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PubMed2006

Differential Noxa/Mcl-1 balance in peripheral versus lymph node chronic lymphocytic leukemia cells correlates with survival capacity.

The gradual accumulation of chronic lymphocytic leukemia (B-CLL) cells is presumed to derive from proliferation centers in lymph nodes and bone marrow. To what extent these cells possess the purported antiapoptotic phenotype of peripheral B-CLL cells is unknown. Recently, we have described that, in B-CLL samples from peripheral blood, aberrant apoptosis gene expression was not limited to protective changes but also included increased levels of proapoptotic BH3-only member Noxa. Here, we compare apoptosis gene profiles from peripheral blood B-CLL (n=15) with lymph node B-CLL (>90% CD5+/CD19+/CD23+ lymphocytes with Ki67+ centers; n=9). Apart from expected differences in Survivin and Bcl-xL, a prominent distinction with peripheral B-CLL cells was the decreased averaged level of Noxa in lymph nodes. Mcl-1 protein expression showed a reverse trend. Noxa expression could be reduced also in vitro by CD40 stimulation of peripheral blood B-CLL. Direct manipulation of Noxa protein levels was achieved by proteasome inhibition in B-CLL and via RNAi in model cell lines. In each instance, cell viability was directly linked with Noxa levels. These data indicate that suppression of Noxa in the lymph node environment contributes to the persistence of B-CLL at these sites and suggest that therapeutic targeting of Noxa might be beneficial.

Apoptosis↗
PubMed2005

NADPH oxidase homologs are required for normal cell differentiation and morphogenesis in Dictyostelium discoideum.

Membrane-associated NADPH oxidase complexes catalyse the production of the superoxide anion radical from oxygen and NADPH. In mammalian systems, NADPH oxidases form a family of at least seven isoforms that participate in host defence and signalling pathways. We report here the cloning and the characterisation of slime mould Dictyostelium discoideum homologs of the mammalian heme-containing subunit of flavocytochrome b (gp91(phox)) (NoxA, NoxB and NoxC), of the small subunit of flavocytochrome b (p22(phox)) and of the cytosolic factor p67(phox). Null-mutants of either noxA, noxB, noxC or p22(phox) show aberrant starvation-induced development and are unable to produce spores. The overexpression of NoxA(myc2) in noxA null strain restores spore formation. Remarkably, the gene alg-2B, coding for one of the two penta EF-hand proteins in Dictyostelium, acts as a suppressor in noxA, noxB, and p22(phox) null-mutant strains. Knockout of alg-2B allows noxA, noxB or p22(phox) null-mutants to return to normal development. However, the knockout of gene encoding NoxC, which contains two penta EF-hands, is not rescued by the invalidation of alg-2B. These data are consistent with a hypothesis connecting superoxide and calcium signalling during Dictyostelium development.

Amino Acid Sequence↗
PubMed2005

Melanocyte and keratinocyte carcinogenesis: p53 family protein activities and intersecting mRNA expression profiles.

Melanocytes and keratinocytes were analyzed for potential roles of p53, p73, and p63 tumor suppressor family proteins and of malignancy-specific gene expression changes in the etiology of multi-step cancer. Melanocytes expressed deltaNp73alpha, two p63 isoforms and p53. Although p21 and Noxa mRNA levels increased following DNA damage, p53 family member binding to p21 and Noxa DNA probes was undetectable, suggesting p53 family-independent responses. In contrast, keratinocytes expressed multiple isoforms each of p73 and p63 that were induced to bind p21 and Noxa DNA probes after ionizing (IR) or after ultraviolet B (UVB) irradiation, correlating with p21 and Noxa mRNA induction and with apoptosis. Interestingly, IR-resistant malignant melanocytes and keratinocytes both exhibited Noxa mRNA induction after UVB treatment, correlating with DNA binding of p53 family proteins to the Noxa probe only in keratinocytes. To uncover other malignancy-specific events, we queried mouse initiated keratinocyte clones for early changes that were exacerbated in malignant derivatives and also differentially expressed in human advanced melanoma versus normal melanocytes. Using a new method for ranking and normalization of microarray data for 5000 probe sets, 27 upregulated and 13 downregulated genes satisfied our query. Of these, the majority was associated with late-stage human cancers and six were novel genes. Thus, clonal lineage mouse models representing early through late cancer progression stages may inform the focus on early, potentially causal events from microarray studies of human cancers, facilitating prognosis and molecular therapy.

Animals↗
PubMed1997

Quantitative assessment of cell damage in situ: electron microprobe X-ray analysis of model organisms treated with noxious species.

The existing set of methods for assessing toxicity of noxas, based on experiments with whole animals (subclinical toxicity, toxicokinetics, carcinogenity, teratogenity, neurotoxicology etc.) does not provide much information about cellular and subcellular effects such compounds may exert. We suggest to complement the current methodology by combining a traditional morphological observation in an electron microscope with a spectroscopic method of electron microprobe X-ray analysis (or X-ray microanalysis). The latter makes it possible to measure concentrations of chemical elements in individual cells and organelles and effects of noxas can thus be assessed (i) at subcellular level, (ii) directly in situ and (iii) quantitatively. Concentrations of biologically important elements such as phosphorus, sulfur or zinc were measured in individual organelles in both intact and noxa-treated tissues, thus offering a possibility of comparing the effects of various noxious species at subcellular level (with the noxa previously applied to whole tissue or animal). The suggested correlation of analytical and morphological information may also provide new insights into cellular targeting of noxas (and potentially also drugs) as some organelles appear to be much more susceptible to damage than others.

Animals↗
PubMed1985

The estimation of host-resistance in cancer.

From the third year after its clinical diagnosis and onward the cancer hazard rate continuously declines. This phenomenon is common to all cancers irrespective of stage, and far less pronounced in other chronic diseases. It is so typical of cancer as to be regarded as a "law of the improving chances of the cancer patient". Although the cancer hazard rate itself is higher than in most other chronic diseases, it always declines while in other chronic diseases it rises. Two kinds of processes operate in cancer: a noxa and host resistance. Throughout cancer progression the organism maintains a delicate equilibrium with the noxa, only its reserves are continuously depleted and when exhausted the noxa overpowers the host's resistance and the patient dies. The hazard rate is inversely proportional to the patient's reserve. Its decline indicates that the host resists the noxa better and better, since however his reserves are limited, he ultimatelly succumbs to it. This phenomenon also shapes cancer age specific incidence and mortality rates. From the age of 15 years and onward the curves ascend in an exponential fashion, gradually tapering off, which is viewed here as a token of a mounting resistance of the organism to the carcinogenic noxa. Host resistance operates also during tumor growth, accounting for the Gompertzian shape of its growth curve. The growth rate of most human tumors progressively decreases and is therefore best described by the Gompertz function which initially rises in an exponential fashion and gradually tapers off. Tumor size and growth rate indirectly reflect the host's condition or reserve. The two tumor attributes are related to the hazard rate in the following manner: Tumor size is proportional to the hazard rate, indicating host reserve. Tumor growth rate is proportional to the hazard rate change, indicating host resistance. Both indicators may be estimated independently and applied to the assessment of the host's reserve and resistance during cancer progression.

Adolescent↗
PubMed1996

Differential effects of endotoxin and cytokines on prostaglandin E2 formation in cerebral microvessels and brain parenchyma: implications for the pathogenesis of fever.

Prostaglandin(PG) E2 is regarded as an essential mediator in the central action of pyrogens and fever. However, it is not clear how the appearance of cytokines in the circulation leads to the rise of PGE2 in brain (fever to an external noxa), nor is it clear whether bacterial toxins originating within the brain activate PGE2 directly or via the cytokines (fever to a central noxa). We have previously reported that human interleukin 1 (hIL-1) has no effect on PGE2 synthesis in isolated, feline cerebral microvessels. Since cytokine action may be species-specific and interleukin 6 (IL-6) is considered as important as IL-1 for fever, we have now examined the response of isolated, murine cerebral microvessels to homologous and heterologous IL-1 beta (rIL-1 beta and hIL-1 beta), heterologous IL-6 (hIL-6), and endotoxin. The same pyrogens were tested on rat cerebrocortical minces. We have found that PGE2 formation in the microvessels is not changed by either IL-1 beta (both forms) or hIL-6. Conversely, in brain minces rIL-1 beta (but not hIL-1 beta or hIL-6) is a PGE2 activator. Endotoxin stimulated PGE2 synthesis in both preparations and its action in brain was fully reversed by the hIL-1 receptor antagonist (hIL-1ra). Our data indicate that the cerebral microvasculature does not lend itself to a transducing function in the fever to an external noxa. In addition, they point to a mediator role of IL-1 in the fever to a central noxa.

Animals↗
PubMed2006

The Noxa/Mcl-1 axis regulates susceptibility to apoptosis under glucose limitation in dividing T cells.

Throughout lymphocyte development, cellular persistence and expansion are tightly regulated by survival and apoptosis. Within the Bcl-2 family, distinct apoptogenic BH3-only members like Bid, Bim, and Puma appear to function in specific cell death pathways. We found that naive human T cells after mitogenic activation, apart from expected protective Bcl-2 members, also rapidly upregulate the BH3-only protein Noxa in a p53-independent fashion. The specific role of Noxa became apparent during glucose limitation and involves interaction with the labile Bcl-2 homolog Mcl-1. Knockdown of Noxa or Mcl-1 results in protection or susceptibility, respectively, to apoptosis induced by glucose deprivation. Declining Mcl-1 levels and apoptosis induction are inversely correlated to Noxa levels and prevented by readdition of glucose. We propose that the Noxa/Mcl-1 axis is an apoptosis rheostat in dividing cells, in a selective pathway that functions to restrain lymphocyte expansion and can be triggered by glucose deprivation.

Apoptosis↗
PubMed2006

Teratogen-induced activation of p53 in early postimplantation mouse embryos.

Hyperthermia (HS) and 4-hydroperoxycyclophosphamide (4CP) activate the mitochondrial apoptotic pathway in day 9 mouse embryos. Previous microarray analyses Microarray analyses revealed that several p53 target genes are upregulated after exposure to HS or 4CP, suggesting a role for p53 in teratogen-induced apoptosis. To explore the role of p53, we assessed the activation of p53 in day 9 mouse embryos exposed to HS or 4CP in vitro. Both teratogens induced the accumulation of p53 and phosphorylation of p53 at ser-15, two hallmarks of p53 activation. HS and 4CP also induced an increase in Noxa and Puma mRNAs, transcripts of two known proapoptotic p53 target genes; however, these two teratogens did not induce significant increases in NOXA and PUMA proteins, suggesting that p53 does not activate the mitochondrial apoptotic pathway by transcriptionally upregulating the expression of NOXA and PUMA proteins. HS and 4CP also induced the expression of p21 mRNA and protein, suggesting a role for p53 in teratogen-induced cell cycle arrest. Previously, we also showed that HS and 4CP activate the apoptotic pathway in the embryo proper (head and trunk) but not in the heart. We now show that HS and 4CP induce a robust activation of p53 in the embryo proper but an attenuated induction in the heart. HS and 4CP induce the expression of p21 protein in majority of the cells in the embryo; however, expression of NOXA and PUMA proteins were not significantly induced in heads, hearts, or trunks of day 9 embryos. Overall, our results suggest that p53 may play a transcription-dependent role in teratogen-induced cell cycle arrest but a transcription-independent role in teratogen-induced apoptosis in day 9 mouse embryos exposed to HS or 4CP.

Animals↗
PubMed2005

Adaptive responses to oxygen stress in obligatory anaerobes Clostridium acetobutylicum and Clostridium aminovalericum.

Clostridium acetobutylicum and Clostridium aminovalericum, both obligatory anaerobes, grow normally after growth conditions are changed from anoxic to microoxic, where the cells consume oxygen proficiently. In C. aminovalericum, a gene encoding a previously characterized H2O-forming NADH oxidase, designated noxA, was cloned and sequenced. The expression of noxA was strongly upregulated within 10 min after the growth conditions were altered to a microoxic state, indicating that C. aminovalericum NoxA is involved in oxygen metabolism. In C. acetobutylicum, genes suggested to be involved in oxygen metabolism and genes for reactive oxygen species (ROS) scavenging were chosen from the genome database. Although no clear orthologue of C. aminovalericum NoxA was found, Northern blot analysis identified many O2-responsive genes (e.g., a gene cluster [CAC2448 to CAC2452] encoding an NADH rubredoxin oxidoreductase-A-type flavoprotein-desulfoferrodoxin homologue-MerR family-like protein-flavodoxin, an operon [CAC1547 to CAC1549] encoding a thioredoxin-thioredoxin reductase-glutathione peroxidase-like protein, an operon [CAC1570 and CAC1571] encoding two glutathione peroxidase-like proteins, and genes encoding thiol peroxidase, bacterioferritin comigratory proteins, and superoxide dismutase) whose expression was quickly and synchronously upregulated within 10 min after flushing with 5% O2. The corresponding enzyme activities, such as NAD(P)H-dependent peroxide (H2O2 and alkyl hydroperoxides) reductase, were highly induced, indicating that microoxic growth of C. acetobutylicum is associated with the expression of a number of genes for oxygen metabolism and ROS scavenging.

Acclimatization↗
PubMedDate not supplied

[Neurotoxic effects of organic solvents among workers in paint and lacquer manufacturing industry].

INTRODUCTION: Organic solvents are chemically different compounds with one common feature: they dissolve fats, oils, resins, cellulose acetate and cellulose nitrate, which makes them widely used in industry. Most often organic solvents are used in paint and lacquer industries, in production of pesticides, plastics, explosives, rubber, cellulose, air conditioners, in pharmaceutical industry and in leather industry. The aim of this research was to analyze the working environment and professional hazards in paint and lacquer manufacturing industry and evaluate effects of chronic exposure to mixture of organic solvents on nervous system of exposed workers. METHODOLOGY: The exposed group consisted of 50 workers professionally exposed to these noxae, while the control group consisted of 30 workers who have never been exposed to these noxae. RESULTS: Examination of working environment in departments of paint and lacquer manufacturing revealed presence of white spirit and toluene above allowed levels. Exposed workers more frequently complained of fatigue, hand numbness, enhanced excitation, and concentration difficulties, forgetfulness and headaches, than workers from the control group. Electroneurographic examination of n. medianus showed reduced motor and sensitive conduction velocity among exposed in comparison to workers from the control group. Reduced motor and sensitive conduction velocity was correlated with duration of exposure to these noxae. Terminal latency of n. medianus was statistically, significantly longer in the exposed group than in the control group. Workers in the exposed group have statistically significantly longer reaction time in response to acoustic and visual stimuli. DISCUSSION: Segmental demyelination and axonal degeneration, as forms of damage to peripheral nerves, were identified as responsible for peripheral neuropathy associated with occupational exposure to organic solvents. CONCLUSION: Results of this study show possible neurotoxic effects of noxae detected in the phase of analysis of working conditions and working environment of examined workers.

Air Pollutants, Occupational↗
PubMed1989

Contribution to the survey of epidemiological studies on industrial stomatology from available foreign literature. Part II.

The epidemiological studies from available foreign literature deal with statistical processing of results obtained from the examination of workers from hazard workplaces in light and heavy industries. The effect of chemical and biological noxae on teeth decay and mucosa of the oral cavity was studied in a series of workers divided according to sex, age, and duration of employment. The harmful effect of noxae was found on the incidence and course of periodontopathies and worsened oral hygiene. No correlation was observed between the type of noxa and teeth decay. Noxae affect negatively the whole organism.

Air Pollutants, Occupational↗
PubMed1988

[Supplementary treatment with Esberitox of female patients undergoing curative adjuvant irradiation following breast cancer].

1. The study was supposed to investigate a possible prevention or reduction of the toxicity of radiotherapy by an additional treatment with Esberitox. This question arose when performing an investigation about the effect of Esberitox in a combined chemo-radiotherapy. Whereas the latter induces above all a systemic damage to the hemopoietic system, radiotherapy is a regional noxa. 2. The present prospective, randomized study was conducted with 50 patients submitted to curative adjuvant irradiation following surgery for mammary carcinoma. The radiotherapy was performed in the same way in all patients with irradiations of the thoracic wall and the regional lymph nodes. Two groups were built by randomization. The study group received an additional treatment with Esberitox, the control group did not receive an additional treatment. 3. As a result, no protective influence of Esberitox could be demonstrated. The parameters investigated were the peripheral blood count (leucocytes, granulocytes, lymphocytes, monocytes, thrombocytes, hemoglobin, hematocrit) and the incidence of infections. 4. This result diverging from literature is discussed. It is probably affected by volume and extension of the injury induced by a hematotoxic noxa and furthermore by the ability of regeneration. If this ability is exhausted, the protective effect of Esberitox can act no longer. Therefore the essential factor seems to be the duration of exposure to the noxa. Esberitox was effective in case of a short toxicity, it was ineffective in case of prolonged toxicity, if the treatment continuity (noxa) was not broken up by some regeneration intervals. The radiotherapy studied in this trial had a duration of 50 days, and its effect was that of a longterm injury.

Adult↗
PubMed2006

Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies.

Although the BCL-2 family constitutes a crucial checkpoint in apoptosis, the intricate interplay between these family members remains elusive. Here, we demonstrate that BIM and PUMA, similar to truncated BID (tBID), directly activate BAX-BAK to release cytochrome c. Conversely, anti-apoptotic BCL-2-BCL-X(L)-MCL-1 sequesters these 'activator' BH3-only molecules into stable complexes, thus preventing the activation of BAX-BAK. Extensive mutagenesis of BAX-BAK indicates that their activity is not kept in check by BCL-2-BCL-X(L)-MCL-1. Anti-apoptotic BCL-2 members are differentially inactivated by the remaining 'inactivator' BH3-only molecules including BAD, NOXA, BMF, BIK/BLK and HRK/DP5. BAD displaces tBID, BIM or PUMA from BCL-2-BCL-X(L) to activate BAX-BAK, whereas NOXA specifically antagonizes MCL-1. Coexpression of BAD and NOXA killed wild-type but not Bax, Bak doubly deficient cells or Puma deficient cells with Bim knockdown, indicating that activator BH3-only molecules function downstream of inactivator BH3-only molecules to activate BAX-BAK. Our data establish a hierarchical regulation of mitochondrion-dependent apoptosis by various BCL-2 subfamilies.

Animals↗
PubMed2024

Contribution of A1 to macrophage survival in cooperation with MCL-1 and BCL-XL in a murine cell model of myeloid differentiation.

Myeloid cells are the first line of defence against pathogens. Mitochondrial apoptosis signalling is a crucial regulator of myeloid cell lifespan and modulates the function of myeloid cells. The anti-apoptotic protein BCL-2-family protein BCL2A1/A1/BFL-1 is strongly upregulated in inflammation in macrophages. We analysed the contribution of A1 to apoptosis regulation in a conditional system of in vitro differentiation of murine macrophages from immortalised progenitors. We disabled the expression of A1 by targeting all murine A1 isoforms in the genome. Specific inhibitors were used to inactivate other anti-apoptotic proteins. Macrophage progenitor survival mainly depended on the anti-apoptotic proteins MCL-1, BCL-XL and A1 but not BCL-2. Deletion of A1 on its own had little effect on progenitor cell survival but was sensitised to cell death induction when BCL-XL or MCL-1 was neutralised. In progenitors, A1 was required for survival in the presence of the inflammatory stimulus LPS. Differentiated macrophages were resistant to inhibition of single anti-apoptotic proteins, but A1 was required to protect macrophages against inhibition of either BCL-XL or MCL-1; BCL-2 only had a minor role in these cells. Cell death by neutralisation of anti-apoptotic proteins completely depended on BAX with a small contribution of BAK only in progenitors in the presence of LPS. A1 and NOXA appeared to stabilise each other at the posttranscriptional level suggesting direct binding. Co-immunoprecipitation experiments showed the binding of A1 to NOXA and BIM. Interaction between A1 and Noxa may indirectly prevent neutralisation and destabilization of MCL-1. Our findings suggest a unique role for A1 as a modulator of survival in the macrophage lineage in concert with MCL-1 and BCL-XL, especially in a pro-inflammatory environment.

Animals↗
PubMed2001

[The early postnatal development of the hamster cochlea].

The Early Postnatal Development of the Hamster Cochlea. Inborn deafness can be diagnosed very early. Deafness in early childhood can be caused by: genetic defects (30 % - 40 %), embryopathies, embryonic noxae (60 %) and pre-, peri- and postnatal noxae. Which structures of the cochlea are disturbed, is unknown in most cases. Systematic studies are necessary with directed experimental impairments of the cochlea in the early development to elucidate these mechanisms. An animal model has to be established in which directed impairments can be carried out in single individuals. The cochlea of the hamster is at birth in a very early state of development. In the apical turn the epithelial layer of the cochlear duct is undifferentiated, whereas in the basal turn the papilla basilaris (Kölliker's organ), the lateral wall and Reissner's membrane are visible. Between the base of the cochlea (1st coil lateral) and the apical part (3rd coil lateral) the difference in the development of the hamster cochlea is exactly four days. This is evident for the 1st and the 5th day after birth. The cochlea development of the hamster is very rapid. The development during one day represents one week of development in the human cochlea. The difference in development in one hamster cochlea from the apex to the base at a certain day representing four days of development is comparable with the development time of four weeks in human. The different developmental stages which are present in the hamster cochlea of a certain day represent the development of the human cochlea of a whole month. The hamster cochlea at the 1st day after birth covers the 2nd embryonic month of the human (4th to 8th week) and at the 5th day the 3rd embryonic month (8th to 12th week). The hamster cochlea at the 1st and the 5th day after birth is especially suitable to study experimental disturbances in the early stages of the development of the cochlear duct when the tectorial membrane, the spiral limbus, the stria vascularis, Reissners membrane and the external spiral Sulcus with the root cells are differentiating. The biggest advantage is that the noxae (hypoxia, teratogenic substances, ototoxic antibiotics and intense noise) can be applied to single individuals which offers better control than the treatment of the mother.

Animals↗
PubMed2003

Up-regulation of Bcl-2 homology 3 (BH3)-only proteins by E2F1 mediates apoptosis.

The E2F1 transcription factor is a critical downstream target of the tumor suppressor pRB. The retinoblastoma (RB) pathway is often inactivated in human tumors, resulting in deregulated E2F activity that can induce both proliferation and apoptosis. Bcl-2 homology 3 (BH3)-only proteins are pro-apoptotic members of the Bcl-2 protein family that trigger apoptosis in response to diverse stimuli. We show here that E2F1 up-regulates the expression of the pro-apoptotic BH3-only proteins PUMA, Noxa, Bim, and Hrk/DP5 through a direct transcriptional mechanism. Expression of the E7 protein of HPV16, which disrupts RB/E2F complexes, also up-regulates the expression of these four BH3-only proteins, implicating endogenous E2F in this phenomenon. Indeed, endogenous E2F1 binds the promoters of these four genes. Furthermore, inhibition of E2F1-induced expression of either Noxa or PUMA results in a significant reduction in E2F1-induced apoptosis, indicating that increased Noxa and PUMA levels mediate this E2F1-induced apoptosis. Importantly, inhibition of E2F activity abolishes DNA damage-induced elevation of PUMA levels, implicating E2F in the physiological regulation of PUMA expression. These data provide a novel direct link between E2F and the apoptotic machinery and may explain the increased sensitivity of cells with a defective RB/E2F pathway to chemotherapy.

Animals↗
PubMed2006

Reactive oxygen species play a role in regulating a fungus-perennial ryegrass mutualistic interaction.

Although much is known about the signals and mechanisms that lead to pathogenic interactions between plants and fungi, comparatively little is known about fungus-plant mutualistic symbioses. We describe a novel role for reactive oxygen species (ROS) in regulating the mutualistic interaction between a clavicipitaceous fungal endophyte, Epichloë festucae, and its grass host, Lolium perenne. In wild-type associations, E. festucae grows systemically in intercellular spaces of leaves as infrequently branched hyphae parallel to the leaf axis. A screen to identify symbiotic genes isolated a fungal mutant that altered the interaction from mutualistic to antagonistic. This mutant has a single-copy plasmid insertion in the coding region of a NADPH oxidase gene, noxA. Plants infected with the noxA mutant lose apical dominance, become severely stunted, show precocious senescence, and eventually die. The fungal biomass in these associations is increased dramatically, with hyphae showing increased vacuolation. Deletion of a second NADPH oxidase gene, noxB, had no effect on the E. festucae-perennial ryegrass symbiosis. ROS accumulation was detected cytochemically in the endophyte extracellular matrix and at the interface between the extracellular matrix and host cell walls of meristematic tissue in wild-type but not in noxA mutant associations. These results demonstrate that fungal ROS production is critical in maintaining a mutualistic fungus-plant interaction.

Amino Acid Sequence↗
PubMed2006

The BH3-only protein Puma is both necessary and sufficient for neuronal apoptosis induced by DNA damage in sympathetic neurons.

DNA damage activates apoptosis in several neuronal populations and is an important component of neuropathological conditions. While it is well established that neuronal apoptosis, induced by DNA damage, is dependent on the key cell death regulators p53 and Bax, it is unknown which proteins link the p53 signal to Bax. Using rat sympathetic neurons as an in vitro model of neuronal apoptosis, we show that cytosine arabinoside is a DNA damaging drug that induces the expression of the BH3-only pro-apoptotic genes Noxa, Puma and Bim. Increased expression occurred after p53 activation, measured by its phosphorylation at serine 15, but prior to the conformational change of Bax at the mitochondria, cytochrome c (cyt c) release and apoptosis. Hence Noxa, Puma and Bim could potentially link p53 to Bax. We directly tested this hypothesis by the use of nullizygous mice. We show that Puma, but not Bim or Noxa, is a crucial mediator of DNA damage-induced neuronal apoptosis. Despite the powerful pro-apoptotic effects of overexpressed Puma in Bax-expressing neurons, Bax nullizygous neurons were resistant to Puma-induced death. Therefore, Puma provides the critical link between p53 and Bax, and is both necessary and sufficient to mediate DNA damage-induced apoptosis of sympathetic neurons.

Animals↗