Biomedical subjects

Bozena Kaminska

Publications and source records attributed to Bozena Kaminska.

At least 19 recordsLinked to original sources

PubMed2006

The invasion promoting effect of microglia on glioblastoma cells is inhibited by cyclosporin A.

The invasion of tumour cells into brain tissue is a pathologic hallmark of WHO grades II-IV gliomas and contributes significantly to the failure of current therapeutic treatments. Activated microglial cells are abundant in brain tumours and may support tumour invasiveness. We have previously demonstrated that cyclosporin A (CsA) can affect growth of glioma cells in vitro by inhibiting signalling pathways, which are essential for tumour proliferation and invasiveness. In this work, we demonstrate that migration of EGFP-transfected glioblastoma cells in organotypic brain slices was significantly inhibited by treatment with CsA. On average 77% of untreated cells migrated beyond 500 mum, while only 28-33% cells migrated as far in the brain slices treated with CsA (P < 0.001). This inhibitory effect on glioblastoma invasion was lost when glioblastoma cells were injected into microglia-depleted brain slices. Moreover, CsA significantly inhibits intracranial glioma growth in vivo. We demonstrate that microglia-derived factors increase glioma invasiveness in Matrigel assay in vitro and this is associated with activation of the PI-3K/Akt signalling pathway. The invasion promoting effect of microglia is abolished in the presence of CsA. Furthermore, glioma-derived soluble factors induce morphological transformation of microglia and activate MAPK signalling, although production of pro-inflammatory factors was not observed. Our findings that CsA interferes at clinically relevant concentrations with the tumour-promoting role of microglia and impairs invasive growth of glioma cells in vivo may provide a novel therapeutic strategy against gliomas.

Animals↗

PubMed2006

Neuroprotective activity of selective mGlu1 and mGlu5 antagonists in vitro and in vivo.

The neuroprotective potential of allosteric mGlu5 and mGlu1 antagonists such as 6-methyl-2-(phenylethynyl)-pyridin (MPEP)/[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) and (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate (EMQMCM), was tested in vitro in organotypic hippocampal cultures and in the middle cerebral artery occlusion model of stroke in vivo. Both classes of agent have high selectivity toward mGlu sub-types and are active in animal models of various diseases indicating satisfactory CNS penetration. In organotypic hippocampal cultures MPEP showed high neuroprotective potency against sub-chronic (12 days) insult produced by 3-NP with an IC50 of c.a. 70 nM. In contrast, although the mGlu1 antagonist EMQMCM was also protective, it seems to be weaker yielding an IC50 of c.a. 1 microM. Similarly, in the transient (90 min) middle cerebral artery occlusion model of ischaemia in rats, MTEP seems to be more effective than EMQMCM. MTEP, at 2.5 mg/kg and at 5 mg/kg provided 50 and 70% neuroprotection if injected 2 h after the onset of ischaemia. At a dose of 5 mg/kg, significant (50%) neuroprotection was also seen if the treatment was delayed by 4 h. EMQMCM was not protective at 5 mg/kg (given 2 h after occlusion) but at 10 mg/kg 50% of neuroprotection was observed. The present data support stronger neuroprotective potential of mGlu5 than mGlu1 antagonists.

Animals↗

PubMed2006

Prediction of a key role of motifs binding E2F and NR2F in down-regulation of numerous genes during the development of the mouse hippocampus.

BACKGROUND: We previously demonstrated that gene expression profiles during neuronal differentiation in vitro and hippocampal development in vivo were very similar, due to a conservation of the important second singular value decomposition (SVD) mode (Mode 2) of expression. The conservation of Mode 2 suggests that it reflects a regulatory mechanism conserved between the two systems. In either dataset, the expression vectors of all the genes form two large clusters that differ in the sign of the contribution of Mode 2, which for the majority of them reflects the difference between down- or up-regulation. RESULTS: In the current work, we used a novel approach of analyzing cis-regulation of gene expression in a subspace of a single SVD mode of temporal expression profiles. In the putative upstream regulatory sequences identified by mouse-human homology for all the genes represented in either dataset, we searched for simple features (motifs and pairs of motifs) associated with either sign of the loading of Mode 2. Using a cross-system training-test set approach, we identified E2F binding sites as predictors of down-regulation of gene expression during hippocampal development. NR2F binding sites, for the transcription factors Nr2f/COUP and Hnf4, and also NR2F_SP1 pairs of binding sites, were predictors of down-regulation of expression both during hippocampal development and neuronal differentiation. Analysis of another dataset, from gene profiling of myoblast differentiation in vitro, shows that the conservation of Mode 2 extends to the differentiation of mesenchymal cells. This permitted the identification of two more pairs of motifs, one of which included the CDE/CHR tandem element, as features associated with down-regulation both in the differentiating myoblasts and in the developing hippocampus. Of the features we identified, the E2F and CDE/CHR motifs may be associated with the cycling progenitor cell status, while NR2F may be related to the entry into differentiation along the neuronal pathway. CONCLUSION: Our results constitute the first prediction of an expression pattern from the genomic sequence for the developing mammalian brain, and demonstrate a potential for the analysis of gene regulation in a subspace of a single SVD mode of expression.

Amino Acid Motifs↗

PubMed2006

Identification of conserved modes of expression profiles during hippocampal development and neuronal differentiation in vitro.

Gene expression profiles can be regarded as sums of simpler modes, analogous to the modes of a vibrating violin string. Decomposition of temporal gene expression profiles into modes by singular value decomposition (SVD) was reported before, but the question as to what degree the SVD modes can be interpreted in terms of biology remains open. We report and compare the results of SVD of published datasets from hippocampal development, neuronal differentiation in vitro, and a control time-series hippocampal dataset. We demonstrate that the first SVD mode reflects the magnitude of expression, interpretable on the Affymetrix platform. In the datasets from gene profiling of hippocampal development and neuronal differentiation, the second mode reflects a monotonous change in expression, either up- or down-regulation, in the time course of experiment. We demonstrate that the top two SVD modes are conserved between datasets and therefore, likely reflect properties of the underlying system (gene expression in hippocampus) rather than of a particular experiment or dataset. Our results also indicate that the magnitude of expression, and the direction of change in expression during hippocampal development, are uncorrelated, suggesting that they are regulated by largely independent mechanisms.

Animals↗

PubMed2006

Neuroprotectant FK506 inhibits glutamate-induced apoptosis of astrocytes in vitro and in vivo.

Neuron-astrocyte interactions are critical for signalling, energy metabolism, extracellular ion and glutamate homeostasis, volume regulation and neuroprotection in the CNS. Glutamate uptake by astrocytes may prevent excitotoxic glutamate elevation and determine neuronal survival. However, an excess of glutamate can cause the death of astrocytes. FK506, an inhibitor of calcineurin, and an immunosuppressive drug, is neuroprotective in animal models of neurologic diseases, including focal and global ischaemia. In the present work, we demonstrate that a single injection of FK506 60 min after a transient middle cerebral artery occlusion (MCAo) significantly decreases the number of terminal deoxynucleotidyl transferase nick-end labelling (TUNEL)-positive cells in the ischaemic cortex and striatum. Using 3-D confocal microscopy we found that, 24 h after MCAo, many TUNEL-positive cells in the ischaemic striatum and cortex are astrocytes. Furthermore, we demonstrate that exposure of cultured cortical astrocytes to 50-100 mM Glu for 24 h induces apoptotic alterations in nuclear morphology, DNA fragmentation, dissipation of mitochondrial transmembrane potential (DeltaPsi) and caspase activation. FK506 (1 muM) efficiently inhibits Glu-induced apoptosis of cultured astrocytes, DNA fragmentation and changes in mitochondrial DeltaPsi. Our findings suggest that modulation of glutamate-induced astrocyte death early after reperfusion may be a novel mechanism of FK506-mediated neuroprotection in ischaemia.

Animals↗

PubMed2005

Cyclosporine A and its non-immunosuppressive derivative NIM811 induce apoptosis of malignant melanoma cells in in vitro and in vivo studies.

Advanced melanoma is a highly malignant tumor with an increasing incidence that has a poor prognosis due to resistance to common therapeutic strategies. We have demonstrated previously that cyclosporine A (CsA) induces apoptosis of rat glioma cells, reactive astrocytes, and fibroblasts. In our present study, we investigated effects of CsA and its nonimmunosuppressive derivative NIM811 on survival of human and murine melanoma cells. We demonstrated that CsA and NIM811 affect survival of human and murine melanoma cells and induce morphological changes, alterations in nuclear morphology and an internucleosomal DNA fragmentation, consistent with an apoptotic type of death. Western blot analysis showed an activation of caspases 9, 7, 3 and PARP cleavage detectable at 24 hr after exposure of human melanoma cells to the drugs. CsA and NIM811 induced a significant increase in subG1 population of murine B16F10 melanoma cells indicative of apoptotic DNA fragmentation. Studies in murine model of melanoma showed that NIM811, but not CsA, retards tumor progression and significantly decreases tumor volume after intratumoral application. Our findings indicate that CsA and its derivatives may be new candidates for the treatment of melanoma patients.

Animals↗

PubMed2005

MAPK signalling pathways as molecular targets for anti-inflammatory therapy--from molecular mechanisms to therapeutic benefits.

Excessive inflammation is becoming accepted as a critical factor in many human diseases, including inflammatory and autoimmune disorders, neurodegenerative conditions, infection, cardiovascular diseases, and cancer. Cerebral ischemia and neurodegenerative diseases are accompanied by a marked inflammatory reaction that is initiated by expression of cytokines, adhesion molecules, and other inflammatory mediators, including prostanoids and nitric oxide. This review discusses recent advances regarding the detrimental effects of inflammation, the regulation of inflammatory signalling pathways in various diseases, and the potential molecular targets for anti-inflammatory therapy. Mitogen-activated protein kinases (MAPKs) are a family of serine/threonine protein kinases that mediate fundamental biological processes and cellular responses to external stress signals. Increased activity of MAPK, in particular p38 MAPK, and their involvement in the regulation of the synthesis of inflammation mediators at the level of transcription and translation, make them potential targets for anti-inflammatory therapeutics. Inhibitors targeting p38 MAPK and JNK pathways have been developed, and preclinical data suggest that they exhibit anti-inflammatory activity. This review discusses how these novel drugs modulate the activity of the p38 MAPK and JNK signalling cascades, and exhibit anti-inflammatory effects in preclinical disease models, primarily through the inhibition of the expression of inflammatory mediators. Use of MAPK inhibitors emerges as an attractive strategy because they are capable of reducing both the synthesis of pro-inflammatory cytokines and their signalling. Moreover, many of these drugs are small molecules that can be administered orally, and initial results of clinical trials have shown clinical benefits in patients with chronic inflammatory disease.

Anti-Inflammatory Agents↗

PubMed2005

TGF beta signalling and its role in tumour pathogenesis.

Transforming growth factor beta (TGF-beta) is a multifunctional cytokine involved in the regulation of cell proliferation, differentiation and survival/or apoptosis of many cells. Knock-out experiments in mice for the three isoforms of TGF-beta have demonstrated their importance in regulating inflammation and tissue repair. TGF-beta is implicated in the pathogenesis of human diseases, including tissue fibrosis and carcinogenesis. TGF-beta receptors act through multiple intracellular pathways. Upon binding of TGF-beta with its receptor, receptor-regulated Smad2/3 proteins become phosphorylated and associate with Smad4. Such complex translocates to the nucleus, binds to DNA and regulates transcription of specific genes. Negative regulation of TGF-beta/Smad signalling may occur through the inhibitory Smad6/7. Furthermore, TGF-beta-activated kinase-1 (TAK1) is a component of TGF-beta signalling and activates stress-activated kinases: p38 through MKK6 or MKK3 and c-Jun N-terminal kinases (JNKs) via MKK4. In the brain TGF-beta, normally expressed at the very low level, increases dramatically after injury. Increased mRNA levels of the three TGF-beta isoforms correlate with the degree of malignancy of human gliomas. TGF-betas are secreted as latent precursors requiring activation into the mature form. TGF-beta may contribute to tumour pathogenesis by direct support of tumour growth and influence on local microenvironment, resulting in immunosuppression, induction of angiogenesis, and modification of the extracellular matrix. TGF-beta1,2 may stimulate production of vascular endothelial growth factor (VEGF) as well as plasminogen activator inhibitor (PAI-I), that are involved in vascular remodelling occurring during angiogenesis. Blocking of TGF-beta action inhibits tumour viability, migration, metastases in mammary cancer, melanoma and prostate cancer model. Reduction of TGF-beta production and activity may be a promising target of therapeutic strategies to control tumour growth.

Animals↗

PubMed2005

Neurotrophic factor expression after focal brain ischemia preceded by different preconditioning strategies.

BACKGROUND: Both prolonged brain ischemia and preconditioning (PC) induce expression of neurotrophic factors. However, the influence of PC on their expression after a long-term ischemia remains vague. Previously, we have found various effects of PC on mRNA levels of different cytokines after focal brain ischemia. Thus, we investigated mRNA expression of nerve growth factor, brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor after 90-min middle cerebral artery occlusion (MCAo) preceded by ischemic or chemical PC. METHODS: MCAo was induced in rats using the suture method. PC had been carried out 3 days earlier. There were 4 experimental groups: MCAo alone; ischemic PC and MCAo; chemical PC and MCAo, and sham-operated rats. Expression of mRNAs in the ipsi- and contralateral cortex was studied by semiquantitative RT-PCR at 12 and 24 h after MCAo. RESULTS: Despite clearly neuroprotective effects of both PC strategies, mRNA levels of neurotrophic factors were similar in tolerant and nontolerant rats. Only BDNF mRNA expression, 12 h after reperfusion, was lower when ischemic PC was applied prior to long-term ischemia. CONCLUSIONS: These results suggest that PC generally does not change the expression of neurotrophic factor expression after a long-term focal brain ischemia compared to the nontolerant state.

Animals↗

PubMed2005

A novel mechanism of FK506-mediated neuroprotection: downregulation of cytokine expression in glial cells.

Immunosuppressant FK506 is neuroprotective in experimental models of cerebral ischemia, but the molecular mechanisms underlying this neuroprotection remain unknown. We have demonstrated that FK506 inhibits the signaling pathways that regulate hypertrophic/proliferative responses in cultured astrocytes. Ischemia/reperfusion injury is associated with the proliferation and hypertrophy of astrocytes and with inflammatory responses. In the present work, we sought to determine whether FK506 neuroprotection after middle cerebral artery occlusion (MCAo) in rat is mediated via suppression of glia activation and changes in cytokine expression. Neurological deficits, infarct size, and astrocyte/microglial response were quantified in rats subjected to 90 min of MCAo. Changes in the mRNA expression of interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha) in ipsilateral and contralateral cortices were determined by reverse transcription-polymerase chain reaction (RT-PCR). FK506 administered at 1 mg/kg, 60 min after MCAo, produced a significant improvement in neurological function and reduction of infarct volume. In FK506-treated rats, a significant reduction of IL-1beta, IL-6, and TNF-alpha expression was observed 12 h after reperfusion. FK506 neuroprotection was associated with a significant downregulation of IL-1beta expression in astrocytes and microglia in the injured side. FK506 selectively decreased the levels of TNF-alpha, and IL-1beta mRNAs in astrocytes in vitro, with no effect on transforming growth factor-beta 1 (TGF-beta1) and IL-6 expression. Moreover, FK506 inhibits lipopolysaccharide (LPS)-induced activation and cytokine expression in microglia in vitro. Our findings suggest that astrocytes and microglia are targets for FK506, and that modulation of glial response and inflammation may be a mechanism of FK506-mediated neuroprotection in ischemia.

Animals↗

PubMed2005

Cannabinoids down-regulate PI3K/Akt and Erk signalling pathways and activate proapoptotic function of Bad protein.

Cannabinoids were shown to induce apoptosis of glioma cells in vitro and tumor regression in vivo, but mechanisms of their antiproliferative action remain elusive. In the present studies, C6 cells were exposed to a synthetic cannabinoid, WIN 55,212-2, which produced down-regulation of the Akt and Erk signalling pathways prior to appearance of any sign of apoptosis. We hypothesized that cannabinoid-induced cell death may be mediated by a Bcl-2 family member--Bad, whose function is hampered by these kinases due to control of its phosphorylation state. Using Western blot analysis, we found that levels of phosphorylated Bad, but not total Bad protein, decreased under exposure to WIN 55,212-2. WIN 55,212-2 treatment further resulted in mitochondrial depolarization and activation of caspase cascade. Thus, we suggest that the increase of proapoptotic Bad activity is an important link between the inhibition of survival pathways and an onset of execution phase of cannabinoid-induced glioma cell death.

Animals↗

PubMed2005

Cyclosporine a induces growth arrest or programmed cell death of human glioma cells.

Human malignant gliomas are highly resistant to current therapeutic approaches. We previously demonstrated that cyclosporine A (CsA) induces an apoptotic cell death in rat C6 glioma cells. In the present study, we found the induction of growth arrest or cell death of human malignant glioma cells exposed to CsA. In studied glioma cells, an accumulation of p21Cip1/Waf1 protein, a cell cycle inhibitor, was observed following CsA treatment, even in the absence of functional p53 tumour suppressor. CsA induced a senescence-associated growth arrest, in U87-MG glioma cells with functional p53, while in U373 and T98G glioma cells with mutated p53, CsA treatment triggered cell death associated with alterations of cell morphology, cytoplasm vacuolation, and condensation of chromatin. In T98G cells this effect was completely abolished by simultaneous treatment with an inhibitor of protein synthesis, cycloheximide (CHX). Moreover, CsA-induced cell death was accompanied by activation of executory caspases followed by PARP cleavage. CsA treatment did not elevate fasL expression and had no effect on mitochondrial membrane potential. We conclude that CsA triggers either growth arrest or non-apoptotic, programmed cell death in human malignant glioma cells. Moreover, CsA employs mechanisms different to those in the action of radio- and chemotherapeutics, and operating even in cells resistant to conventional treatments. Thus, CsA or related drugs may be an effective novel strategy to treat drug-resistant gliomas or complement apoptosis-based therapies.

Antineoplastic Agents↗

PubMed2004

Influence of chemical and ischemic preconditioning on cytokine expression after focal brain ischemia.

Inflammation, upregulation of cytokines, proapoptotic molecules, and apoptosis are accepted widely as crucial players in stroke-induced brain damage. Induction of brain tolerance against ischemia by pretreatment with nonlethal stressors (preconditioning) has been found to influence expression of different molecules, in addition to reduction of infarct size. It remains unclear, however, whether and how preconditioning changes expression of cytokines after subsequent brain ischemia. We sought to analyze cortical expression of interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta, Fas, and Fas ligand (FasL) mRNA after a transient, focal brain ischemia in rats subjected to preconditioning. The mRNA levels were determined using a semiquantitative RT-PCR in the ischemic and contralateral cortex, separately. Transient ischemia was induced by 90-min middle cerebral artery occlusion (MCAo) and neurologic deficits as well as infarct size were quantified. Preconditioning was carried out by a short-term MCAo or an injection of 3-nitropropionic acid 3 days before MCAo. In both preconditioning paradigms, similar effects on investigated mRNA levels were observed. IL-1beta and IL-6 levels were decreased in tolerant rats compared to those in nontolerant ones. Changes in TNF-alpha, TGF-beta, and Fas levels were comparable independently of tolerance state. FasL mRNA was at similar level in rats subjected to chemical preconditioning but lower after ischemic preconditioning. Our findings demonstrate that both preconditioning methods exert a very similar effect on the expression of investigated cytokines. Interestingly, we observed a selective effect of preconditioning on IL-1beta and IL-6 expression that suggests different functional properties as well as different regulation of analyzed molecules during an induction of the brain tolerance against ischemia.

Animals↗

PubMed2004

Impaired AP-1 dimers and NFAT complex formation in immature thymocytes during in vivo glucocorticoid-induced apoptosis.

Ca2+-regulated nuclear factor of activated T cell (NFAT) family members are transcription factors crucial for the expression of various cytokine and other immunoregulatory genes. Moreover, NFAT transcription factors are involved in the regulation of development, maturation and selection of thymocytes. Typically, the NFAT complex is made up of NFATc (NFATc1-4) protein and activator protein-1 (AP-1) transcription factor. AP-1 is a dimer consisting of two Jun proteins (homodimers) or Jun and Fos proteins (heterodimers). We have previously reported that NFAT DNA-binding activity significantly decreases in the thymus during glucocorticoid-induced apoptosis. In this study, we demonstrate that the expression and phosphorylation status of the NFAT proteins do not change during glucocorticoid-induced apoptosis. This suggests that glucocorticoids do not disturb a signal transduction pathway leading to the activation of NFATc proteins in thymocytes. Although the levels of particular Jun and Fos proteins do not decrease after glucocorticoid administration, the formation or DNA-binding activity of some AP-1 dimers is specifically abolished. Thus, the observed inhibition of NFAT transcription factor activity during glucocorticoid-induced apoptosis is likely to be a consequence of this perturbation or the lack of a proper AP-1 component.

Animals↗

PubMed2003

Inhibition of Akt kinase signalling and activation of Forkhead are indispensable for upregulation of FasL expression in apoptosis of glioma cells.

Activation of Akt signalling pathway is frequently found in glioma cells and may contribute to their resistance to undergo apoptosis in response to conventional therapies. We found that cyclosporin A (CsA) induces apoptosis of C6 glioma cells, which is associated with transcriptional activation of fasL. In the present paper, we investigated an involvement of Akt signalling in the regulation of FasL expression in CsA-induced apoptosis. We demonstrated that the level of active Akt decreases significantly after CsA treatment, which results in the decrease of Forkhead phosphorylation and its translocation to the nucleus. It correlated with an increase of binding to the Forkhead-responsive element FHRE from the FasL promoter, as demonstrated by gel-shift assays. Although treatment with LY294002, a specific inhibitor of PI3 K, decreased the phosphorylation of Akt and increased Fkhr translocation to the nucleus, these events were not sufficient to induce FasL expression and apoptosis of C6 glioma cells. Interference with Akt/Forkhead signalling by membrane-targeted Akt or removal of the FKHR-binding sites from the FasL promoter significantly abolished its activation. These results indicate that downregulation of Akt signalling and activation of Forkhead is a prerequisite for the induction of FasL promoter. It may be clinically important for pharmacological intervention in gliomas.

Animals↗

PubMed2003

Immunosuppressant FK506 affects multiple signaling pathways and modulates gene expression in astrocytes.

Brain injury is often associated with proliferation and hypertrophic response of glial cells (reactive gliosis). We have previously reported immunosuppressant effects on survival of glioma cells and adult reactive astrocytes. In the present study, we demonstrate growth-inhibitory effect of FK506 on cortical astrocytes from newborn rats. FK506 inhibits Erk and PI-3K/Akt signaling, two crucial pro-survival pathways. The levels of phosphorylated Akt and p42/44 Erk decline in few hours after FK506 addition. Furthermore, in FK506-treated astrocyte cultures the levels of mRNA encoding PDGF, bFGF, and CNTF decreased. Downregulation of growth factor expression by FK506 may play a role in the inhibition of mitogenic/hypertrophic responses. FasL mRNA level was elevated and interaction of FasL with Fas receptor expressed in astrocytes may trigger cell death. Interestingly, expression of BDNF increased in a dose-dependent manner in FK506-treated astrocytes. Upregulation of BDNF mRNA and protein level in astrocytes exposed to FK506 may underlie neuroprotective action of FK506.

Animals↗

PubMed2002

Tumor suppressor p53 mediates apoptotic cell death triggered by cyclosporin A.

The tumor suppressor p53 can induce growth arrest and cell death via apoptosis in response to a number of cellular stresses. We have shown previously that the immunosuppressant cyclosporin A (CsA) induces programmed cell death with typical features of apoptosis in rat glioma cells. We report that CsA treatment results in increased level of the p53 tumor suppressor, its nuclear accumulation, and transcriptional activation of p53-dependent genes. The increase of p53 correlates with the elevation of p21(Waf1) and Bax protein expression. The increased level of Bax protein was accompanied with changes in its subcellular localization and association with mitochondria. Importantly, we demonstrate that glioma cells stably transfected with a mutant p53 (p53Val135) fail to increase p21 and Bax protein levels and are less sensitive to CsA-induced apoptosis. Furthermore, primary fibroblasts from p53-/- knockout mice are significantly more resistant to CsA-induced apoptosis compared with their corresponding counterparts containing functional p53. Together, our results suggest that the apoptotic program activated by CsA can be mediated by activation of p53 tumor suppressor and potentiation of its ability to initiate apoptosis.

Animals↗

PubMed2002

The diversity of p53 mutations among human brain tumors and their functional consequences.

The p53 tumor suppressor is implicated in cell cycle control, DNA repair, replicative senescence and programmed cell death. Inactivation of the p53 contributes to the wide range of human tumors, including glial neoplasms. In this review, we describe the regulation and biochemical properties of p53 protein that may explain its ability to activate various genetic programs underlying cellular responses to stress conditions. The overall spectrum of p53 mutations is rather shared between tumor types indicating that these mutations are not tumor type-specific. However, there is one example of germ-line mutation of p53 gene (the deletion of the codon 236) that is associated with a familiar brain tumor syndrome. We compare the frequency and type of most common mutations among various brain tumours (focusing on glioblastomas) and their consequences on protein functions. Furthermore, we discuss the most promising approaches of potential brain tumor therapy, including an adenovirus-mediated p53 gene transfer. Human glioblastomas are highly sensitive to the effects of p53 activity when the wild-type p53 is introduced ectopically. It suggests that the genetic or pharmacological modulation of the p53 pathway is potentially important strategy in the treatment of human cancers.

Brain Neoplasms↗