymes over 3 years of metabolic follow-up. DESIGN AND METHODS: Longitudinal study of 46 phenylketonuric patients (age range: 6 months-34 years). Antioxidants were measured by atomic absorption spectrophotometric, chromatographic and spectrophotometric procedures. RESULTS: Plasma selenium concentrations in phenylketonuria (PKU) were not different from those of a healthy population. Decreased plasma Q10 concentrations were mainly related to the dietary control and the age of patients. Erythrocyte catalase activity was significantly decreased in PKU while the other enzyme activities were not different from those of a healthy population. CONCLUSION: Selenium status is not impaired in phenylketonuric patients under dietary treatment. Q10 values tend to decrease with increased patient age. Catalase activity was negatively associated with plasma phenylalanine values.

Adolescent↗
PubMed2006

Sex, death and tragedy.

The population consequences of sexual conflict are relatively unexplored. In a recent paper, Le Galliard et al. now show that males of the common lizard Lacerta vivipara cause such damage to females that male-biased populations decrease in size, posing a real risk to the persistence of local lizard populations. Their study reveals surprising parallels between sexual conflict and the tragedy of the commons, where selfish competition over females destroys the very resource (i.e. the females) over which the males are fighting.

Aggression↗
PubMed2003

Effect of ammonia toxicity on the competition among three species of cladocerans (Crustacea: Cladocera).

Among the natural abiotic variables affecting the species density and composition of cladocerans, ammonia is important. Using population growth data as tool, we studied the competitive outcome of three cladoceran species (Ceriodaphnia dubia, Daphnia pulex, and Moina macrocopa) grown alone and together at three different concentrations (0, 25, and 100 mg L(-1)) of ammonia at one density (1 x 10(6)cells ml(-1)) of the microalga Chlorella vulgaris. Regardless of the presence or absence of competing species, C. dubia showed little population growth at 100 mg L(-1) of ammonia. At 25 mg L(-1) of ammonia, the population density of C. dubia increased but the value was much lower than that in control. D. pulex was able to grow at the ammonia concentration of 25 mg L(-1), comparable to controls. However, at 100 mg L(-1) of ammonia, the population declined and more rapidly when competed with other cladocerans. M. macrocopa showed decreased population density with increasing ammonia concentration in the medium. This trend was accelerated by the presence of competing cladocerans. M. macrocopa was benefited by the presence of D. pulex at 0 and 25 mg L(-1) of ammonia in the medium. The peak population density of C. dubia varied from 0.5 to 9 ind.ml(-1), whereas for D. pulex and M. macrocopa, these values varied from 1 to 3 ind.ml(-1) and 7 to 18 ind.ml(-1), respectively, depending on the ammonia concentration and the presence of competing species. The rates of population increase per day of C. dubia, D. pulex, and M. macrocopa ranged from -0.12+/-0.001 to 0.30+/-0.01, 0.04+/-0.001 to 0.22+/-0.002, and 0.201+/-0.028 to 0.235+/-0.019, respectively, depending on the ammonia concentration and the presence of competitors. Our study showed that while competition within the chosen cladoceran species caused suppression of one or two competing species, the presence of ammonia expedited this process based on the relative sensitivities of the tested zooplankton.

Ammonia↗
PubMed1997

MCF-7 breast carcinoma cells overexpressing FGF-1 form vascularized, metastatic tumors in ovariectomized or tamoxifen-treated nude mice.

FGF-1 is expressed in a high proportion of breast tumors. While overexpression of FGF-4 in the MCF-7 breast carcinoma cell line confers the ability to form spontaneously metastasizing tumors in ovariectomized nude mice without estrogen supplementation and in mice that receive tamoxifen pellets, the response of a cell to individual FGFs can be controlled at multiple levels, and the significance of FGF-1 expression in human breast tumors is uncertain. To study the role of FGF-1, MCF-7 human breast cancer carcinoma cells, previously transfected with bacterial beta-galactosidase, were retransfected with FGF-1 expression vectors. FGF-1 transfectants formed large, vascularized tumors in ovariectomized nude mice without estrogen supplementation as well as in mice that received tamoxifen pellets. Lymphatic and pulmonary micrometastases were detected as deposits of X-gal-stained cells as early as 17 days after cell inoculation whereas no metastases were detected in estrogen-supplemented mice bearing similar-sized control tumors. When compared with controls, both clonal and polyclonal populations of FGF-1 overexpressing cells exhibited increased anchorage-independent growth and decreased population doubling times in estrogen-depleted or 4-hydroxytamoxifen containing medium. These results suggest that FGF signaling may be important in the transition of breast cancer cells from hormone-dependent to hormone-independent and from nonmetastatic to metastatic.

Animals↗
PubMed1997

Serotonergic modulation of hippocampal pyramidal cells in euthermic, cold-acclimated, and hibernating hamsters.

Serotonergic fibers project to the hippocampus, a brain area previously shown to have distinctive changes in electroencephalograph (EEG) activity during entrance into and arousal from hibernation. The EEG activity is generated by pyramidal cells in both hibernating and nonhibernating species. Using the brain slice preparation, we characterized serotonergic responses of these CA1 pyramidal cells in euthermic, cold-acclimated, and hibernating Syrian hamsters. Stimulation of Shaffer-collateral/commissural fibers evoked fast synaptic excitation of CA1 pyramidal cells, a response monitored by recording population spikes (the synchronous generation of action potentials). Neuromodulation by serotonin (5-HT) decreased population spike amplitude by 54% in cold-acclimated animals, 80% in hibernating hamsters, and 63% in euthermic animals. The depression was significantly greater in slices from hibernators than from cold-acclimated animals. In slices from euthermic animals, changes in extracellular K+ concentration between 2.5 and 5.0 mM did not significantly alter serotonergic responses. The 5-HT1A agonist 8-hydroxy-2(di-n-propylamino)tetralin mimicked serotonergic inhibition in euthermic hamsters. Results show that 5-HT is a robust neuromodulator not only in euthermic animals but also in cold-acclimated and hibernating hamsters.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2005

Sensitization of DNA damage-induced apoptosis by the proteasome inhibitor PS-341 is p53 dependent and involves target proteins 14-3-3sigma and survivin.

Proteasome inhibition following DNA damage results in the synergistic induction of apoptosis via a nuclear factor-kappaB-independent mechanism. In this study, we identify the role of p53 in mediating apoptosis by the sequence-specific treatment involving the DNA-damaging, topoisomerase I-targeting drug SN-38 followed by the proteasome inhibitor PS-341 (SN-38-->PS-341). The p53-dependent sensitization of DNA damage-induced apoptosis by PS-341 is accompanied by persistent inhibition of proteasome activity and increased cytosolic accumulation of p53, including higher molecular weight forms likely representing ubiquitinated species. In contrast, pretreatment with PS-341 followed by treatment with SN-38 (PS-341-->SN-38), which leads to an antagonistic interaction, results in transient inhibition of proteasome activity and accumulation of significantly lower levels of p53 localized primarily to the nucleus. Whereas cells treated with PS-341-->SN-38 undergo G2 + M cell cycle arrest, cells treated with SN-38-->PS-341 exhibit a decreased G2 + M block with a concomitant increase in the sub-G1 population. Decreased accumulation of cells in the G2 + M phase of the cell cycle in SN-38-->PS-341-treated cells compared with PS-341-->SN-38-treated cells correlates with enhanced apoptosis and reduced expression of two p53-modulated proteins, 14-3-3sigma and survivin, both of which play critical roles in regulating G2 + M progression and apoptosis. The functional role of 14-3-3sigma or survivin in regulating the divergent function of p53 in response to SN-38-->PS-341 and PS-341-->SN-38 treatment in inducing apoptosis versus G2 + M arrest/DNA repair, respectively, was confirmed by targeted down-regulation of these proteins. These results provide insights into the mechanisms by which inhibition of proteasome activity modulates DNA damage-induced apoptosis via a p53-dependent pathway.

14-3-3 Proteins↗